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NEOPLASTIC DISEASES

A TEXT-BOOK ON TUMORS

JAMES EWING, A. M., M. D., Sc. D.

Professor of Pathology at Cornell University Medical College
New York City

WITH 479 ILLUSTRATIONS

PHILADELPHIA AND LONDON

W. B. SAUNDERS COMPANY

1919

PRINTED IN AMERICA

PREFACE

IT is the object of this work to present within reasonable space and in
accessible form the main features of the origin, structure, and natural history
of tumors.

Up to a very recent time it has been the prevailing impression that
tumors fall into a limited number of grand classes in which the forms occur-
ring in the several organs are so nearly related as to be virtually identical.
Hence the practical physician or surgeon has been content to regard all
fibromas, sarcomas, or cancers, as equivalent conditions without regard to
the organ involved, and on this theory to treat the members of each class
alike. Upon this theory also it was legitimate to conceive of a universal
causative agent of malignant tumors and thus to subordinate many very
obvious differences which clinical experience has established in the origin
and behavior of different related tumors.

1 believe that this point of view has greatly retarded the progress of the
knowledge of tumors, and it has been the writer's effort to combat such a
conception, so far as present knowledge permits. He has endeavored to
analyze the numerous etiologic factors which meet in such diverse fashions
in the inception of tumors, to emphasize the general dependence of clinical
course upon histologic structure, to ^race the histogenesis to the last de-
gree, impressing its essential importance when known, and to enumerate
and contrast the more striking clinical features which are often highly
characteristic of different tumors.

No one would think of confusing lobar pneumonia with pneumonic
plague, although both are examples of acute exudative pneumonitis, but it is
quite the rule to identify for statistical studies several equally different forms
of mammary cancer. The former diseases are related only as forms of
inflammation, the latter only as types of neoplasia. From this point of
view it may safely be said that there are more distinct clinical and pathologic
entities within the groups of neoplasms than exist outside of them.

While a great volume of information regarding the clinical phenomena of
the main forms of tumors is available in special works on medicine, surgery,
and the specialties, the task of unraveling their separate varieties, tracing
their mode of origin and growth, and establishing the nature of the less com-
mon forms, falls to the lot of the pathologist. For the final classification
of tumors must depend chiefly on histogenesis and structure. Present-day
oncology is chiefly concerned with these topics and the space devoted
to them can safely be reduced only when our knowledge is much further
advanced.

In spite of several laborious years spent in the task the writer acknowl-
edges disappointment with the results attained in many departments, but
can only claim that the effort to present tumors as specific diseases is in the
right direction. He first undertook to write a book on the general principles
of oncology, but soon found that the significant facts about tumors are not
of general application, but are best revealed in the study of special tumor
groups or even of special cases.

In the compilation of the work the writer has endeavored to consult with

390113

12 PREFACE

due respect all the standard authorities, and as far as possible the original
contributions in the literature. The rather extensive bibliographic lists
seem necessary for the guidance of the reader who desires complete informa-
tion and to whom the work is chiefly addressed. The recent rapid increase
in original contributions from the United States has made it impossible to
do full justice to American literature.

It is a pleasure to acknowledge the valuable assistance received from
many friends and colleagues here and abroad. The author acknowledges
especially his indebtedness to Messrs. W. B. Saunders Company for under-
taking the publication of a highly specialized work. Through the pains-
taking assistance of Mr. William Dunn it has been possible to rely almost
entirely upon photographs for illustrations.

While confessing a deep interest in the theoretic problems which render
oncology the most complex and fascinating field in pathology, the chief
object and hope of the author have been that by rendering more accessible
to English readers the knowledge of tumors he may contribute something
toward the reduction of the mortality from cancer.

JAMES EWING.

January, 1919.

CONTENTS

GENERAL ONCOLOGY

CHAPTER I

PAGE

HISTORICAL 17

CHAPTER II

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 25

CHAPTER III
MALIGNANCY AND ITS EFFECTS ON THE ORGANISM 62

CHAPTER IV
METASTASIS 76

CHAPTER V

CHEMISTRY OF TUMORS; SEROLOGY 89

CHAPTER VI
THEORIES OF THE NATURE OF CANCER 94

CHAPTER VII

THE SPECIAL ETIOLOGY OF TUMORS; TRAUMA 109

CHAPTER VIII
THE PARASITIC THEORY 114

CHAPTER IX
EXPERIMENTAL CANCER RESEARCH 127

SPECIAL ONCOLOGY

CHAPTER X

FIBROMA *49

14 CONTENTS

CHAPTER XI

PAGE

MYXOMA 166

CHAPTER XII
LIPOMA 173

CHAPTER XIII
CHONDROMA 180

CHAPTER XIV

OSTEOMA 191

CHAPTER XV
MYOMA 199

CHAPTER XVI
ANGIOMA 218

CHAPTER XVII
SARCOMA 235

CHAPTER XVIII

CLINICAL TYPES OF SARCOMA 244

CHAPTER XIX

SARCOMAS OF BONE AND BONE-MARROW 264

CHAPTER XX

ENDOTHELIOMA 290

CHAPTER XXI

LYMPHOMA AND LYMPHOSARCOMA 334

CHAPTER XXII

TUMORS OF THE BRAIN 378

CONTENTS 15

CHAPTER XXIII

PAGE

TUMORS OF NERVE TRUNKS 411

CHAPTER XXIV
TUMORS OF SPINAL CORD AND MEMBRANES 419

CHAPTER XXV
GENERAL PATHOLOGY OF EPITHELIAL TUMORS 429

CHAPTER XXVI

EPITHELIAL AND OTHER TUMORS OF THE BREAST 467

CHAPTER XXVII

CANCER OF UTERUS, VULVA, VAGINA 523

CHAPTER XXVIII

CHORIOMA (CHORIONEPITHELIOMA) 546

CHAPTER XXIX
CYSTS AND EPITHELIAL TUMORS OF THE OVARY 562

CHAPTER XXX
THE OVARIAN TERATOMA 593

CHAPTER XXXI
CARCINOMA OF STOMACH 605

CHAPTER XXXII
CARCINOMA OF INTESTINE 640

CHAPTER XXXIII

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 654

CHAPTER XXXIV

TUMORS OF PANCREAS 681

CHAPTER XXXV
MAXILLARY TUMORS OF DENTAL ORIGIN 686

CHAPTER XXXVI

EPITHELIAL TUMORS OF THE SALIVARY GLANDS .' 704

CHAPTER XXXVII
TUMORS OF KIDNEY 717

16 CONTENTS

CHAPTER XXXVIII

PAGE

TUMORS OF THE ADRENAL. 746

CHAPTER XXXIX
TUMORS OF PROSTATE 757

CHAPTER XL
TUMORS OF TESTIS 768

CHAPTER XLI
TUMORS OF LUNG 785

CHAPTER XLII
EPIDERMOID CARCINOMA 797

CHAPTER XL1II
EPIDERMOID CARCINOMA (Continued) 835

CHAPTER XLIV
MELANOMA 849

CHAPTER XLV
TUMORS OF THE THYROID 869

CHAPTER XL VI
THE THYMUS AND ITS TUMORS 889

CHAPTER XL VII
TUMORS OF THE HYPOPHYSIS 901

CHAPTER XL VIII
THE PINEAL GLAND AND ITS TUMORS 925

CHAPTER XLIX
TERATOLOGY . 931

BIBLIOGRAPHY 963

INDEX 1007

NEOPLASTIC DISEASES

GENERAL ONCOLOGY

CHAPTER I

HISTORICAL

The Ancients knew cancer well. They treated it by excision and by a
variety of escharotics, including the Egyptian arsenical ointment. Cancer is
mentioned in the Papyrus Ebers (B.C. 1500) and in the oldest remnants of
the literature of India and Persia.

Hippocrates (B.C. 460-375) received from earlier days a considerable
body of descriptive facts regarding cancer of the skin, breast, uterus and
internal organs, and he first employed the terms /cap/ar/os for all indolent
ulcers, and KapKivupa for progressive malignant tumors. The humoral
pathology then disseminated conceptions of the origin of cancer. Deficiency
or excess of blood, mucus or bile, formed the basis of all disease. Herodotus
mentions that Democedes (B.C. 520) cured Atossa, the daughter of Darius
Hystaspis, of breast cancer, and Hippocrates burnt out a carcinoma of the
neck, the earliest record of diathermia.

Celsus (B.C. 30-A.D. 38) distinguished several gross varieties of cancer,
and he excised breast cancer, advising against removal of the pectoralis
major. Treatment by charcoal was employed by Cato, and a variety of
crude internal remedies are mentioned by Pliny.

Galen (A.D. 131-203), the founder of experimental physiology and
pathology, failed to make any significant advance in the conception of
cancer, but the presentation of the humoral doctrine of atra bilis in his
writings formed a Scripture which dominated medical thought for more than
a thousand years. Swellings were secundam naturam (gravid uterus), supra
naturam (callus formations) , or pr&ter naturam (true tumors) . The pneuma,
composed of solid parts and four fluids, blood, mucus, yellow and black
bile, ruled the processes of the body. Cancer developed from the concen-
tration of black bile.

Suppression of menses and hemorrhoids, preventing the discharge of black
bile, were chiefly responsible for cancer, which appeared where the bile gravi-
tated in face, lips, breast, etc. No modern writer has been able to reflect
the thought of that period or to explain the firm entrenchment of the crude
humoral theories. Since capable logic could not have been lacking, one
must suppose that religious and esthetic tendencies in the race unfitted the
human mind for natural thought regarding the structure and functions of
human body. For internal cancer, of which little was known, a diet, chiefly
vegetable was recommended. Walnuts were specifically forbidden.
2 17

18 ._ t t .. v „ k fc '/ XEOPLASTIC DISEASES

Diagnosis' rested 'chiefly on the cause of the disease, while treatment
by excision, ligation of vessels, and cautery was comparatively successful.
Leonides of Alexandria (A.D. 180) broke away from Hippocrates' conserva-
tism, dissected out breast cancer extensively, cutting through healthy tissue
with knife and cautery and approached closely to the modern technics of
this operation.

In the Byzantine period (475-1500) considerable progress was made in
the description of various tumors. Paulus of Aegina (625-690) separated
chronic metritis from uterine cancer. In Arabia, Avicenna (980-1037) intro-
duced the internal use of arsenic, and Avenzoar (1070-1162) employed the
esophageal sound and the nutrient enema. During the I2th-i5th centuries
the ban of the Church was extended from dissection of the body to the prac-
tice of surgery which could be studied only in private and practised only by
nomads, while the monks gave themselves over to translations of Galen's
writings and to speculations in alchemy, astrology and magic. With the
opening of universities at Paris (mo), Salerno (1150), Montpellier (1150),
and Prag (1348), the Church dictated what books should be used.

The Renaissance (1500-1700) bringing the discovery of the printing press
and the circulation of the blood (Harvey, 1628) greatly facilitated the spread
of knowledge and aided the more accurate diagnosis and better treatment of
cancer, but threw little light on etiology. Andreas Vesal (1514-1564) began
the attack on many of the concepts of Galen, identifying deep seated with
ulcerating cancer. Fabricius (1537-1619) separated many inflammatory
swellings from cancer, warned rigidly against incomplete removal, extirpated
the uterus, and experimented with internal remedies.

Marcus Aurelius Severinus (1580-1656) described myxosarcoma, sepa-
rated cancer from benign tumors of the breast, and extirpated the axillary
nodes.

In Prag, Sennert (1572-1637) and in Lisbon, Lusitanus (1642) first claimed
that cancer was contagious, a doctrine which prevailed extensively and
with little dissent. Paracelsus (1413-1541) stands out as the first successful
opponent of Galen's theory of atr a bills as the cause of cancer. He claimed
that the disease was due to mineral salts in the blood. He seemed to think
that cancer developed where various animal salts became concentrated and
sought an outlet. At this period it is interesting to note that the decline
of Galen's authority and distrust of even his crude theories of etiology led
to complete demoralization in the treatment of cancer, encouraged great
abuse of arsenic and other internal and external remedies, permitted the
faith cure career of Queen Elizabeth (1602), and developed many fantastic
theories regarding the nature of cancer.

The Lymph Theory. — In the i7th century Galen's doctrine was completely
demolished by the discovery of the circulation by Harvey (1628), of the
lymph-vessels by Olens (1652), and of the red blood-cells by Malpighi (1661).
Malpighi used the microscope which had been in existence since 1592.
The black bile was nowhere to be found but everywhere was blood and lymph.
Lymph coagulated and foamed on boiling, hence cancer was composed of
lymph varying in density, alkalescence, or acidity, and in malignant tumors
fermenting and degenerating. Louis (1723-92) distinguished gelatinous
lymph (goiter) and albuminous lymph (scirrhus). LeDran (1685-1770)
studied cancer by many autopsies, emphasized the local nature of cancer of
the skin, and the internal origin of breast cancer. He conceived that if a
drop of cancer lymph passed the adjacent nodes it contaminated the entire
system.

Astruc (1684-1766) separated cysts from true tumors, showed that

HISTORICAL 19

scirrhus and soft cancer were of the same nature, pointed out important
differences in prognosis of different types of carcinoma, and by incineration
proved that cancer and muscle tissue contained the same salts. Yet he
likened the growth of cancer from lymph to the heating and swelling of
gypsum in water.

Morgagni (1682-1772) established the importance of the pathological
anatomy of cancer, describing many internal tumors studied at autopsy
and separating gumma, struma, exostosis, and liporna from cancer. He
distrusted, without replacing, the lymph theory.

A notable event in the history of cancer research was the essay of Peyrilhe
(1735-1804) submitted to the Academy of Lyons in answer to the question,
Qu' est ce que le cancer? This was the first systematic investigation of the
whole subject and dealt with the cancer toxin, the nature of the disease, the
manner of growth and the treatment.

He spoke of the local origin, the production of a specific virus from
degeneration of the tumor and the development of cachexia from this source.

He endeavored to demonstrate the virus by injecting tumor emulsion
beneath the skin of a dog but an abscess resulted and his servant drowned
the animal. He treated ulceration effectively with the newly discovered
carbonic acid. His imagination was satisfied by the Cartesian lymph theory
of the times.

In Germany the i7th century was occupied by the exploitation of many
personal views of the origin of cancer and other diseases.

Chemical conceptions held sway, and cancer was attributed usually to
excess of acid, to be treated by alkali (Helmont, Ettmuller).

Stahl (1660-1734), supposed that stasis and thickening of the blood
were the essential factors. Hoffmann held that life and health depended
on normal movements of the tissues, cancer and other diseases resulting
from atony, stasis, and abnormal fermentation of blood and lymph. He
constructed his anodyne as a panacea to restore tissue tone.

In England, John Hunter's (1728-93) conception of the lymph theory
represented a distinct advance toward the cellular pathology. He held that
tumors grew from the coagulable lymph constantly thrown out of the blood,
that tumor tissue like normal tissue was nourished by the organism, and
developed according to the same biological laws. In 1802, The Society for
investigating the Nature and Cause of Cancer was formed in London, and
formulated the problems of the disease as they stand to-day. The Society
dissolved in 1806.

The pathological anatomy of malignant tumors chiefly interested the
English observers, and Hey (1736-1819) described in detail the structure
of certain vascular tumors which he found to be composed of organized
blood-fluid and a large proportion of lymph, and for which he employed the
term "fungus hematodes." Wardrop, 1809, described in great detail miscella-
neous tumors of this gross type, attempting to separate them from cancer.
Many of his cases occurred in children, some involved the eye, and one arose
from a wart.

Abernethy, 1804, attempted to define the old term sarcoma by applying
it to various soft tumors, and he called Key's fungus hematodes, medullary
sarcoma. Maunoir, 1820, showed the beneficent result of anatomical study,
by announcing that each tumor is the result of a morbid change of the fluid
or tissue from which it arises, and retains the original characters of this
tissue. He employed many crude chemical and physical tests to support
this claim.

The close attention then being given to clinical data led Pott (1775) to

20 NEOPLASTIC DISEASES

recognize and describe chimney-sweeps' cancer and to point out its etiology.
The English contributions of this period were completed by Home, who,
using the microscope, described and depicted rounded bodies which he
regarded as lymph corpuscles.

In France, Bichat's studies of tissue structure opened a new era with the
appearance of his Anatomie generate in 1801. He first distinguished the
stroma from the parenchyma of tumors, deriving the former from the origi-
nating tissue and the latter by proliferation from the stroma. Without reli-
ance upon the microscope he regarded the stroma as cellular and conceived of
its growth by proliferation.

Following Bichat, Laennec made a systematic study of the gross features
of cancer in thin slices, and introduced the term " encephaloid " for the soft
parts. Dupuytren attempted to prove the infectiousness of the disease by
ingestion and intravenous inoculation of cancer tissue. Bayle and Cayol
argued in favor of the constitutional nature of the disease and fully pointed
out the difference between chronic mastitis and cancer.

Broussais' doctrine that cancer was the sequel of recurrent inflammation
had made some influence on the thought of this period. Based on chemical
observation, his claim that cancer never arises in normal tissues but only
after inflammatory alterations, found many adherents and is of interest in
connection with later theories.

Lobstein used the term "plastic lymph" and formulated the view that the
tumor-forming lymph was not under control of the biological laws of the
organism. Recamier studied especially the infiltration of cancer, observed
the destruction of veins and applied the term " metastases " to nodules in
the brain in cases of mammary cancer. He recognized the importance of
supernumerary organs and nevi as sources of cancer. Andral reflected the
confusion of ideas then prevailing by offering his theory that products of
secretion became organized into cancer. Cruveilhier regarded cancer as a
malignant degeneration which like inflammation affected all the organs. Its
chief pathognomonic feature was the cancer juice exuded on pressure. Andral
thought tumor masses floating in the veins were derived from the fibrin, but
Velpeau, in a case of intravenous tumor, searched the blood in vain for can-
cerous elements. Such questions as the identity of encephaloid or soft cancer
with brain tissue were hardly settled. Tubercle was commonly confused
with cancer and gummata imperfectly distinguished from it. Cancers were
classified upon crude gross characters as in Jager's Handworterbuch, Leip-
sic, 1837, where they were divided in four types, hard, soft, pigmented, and
blood-cancer.

Thus during the sway of the lymph theory, English and French students
while adding important contributions to the descriptive history and gross
pathology of malignant tumors, failed to pass beyond the limits of the pre-
vailing theoretical conceptions of the time. It was the great period of indi-
vidual surmises which in some instances, notably with Hunter, Home, Lob-
stein and Recamier, approached closely toward and prepared the way for
modern conceptions.

In Germany, Richter, Walther and others engaged in the current discus-
sions without adding essentially new data.

It was the general conception that the elements of cancer were fluid and
traveled in the veins.

Great significance was attached to the observation of tumor masses in the
vessels. A special variety of " blood-cancer " supposed to come from irritat-
ing elements was described by Langstaff, 1817, and Carswell, 1834.

Histological Period. — With the construction of the achromatic micro-

HISTORICAL 21

scope in Paris, 1824, a new era opened in cancer research. Wolf finds that
the first fruitful studies of the structure of vegetable and animal tissues by
this instrument were made by Raspail in 1826, who showed that the growth
of tissues resulted from the multiplication of cells. He clearly stated the
doctrine of the cell, finding that tissues were composed of microscopic vesicles.
The structure and growth of fat tissue he described in detail. Collard, 1828,
also described rather clearly the stages in the embryonal development • of
tissues assuming however, that the cells originated from plastic lymph.
Schwann, 1838, established this doctrine of cellular structure as a universal
principle and discovered the nucleus and nucleolus of the cell.

In the same year J. Miiller published his classical study of malignant
tumors. He found them all to be composed of groups of cells, each contain-
ing nuclei and nucleoli. The various current types of cancer he found to be
distinguished only by different proportions and' groupings of cell masses and
stroma. Certain elongated or racquet-shaped cells " geschwanzten Korper-
chen" he regarded as on the way to fiber formation, but not as specific can-
cer elements which he was unable anywhere to detect. Hence his diagnosis
of cancer rested on clinical signs and the anatomical grouping of the cells.
He held the interesting view that cancer developed not from normal tissue
but from germ cells which as a "semmium morbi" lay scattered between the
tissue elements.

In regard to the origin of the cells it was held that most of them de-
veloped from the plastic lymph or blastema by a process of budding. Others
resulted from division of nuclei and cell body, or by the transformation of
intracellular blastema lying in spaces within the cell body (Virchow's Brut-
raume). The originating tumor-cells were not derivatives of the normal
tissue cells but came from the seminium morbi, hence there was urgent de-
mand and search for specific characters in the tumor-cells. Lebert especially
described such specific cells and designated as pseudocancer all tumors, as
rodent ulcer, which failed to contain them. Following this principle, Hann-
over carefully described the group of tumors arising from stratified squamous
epithelium and separated them from cancer under the term "epithelioma."

Hannover believed that cancer-cells circulated in the blood and produced
metastases as pus-cells produced pyemia.

The doctrine of the specific cancer-cell now became the chief topic of dis-
cussion and was supported by many writers. It was opposed by Bruch
who added many details to M tiller's work, by Yirchow who found the tailed
corpuscles in the normal bladder epithelium, and by Velpeau who with
Hannover, established the microscopical diagnosis of tumors. Endogenous
cell formation then took the place denied the ''tailed corpuscle'' as the
pathognomonic sign of cancer, Bruch, Yirchow, Remak and many others
accepting the importance of this supposed type of cell growth. The signi-
ficance of tumor stroma also attracted new attention, especially from Rokit-
ansky who explained many of the gross features from variations in this ele-
ment. He also studied the secondary degenerations of cancer tissue,
including inflammation, necrosis, and saponification, and considered the
possibility of a spontaneous cure by these processes.

In spite of their very careful histological studies of tumor tissue in^the
fresh condition all the authoritative writers of this period including Yirchow
were led to believe in the origin of cancer from a fluid blastema. Cancer
was defined as an organized exudate from the blood with overnutrition and
overgrowth. Much controversy arose concerning the various types of
blastemas supposed to exist and the changes in the blood from which they
were all necessarily derived. Yogel thought there were as many blastemas

22 N EOF LA STIC DISEASES

as tissues, different tumors arising in different tissues according to the type
or analogy of the tissue involved (law of analogous blastemas). These
views led directly to the conception of cancer as a constitutional dyscrasia
(Rokitansky), a belief that gained wide acceptance and seemed to be sup-
ported by the anemia of the disease. The help of the chemists was sought
to separate from the blood the different blastemas and Fiihrer was able to
distinguish albuminous, chondrinous and glutinous varieties, each of which
gave a suitable color reaction with nitric acid, and which were offered as
sources of the corresponding tumors. The idea that exuded elements of the
blood could become organized into cancer was vigorously opposed by Cruveil-
hier who urged that extravasated blood never became organized but had
lost all claim to vitality. Cancer could therefore develop only in the vessels.
This reasoning led Langenbeck to study cancerous masses in the veins which
he found to be composed of fibrin, pus-cells, and cancer-cells. He therefore
drew the important conclusion that cancer-cells possess a remarkable ca-
pacity for independent existence and that they were carried through the veins
producing secondary tumors or metastases. After Peyrilhe, Alibert, 1806,
and Dupuytren, 1817, produced only suppuration by intravenous injections
of tumor emulsion, but Langenbeck, Follin and Velpeau claimed to have
observed tumor nodules in the lungs of dogs receiving intravenous injections.
These results, although failing to receive confirmation seemed then to prove
not only the origin of metastases but the contagiousness of cancer. Yet
Bruch at once interpreted them as transportation of cancer-cells and not as
infection. He held the lymph-vessels to be the chief channels of transport
and with Meckel described backward transport in lymphatics.

While still burdened by the blastema theory of origin the study of cancer
had succeeded up to 1860 in rather accurately describing and classifying
the main classes of tumors chiefly according to microscopical structure. The
description of the benign tumors, the existence of various types of carcinoma,
the malignancy of epithelioma and the separate position of sarcomas, were
generally accepted facts. Correct conceptions of the histogenesis however
were impossible until Virchow founded the cellular pathology upon the doc-
trine of Omnis cellula e cellula. There had been several opponents of the
idea that cells could be formed from exuded lymph, notably Cruveilhier,
while Remak at the same time with Virchow claimed that cells grew ex-
clusively from other cells by endogenous reproduction; but Virchow applied
the new principle rigidly to all departments and especially to the origin and
growth of tumors. Coincidently with this memorable service he fell into
two grave errors. He failed to correctly interpret the deceptive evidence of
endogenous cell formation and he was led to believe that cancer-cells origin-
ated from connective-tissue cells. The latter error he never fully relinquished
and possibly on this account his monumental work "Die krankhaften Gesch-
wiilste" was never extended over the field of cancer.

Remak immediately attacked the connective tissue theory which had
become very popular but which conflicted with the significant principle of the
immutability of the three separate germ layers which he with His had already
established. Remak insisted that epithelial cells could arise only from
epithelium. The appearance of such cells in abnormal places he referred
to the misplacement of embryonal cell groups.

Virchow's authority however prevented the general acceptance of
Remak's views for many years, until the appearance of Thiersch's famous
monograph on epithelial cancer.

Although many authors opposed the theory of the connective origin of
cancer, and Meckel in 1857 had traced the origin of a buccal tumor directly

HISTORICAL 23

from the lining epithelium, it remained for Thiersch to present convincing
evidence of the invariable derivation of epithelioma from lining epithelium.
By improvements in hardening, cutting and staining the tissues in serial
sections he traced the growth of several epitheliomas from the Malpighian
layer or glandular structures of the skin and demonstrated the principle,
omnis cellida e cellula ejusdem generis. He also placed great importance upon
previous changes in the epithelial connective tissue as precipitating the down-
ward growth of epithelium.

By a process of involution associated with diminished nutrition, functional
capacity and mechanical resistance, the histogenetic equilibrium between
stroma and epithelium became disturbed and overgrowth of epithelium
resulted. This was the first competent physiological conception of the patho-
genesis of cancer and with it Thiersch introduced the modern era of our
knowledge of the nature of the disease. Waldeyer extended Thiersch's
observations to the internal organs and traced the origin of .cancer of stomach,
liver and kidney to the epithelial cells of these organs. He first described
the isolation of these cells by indurated connective tissue and held that
tumors developed from these isolated cells. The formation of secondary
tumors he demonstrated to be the result of continuous growth through blood-
and lymph-vessels as well as of cell emboli.

The acceptance of the epithelial theory was briefly delayed by the studies
of Recklinghausen and Koster, who brought forward evidence to show that
many cancers arose from the endothelium of lymph spaces. The outcome
of this controversy was the establishment of the group of endothelioma.
That true cancer has no connection with lymphatic endothelium was shown
by Carmalt who in Waldeyer's laboratory shook thin sections of fresh cancer
in silver solution, thereby removing the cancer-cells from the lymph spaces
and leaving the silvered endothelium intact. Yet Virchow's influence still
predominated and led to the assumption that cancer developed from almost
any mesoblastic cell, as from sarcolemma (Popper), perimysium (R. Volk-
mann), cartilage (Weber), vessel- wall (Gussenbauer) and leucocytes (Classen,
Rollett).

Through the untiring industry of himself and his pupils Waldeyer slowly
forced the acceptance of his views of the origin of cancer. Billroth slowly
abandoned much of his early allegiance to the connective tissue doctrine.
It was of great assistance when the regeneration of epithelium over wounds
was shown to advance from the edges of intact skin. By the minute study
of a large number of cancers of many varieties, Waldeyer eventually
established the principle of the exclusive epithelial origin of cancer and of
its growth from its own resources, and demolished the former belief that
normal tissues could become transformed into cancer.

The classification of tumors upon the histogenetic basis was accomplished
with the data furnished by the studies of this period. The theory of a
cancerous dyscrasia necessarily lost ground with the demonstration that
the disease has a local origin and that secondary tumors arise from trans-
ported cells. Likewise it became evident that the parasitic theory which
had enjoyed a general acceptation must be set aside as an inadequate
explanation of the new facts of tumor origin and growth.

Further than this the cellular pathology seemed incapable of carrying
progress in the etiological explanation of cancer. Irritation, trauma and
infection seemed to be connected with the origin of the disease but the obscure
nature of the relation of any of these factors was fully recognized.

The last decades of the nineteenth century were thus occupied with the
detailed study of the morphology of tumors, the separation of varieties of the

24 N EOF LAST 1C DISEASES

disease, the elucidation of histogenesis, and the writing of the natural history
of malignant diseases. The twentieth century opens as the experimental era
with the systematic study of tumors throughout the animal kingdom, and it
seems likely to become noteworthy as the period of specific etiological
investigation which promises to widely separate many neoplastic diseases
formerly held to be closely related. It may thereby prove to be the era of
successful therapeutics and prophylaxis.

CHAPTER II
DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY

Definition.- — A tumor is an autonomous newgrowth of tissue.

Among most authors there is virtual agreement regarding the essential
parts of the definition of tumors, v. Rindfleisch says briefly: " A tumor is a
localized degenerative excess of growth." Ziegler defines a tumor as a new-
growth of tissue wrhich apparently originates and grows spontaneously,
possesses an atypical structure, does not subserve the uses of the organism,
and reaches no definite termination of its growth. According to Birch-
Hirschfeld, tumors are progressive newgrowths of tissue arising sponta-
neously from cells of its own, and separated from normal tissue both in mor-
phology and in function. Ribbert states that tumors are newgrowths of
tissue, self-centered, largely or wholly uncontrolled by the organism which
supplies only their nutrition, with a structure never entirely normal, and
reaching no definite termination of growth.

Lubarsch includes among tumors all spontaneously arising tissue growths
which, while typical in form, differ in histology from the originating tissue,
and in spite of organic connection with the body pursue an autonomous
course rarely to the benefit of the whole body. Borst emphasizes in the
tumor process the unknown etiology, the local overgrowth, the peculiar
autonomy, the purposeless and endless course, and the atypical morphology
and biology of the tumor product. Adami accepts White's descriptive
definition: " A tumor proper is a mass of cells, tissues, or organs, resembling
those normally present but arranged atypically. It grows at the expense
of the organism without at the same time subserving any useful function."

I believe with Prudden that beyond the autonomy of tumor growth it
is difficult to add any element to our definition which may apply to all true
blastomas. The more descriptive definitions are doubtless more readily
applied but with increasing knowledge the unknown etiology, progressive
growth, and even the atypical morphology, may become less significant, while
the physiological conception of autonomy grows more substantial. Certain
obvious features of tumor growth emphasize the importance of their autonomy.

The nature of tumor growth is different from that of the normal tissues
and from inflammatory hyperplasia, and is something new and foreign to the
organism in which it occurs.

In most tumors growth is progressive, and no natural termination is real-
ized, the tumor growing most rapidly at the death of the patient. Yet the
progressive quality is not invariable as some tumors spontaneously regress;
others, as scirrhus cancer, long remain practically quiescent, and others de-
generate or necrose or become extruded, while fibrosis overtakes a few.

The growth of tumors is new to the organism in that it is usually expansive,
emanating from an isolated group of cells and pushing contiguous tissue be-
fore it. Such tumors are more or less encapsulated, appearing as isolated
or parasitic organoid structures. In some tumors the growth is infiltrative,
single cells or cell groups pushing their way through and destroying adjacent
tissues. In many tumors growth is extensive, beginning in a small focus and
gradually precipitating the contiguous normal cells into the tumor process.

26 N EOF LA STIC DISEASES

Tumor-cells acquire new and greatly increased powers of growth often
exceeding those possessed by any parallel normal tissue.

Ribbert claims that tumor-cells do not reveal any abnormal capacity
for growth since these are determined in the ovum, but merely exhibit their
innate capacities because the restraints to growth have been lost. It is
true that the organized regenerative properties of tissue cells are determined in
the fertilized ovum, but the power of multiplication without organization is
subject to great variations from the environment, and observation and ex-
periment show that tumor-cells have acquired in this sense abnormal capacity
for proliferation. The growth of tumor-cells is peculiar in that it proceeds
under abnormal conditions when the cells have been separated from their
natural connections, and even when they are transferred to other animals of
the same species. In transplanted tumors the cells often grow with increased
activity, when normal cells rapidly necrose or undergo slow regression, or
adjust themselves to the organization. Thus in many particulars the growth
of tumors differs from the organized regeneration of normal tissues.

These physiological peculiarities will later be considered in detail.

CLASSIFICATION AND NOMENCLATURE

There are three obvious and useful plans for the c^ssification of tumors:
histological, regional, and etiological.

1. A thorough etiological classification of tumors cannot with our pres-
ent knowledge be accomplished with sufficient detail for most practical
purposes. Yet many useful terms, which have more or less etiological
significance, are employed to designate tumors. Most tumors are post-
natal in origin; many are congenital, as the multiple chondromas of the spinal
column, sarcoma of the kidney, and angioma of the skin.

There are some notable tumors which show a striking hereditary character,
as glioma of the retina. A large class of tumors of many varieties are appar-
ently of traumatic origin. Partly etiological is the grouping of tumors into
adult and embryonal, arising from adult or embryonal cells and reproducing
adult or embryonal cells and structures.

The list of known specific causes of tumors is small but enlarging, in-
cluding the cancers of pipe-smokers, chimney-sweepers, and workers in
paraffin, o;-ray cancers, Kangri cancer and that of chewers of betelnut among
Africans. Some tumors probably result from exaggerated response to func-
tional stimuli, as the thyroid tumors of fish; others from prolonged mechan-
ical, chemical or thermal irritation; some are closely related to tuberculous,
syphilitic and other infectious processes. As knowledge advances it seems
probable that a much wider extension of etiological classification along these
and other lines will be accomplished.

2. The regional classification of tumors is of great practical utility but
as a rule it only deals with superficial characters of neoplasms and usually re-
solves itself into a grouping of distinct histological varieties occurring in
different organs. Yet there are exceptions to the rule. Hypernephroma is
a regional term referring to tumors chiefly of the head of the kidney but in-
cluding several histological and structural types. Multiple myeloma varies
in structure but is practically the sole primary tumor of bone-marrow. Ter-
atoma of the testis and adamantinoma of the maxillae are almost the only
tumors arising in these regions and both cover such a wide variety of struc-
tures that it is convenient to employ regional terms to designate such tumors.
Moreover the marked peculiarities in the origin and course of similar his-
tological tumors in different organs often render it advisable to emphasize

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 27

the organ involved rather than the structure of the tumors. The mor-
phologist speaks of cancer of mamma, larynx, uterus, etc., as one and the same
disease, while the clinician properly conceives of mammary cancer, laryn-
geal cancer, uterine cancer, etc., as quite distinct clinical entities. There is
much practical value in emphasizing the regional point of view, and as knowl-
edge advances it may well prove that the strictly histological grouping of
many tumors is based on structural resemblances which are less significant
than are now supposed.

3. The histological structure of tumors offers the simplest means of
classification.

A tumor receives a name and position according to the tissue which it
most resembles. Yet this plan meets difficulties at once and applies readily
only to simple and benign tumors. Many malignant tumors do not resemble
any normal tissue and terms drawn from gross pathology, sarcoma and carci-
noma, have been drafted to designate the microscopical structure of the two
main classes of tumors.

Moreover to name a tumor according to its microscopical structure often
conveys very little information about it.

Tumor nomenclature aims to be more specific and there is a constant
tendency to replace histological with histogenetic terms wherever possible.
The main classes of tumors are therefore named from their histology, while
the specific forms are designated, if possible, by their histogenesis, as neuro-
fibroma, adenoma sebaceum, etc.

Where structure varies, histogenesis dominates the nomenclature, as
with adamantinoma, hypernephroma, etc.

HISTOLOGICAL CLASSIFICATION
GROUP I.— TYPE: CONNECTIVE TISSUE

(a) Fibroma, composed of connective tissue.

(b) Chondroma, composed of cartilage.

(d) Osteoma, composed of bone.

(e) Myxoma, composed of mucous tissue.
(/) Lipoma, composed of fat tissue.

(g) Angioma, composed of blood-vessels.
(h) Lymphoma, composed of lymphatic tissue.

(i) Sarcoma, a cellular tumor composed of anaplastic tissue of any of the
above types.

GROUP II.— TYPE: MUSCLE TISSUE. MYOMA AND MYOSARCOMA

(a) Leiomyoma, composed of smooth muscle tissue.

(b) Rhabdomyoma, composed of striated muscle.

GROUP III.— TYPE: THE ELEMENTS OF THE NERVOUS SYSTEM

(a) Neuroma, composed of nerve fibers.

(b) Neuroma ganglionare, of nerve fibers and ganglion cells.

(d) Neuro-epithelioma, composed of neuro-epithelium.

GROUP IV.— TYPE: ENDOTHELIUM. ENDOTHELIOMA
GROUP V.— TYPE: EPITHELIUM, PAVEMENT OR GLANDULAR

(a) Papilloma, a tumor of pavement epithelium, with supporting tissues in
normal arrangement.

28 NEOPLASTIC DISEASES

(b) Adenoma, a benign tumor of glandular epithelium, with supporting
tissue, in normal arrangement.

(d) Carcinoma, a tumor of glandular epithelium in atypical arrangement.

GROUP VI.— TYPE: COMPLEX TISSUES

(a) Simple mixed tumors, composed of more than one type of neoplastic
tissue — named according to composition: as chondro-epithelioma, adeno-
sarcoma.

(b) Teratoma, composed of tissues and organs of one, two, or three
germinal layers, as monodermal, bidermal, or tridermal types.

The variable structure of many simple tumors requires complex terms
for the accurate designation of structure. A fibroma with many neoplastic
blood-vessels is called an angiofibroma, while a tumor chiefly composed of
blood-vessels with much new connective tissue is called a fibro-angioma.

A sarcomatous quality is indicated as fibro-, chondro-, or osteo-sarcoma.
So fibro-adenoma and adenofibroma indicate predominance of one or another
structure. Histioid tumors are composed of a simple tissue, organoid
growths reproduce the structure of organs. Homologous tumors resemble
the tissue in which they arise, as adenoma mammae; heterologous tumors
present a structure foreign to the tissue in which they grow, as chondroma
mammae.

A strictly embryologic classification of tumors presents many advantages over others
but for good reasons has never gained general adoption.

The early segmenting embryo first consists of a mass (morula, blastula) of large un-
differentiated cells (blastomeres). Soon these cells form two distinct layers, epiblast and
hypoblast, both of which have the characters of lining membranes, the pavement quality
being more marked in the former. Next the hypoblast gives rise to a group of cells forming
the mesoblast and lying intermediate between the other two layers. The mesoblast cells
lose their pavement qualities and appear in an undifferentiated cell mass, but, later, certain
of its cells grow out between the epiblast and hypoblast in modified pavement form and
enclose the body cavity (ccelom). Thus the mesoblast comes to possess a lining portion,
mesothelium, and a pulp portion, mesenchyme.

The ccelom with its mesothelial lining eventually becomes the pleura, pericardium
and peritoneum. From a portion of the mesothelium is also developed the parent tissue
of the striated muscles, and later modified mesoblastic cells form the lining cells' of the
blood and lymphatic vessels. Thus the lining cells of the great serous cavities, and the
vessels, and the striated muscles, are derived from mesoblastic cells which have at one time
lost their pavement quality while merged in the mesoblast.

At the same period with these changes, the epiblast proliferates in the region of the
primitive groove and forces inward a mass of cells, which become isolated and modified,
going to form the central nervous system. Coincidently, a portion of hypoblast retaining
some of its pavement qualities arises to form the notochord.

Adami points out that these early embryological processes lead to the development of
two main classes of tissue which permanently retain their early characters, viz. : lining mem-
brane tissues and pulp tissues, and which he proposes to call lepidic (\CTTLS, membrane)
and hylic (v\rj, crude matter). Lepidic tissues are composed of groups of specific cells
which are not penetrated by blood-vessels and possess no intercellular stroma. The epi-
blast and hypoblast are primary, the mesothelium and endothelium are secondary lepidic
tissues. Hylic or pulp tissues of which the mesenchyme is the type, are composed of cells
separated by a homogeneous fibrillar stroma which may or may not be penetrated by
vessels.

Upon this basis Adami has divided the blastomas into two main groups: Lcpidoma
and Hyloma.

I. LEPIDOMATA

A. Primary, (i) Epilepidomata, typical (papilloma and adenoma), and atypical
(carcinoma), all from epiblast. (2) Hypolepidomata, typical (adenoma) and atypical,
(carcinoma) all from hypoblast.

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 29

B. Secondary. (3) Mesolepidomata, typical (adenoma of kidney, etc.) and atypical
(carcinoma of kidney, etc.), all from mesothelium. (4) Endothelial lepidomata.

II. HYLOMATA, OR PULP TUMORS

1. Epihylomata, typical (neuroma, glioma) and atypical (gliosarcoma).

2. Hypohylomata, chordoma.

3. Mesohylomata, typical (fibroma, lipoma, etc.) and atypical (sarcoma) from mesenchy-
mal tissues. Mesothelial hylomata or rhabdomyomata.

There is no doubt that in the above scheme Adami has accomplished a successful
classification and legitimate nomenclature for tissues and tumors, based upon accredited
data. In several directions this classification is of value in the interpretation of many
peculiarities of tumor growth. Thus the essential distinctions between lepidic or pavement
tissues and hylic or pulp tissues established in the early embryo have a strong influence
upon tumors derived from these tissues. The degrees and types of the pavement quality
observed in embryonal epiblast, hypoblast, and mesothelium reappear in much of the
history of tumors derived from such tissues, especially the mesenchymal relations of en-
dothelium. To a less extent, I think, the reversionary tendencies of tumor-cells show the
influence of embryological relations.

Yet there appear to me to be two main objections to the adoption of this most successful
embryological classification and nomenclature:

First, the behavior of tumor-cells is very much more influenced by the acquired char-
acters of the cells of origin than by their embryological derivation.

Second, the neoplastic process does not consist in retracing the steps of embryological
development but probably in a progressive loss of original cell potencies, so that the cells
become a prey to all manner of new external conditions which control their nutrition,
greatly influence their form and render them significant chiefly as pathological parasitic
cells and tissues.

Embryology has been of great value in clearing up many of the disturbances of develop-
ment which lead to the growth of heterologous tumors and teratomas, it aids in the inter-
pretation of many phenomena of tumor growth, especially of teratomas, and will likely be
of further aid in this field, but with the main element in the neoplastic process, anaplasia,
it has nothing to do.

Oncology is not a department of embryology but a separate chapter in the biology of
the cell. Hence strictly embryological classification and nomenclature have never gained
great favor, because they do not serve the largest needs of the student of tumors. The
generally accepted plan of classification and terminology which is based on histology,
modified as much as possible by histogenesis, is a natural product which has become
very firmly established and probably deserves to prevail against the varying prominence
of embryology, chemistry, and etiology.

GENERAL MORPHOLOGY OF TUMORS

The external appearances of tumors present extremely wide variations
far exceeding those of normal structures. Yet these gross features are as a
rule distinctive, so that the recognition of a tumor may usually be made
by inspection and palpation of the tissue.

The terms sarcoma and carcinoma refer to the exuberant fleshy character
of connective tissue growths and the rough similarity of cancer to the crab.

The local circumscription of many tumors is a sufficient gross sign of many
blastomas, but fails to separate miliary or nodular granulomas from many
forms of multiple tumors. There are some cases of diffuse carcinoma, as
of the breast, or carcinosis, as of the meninges, in which no visible tumor is
produced, and only a minute attention to color, consistence, and distribution
saves the gross diagnostician from error.

The color of tumor tissue is often distinctive.

The normal color of tissues is almost invariably altered, becoming opaque,
lighter and often with a tinge of yellow or white, where groups of cancer-cells
are growing. Virchow used to emphasize three zones in a cancer nodule, a
central light or yellowish area of degeneration or cicatrization, a middle,
firm, opaque, cellular zone, and a peripheral reddish area of congestive re-
action. The congestion which marks the advance of many cancers in the
skin may simulate ajbacterial process.

30 NEOPLASTIC DISEASES

Blood content and hemorrhage chiefly determine the color of most tumors
as of other tissues. Most cancers are comparatively bloodless while sarcomas
are usually more vascular and often contain extravasated blood. Angiomas
and angiosarcomas can usually be recognized in the gross from the congeries
of blood-vessels composing them. Some sarcomas of bone are traversed by
wide blood sinuses surrounded by little tumor tissue, and deserve the name of
bone aneurism. Multiple hemorrhagic sarcoma of the skin (Kaposi) is
marked by frequent hemorrhages and pigmentation. Certain types of
carcinoma, as chorioma, and teratoid cancer of the testis usually produce
notably hemorrhagic tumors.

The fungus hematodes of older writers is a cauliflower-like growth rich
in blood sinuses. Hemorrhagic infarction may overtake many tumors
causing them to assume a very dark red or rusty color. Secondary pig-
mentation of large portions of tumors may result from altered extravasated
blood. Carcinoma of the breast in dogs is nearly always pigmented from
this source.

Melanoma of the skin and choroid is a brown or black tumor containing
autochthonous pigment, but in rapidly growing metastases it may pro-
gressively lose its pigment. The greenish yellow color of chloroma is a dis-
tinctive feature possibly caused by lipochromes.

A pearl gray color is seen in chondroma, myxoma, and some scirrhus
cancers. Hypernephroma, except in its highly embryonal types and in
rapidly growing metastases, has an ochre yellow tint.

The consistence yields significant indications of the nature of many
tumors. Osteoma and chondroma reveal themselves at once by stony hard-
ness, but hard fibroma may simulate chondroma.

The peculiar density of many carcinomatous nodules in the breast and
of the bases and borders of carcinomatous ulcers is their chief diagnostic
feature. There are few organs in which the density of carcinoma is equaled
by any other process, but gumma of the testis is usually firmer than the em-
bryonal cancer of this organ.

Many tumors are softened by edema, hemorrhage, necrosis, mucous
degeneration and cyst formation, and some become very hard from fibrosis
or calcification. In each organ carcinoma is usually firmer than adenoma
and sarcoma, which have less fibrous tissue and more vessels. Rapidly
growing and embryonal cancers fail to show the density of older types, and
from this and other characters are difficult to distinguish in the gross from
sarcoma. The soft elasticity of lipoma and especially of myxoma and
colloid tumors is somewhat characteristic. Glioma is usually softer arid more
vascular than adjacent brain tissue.

Cystic tumors are tense but yielding or fluctuating. Angiomas may
be compressible. Lymphosarcoma is rather less firm than Hodgkin's
granuloma, leukemia, or slow tuberculosis of lymph-nodes.

Mucous carcinoma of peritoneum produces jelly-like infiltration or huge
intraperitoneal masses, and endothelioma of pleura may yield peculiar dry
crumbly material. The "sand tumors" of the dura (endothelioma) and
ovary (adenoma), are easily recognized on palpation, and the waxy
plates of cholesteatoma and sebaceous contents of dermoids are equally
characteristic.

The texture and markings revealed by inspection of the surface and
section of tumors often disclose their true nature.

The firm translucent surface of a fibroma, the glistening homogeneous
luster of a chondroma, the intertwined fascicles of muscle fibers in a myoma,
and the branching twigs of a papillary tumor, are readily recognizable

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 31

naked-eye features. Likewise the jelly-like material in myxoma and col-
loid cancer, the whorls of many endotheliomas of the dura, the vascular
twigs of angiosarcoma, and the lobules of fat tissue in lipoma furnish a
ready basis for gross diagnosis.

In dealing with cellular tumors there are many criteria which lead one to a
correct conclusion.

Very cellular tumors without much stroma are invariably soft and fragile
or pultaceous (encephaloid). Soft but coherent tumor masses usually show
abundant stroma. Cellular tumors whether sarcoma or carcinoma are
usually lighter colored and more opaque than the surrounding normal tis-
sues. As a rule, sarcomas are more uniform in texture than carcinomas.
The former may produce wide areas of new tissue unbroken by bands of
connective or areas of necrosis although frequently interrupted by hemor-
rhages. The latter exhibit the tendency of carcinoma to excite the growth
of connective tissue and to undergo focal fatty degeneration which produce
points and masses of yellowish or whitish material. The necrosis of sar-
coma is usually more massive.

Vertical section through an acanthoma shows compact columnar masses
or whorls of cells, of pearly white luster which even when infiltrating are well
banked against the surrounding tissue. Early ulceration is also character-
istic of this common tumor, but it rarely produces bulky masses, either
primary or secondary.

There are peculiar forms of carcinoma, as in the pylorus and rectum,
marked by mucous degeneration and fibrosis, which are sometimes more
safely identified in the gross than by the microscope. They produce annular
constrictions, or wide infiltrations of the submucosa, but most of the cells
may be lost by mucous degeneration.

By naked eye inspection one can frequently recognize the main charac-
ters of tumor structure many of which, from too exclusive reliance on the
microscope, have come to possess chiefly a histological significance.

The growth of a tumor may be mainly central so that it displaces the
surrounding tissue by lateral pressure, as in myoma uteri.

Central growth is well shown in some angiosarcomas in which actively
growing blood-vessels sheathed with tumor-cells compose the central por-
tions, while in the periphery the growth is solid and grades into a firm fibrous
capsule. Or the growth may be peripheral in which case the central portions
are apt to be fibrosed or degenerated and depressed.

Infiltrative growth is revealed by lack of capsule or other demarcation
and by opaque cords of tumor-cells stretching out into the lymph spaces
or vessels. Extensive intravascular growth characterizes hypernephroma,
adenoma of liver, and chorioma. Polypoid, papillary and dendritic,
and cystic architectures reveal themselves best to the naked eye, while
more minute structures designated as fascicular, plexiform, and alveolar
can usually be detected by careful inspection.

Soft cellular tumors are often called medullary, or encephaloid, from
resemblance to brain tissue, to which the counterpart is the hard scirrhus.

Thrombosis of blood-vessels, edema, fatty, hyaline, mucoid and colloid
degeneration, calcification and ossification, are all encountered in extreme
degrees in the gross anatomy of tumors.

Cysts of varying origin, form, and content are notable gross features of
many tumors.

Retention cysts filled with retained secretion develop in many adenomas
especially of the ovary, some of which are the largest tumors ever observed.
Originating in a closed group of alveoli whose secreting function is active

NEOPLASTIC DISEASES

dilatation of alveoli is accompanied by complex systems of papillary in-
growths which constantly add their quota of secretion. Eventually in-
flammatory exudate and hemorrhage are added with rapid increase in volume.
The contents of such cysts are therefore serous fluid with much nucleo-albumin
and mucus, or with pus and disintegrated chocolate colored blood. The
walls are lined with varying quantities of papillary tumor growth.

Liquefaction cysts with smooth walls form in nbromyomas, sarcomas, etc.,
from local edema, necrosis, and autolysis of solid elements. Their contents
are thin and serous or mingled with granular or fatty detritus, blood or pus;
or the fluids are removed by absorption. Extravasation cysts form after
hemorrhages and exhibit all stages of alteration and absorption of blood.
Dilated lymph- or blood-vessels contribute to the structure of some cystic

FIG. i, — Fibrosing epidermoid

carcinoma. Spindle-shaped tumor-cells. Illustrating
infiltrative growth.

sarcomas of bone and other tissues. Cystosarcoma phylloides is an old term
sometimes applied to tumors showing a branching system of more or less
parallel cysts recalling the veins of a leaf.

It is often difficult to distinguish between true cystic blastemas and
simple cysts with inflammatory overgrowth of lining cells.

In most simple retention cysts there is a tendency for the epithelium
to grow up into papillary projections, as in chronic mastitis, and with several
forms of encysted animal parasites. Such inflammatory overgrowth may
reach a considerable grade but usually lacks the distinctive morphology
of a tumor, and regresses when the cyst is evacuated. Yet some of them may
go on to produce genuine neoplasms.

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY

Ulceration overtakes most tumors of the skin and mucous membranes.
The inadequacy and fragility of blood-vessels, degeneration and autolysis
of tumor-cells, trauma, mechanical pressure and tension, contact with irri-
tants causing inflammation, and bacterial infection, are the chief factors in
its origin.

In ulcerating acanthoma the base is formed of dense eroded tumor tissue;
the secretion is scanty or abundant pus, serum and opaque particles of
tumor-cells; the edges are raised, very hard, in mucous membranes often
undermined, rounded, irregular, or serpiginous; and the vicinity is indurated
and inflamed according to the extent of infiltration and infection. Erosion
of bone and cartilage with pain, and of blood-vessels with hemorrhage may
occur, and perforation into adjoining hollow viscera. Considerable masses
may slough, and new skin or mucous membrane may replace portions of the

FIG. 2. — Fungating carcinoma of neck. A recorrence from the lip.

ulcer. Extensive tracts of suppuration may follow invasion of cellular
tissues.

In adenocarcinoma of mucous membranes thrombosis and infection com-
monly leads to the formation of large sloughing excoriated ulcers with much
hemorrhage. Flat, indurated, annular ulcers with extensive infiltration
of the vicinity and constriction of the lumen form in carcinoma of the rectum.
Necrosis of large portions of the tumor together with the distended overlying
skin in carcinoma of the breast and other cancers produces extensive ulcers
in which the sloughing tumor may protrude or suffer deep excavation. In
sarcoma, ulceration is usually marked by massive necrosis and hemorrhage.

The onset of ulceration frequently transforms a comparatively harmless
tumor into a rapidly fatal process through local or general infection, suppura-
tion, absorption of toxic products and hemorrhage, to which chiefly must
be attributed the cachexia of cancer.

In general it may be said that the outward morphology of tumors con-

N EOF LA STIC DISEASES

stitutes an important and very practical chapter in their study since it
not only reveals the general architecture of neoplasms but allows their
separation in most cases from other processes, and usually permits an accu-
rate diagnosis of their histological structure.

HISTOPATHOLOGY

The study of tumor growth must begin with its earliest stages.

In one large group this study leads to the scrutiny of misplaced and
chiefly embryonal cells, or even to the consideration of single cells, giving
rise to the large group of tumors to which Cohnheim's theory applies. In
another equally important class the initial changes affect cells which so far

FIG. 3. — Precancerous changes in breast. Atypical epithelial proliferation in ducts and
acini found in a small portion of the breast.

as we know are normal and here a series of preliminary changes occurs,
belonging to the so-called precancerous stage, which is of importance in the
origin and growth of tumors.

Precancerous Stage of Tumor Growth. — Processes occasionally followed
by neoplastic growth are observed in syphilitic leukoplakia, tuberculosis,
Hodgkin's granuloma, chronic eczema, chronic mastitis, ulcer of the stomach,
cirrhosis of liver, ;r-ray dermatitis, and the chronic processes associated with
mechanical, chemical and thermal irritation.

It is impossible to analyze all the factors acting in such processes. Upon
their interpretation have been built many theories of the nature of tumor
growth. Yet it is possible to enumerate several very constant morphological
changes which in certain combinations seem to be most effective in exciting
the subsequent autonomous growth.

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY

In a study of precancerous changes in several situations Bonney finds
constant loss of elastic tissue, and usually hyaline changes in the collagen,
lymphocytic exudate, and fraying of the edges of the epithelium.

In multiple epithelioma of the skin Janeway has observed that the tumors
are often preceded by a period of local erythema which may slowly disappear
or be followed by cancer. Sections of the skin show focal dilatation of
the blood capillaries adjacent to the basal epithelium about which the epithe-
lium is hypertrophied, hyperplastic and with hyperchromatic nuclei.

In leukoplakia, hyperkeratosis, thickening of the Malpighian layer,
hypertrophy of the epithelium, round-cell infiltration, increased vascularity
and edema long precede epithelioma of the tongue.

FIG. 4. — Atypical epithelial hyperplasia on edge of a beginning carcinoma of skin.

In ulcer of the stomach disordered gland alveoli are drawn into new cellu-
lar connective tissue, detached from their normal relations, pass through
stages of proliferation, hypertrophy of cells and nuclei, and gradually or
suddenly assume neoplastic characters. Here, as in cancer following cir-
rhosis of the liver, it is sometimes difficult to determine just when a true neo-
plastic process exists.

In chronic mastitis single small cancer nodules may appear and I believe
their preliminary stages may be traced in other portions of the breast, chiefly
in the ducts. Here one finds hyperplasia of lining cells with hypertrophy
and increased eosin stain, cyst formation and papillary outgrowths into them,
in which condition they seem usually to be diverted from further dangerous
tendencies. Yet other cells show more active proliferation, increase in size
and in nuclear chromatin; their polarity is lost by growth of round-cells and
connective tissue, and it is possible to trace such cells into types closely
approaching those seen in early carcinoma.

36 NEOPLASTIC DISEASES

It may be true as Ribbert asserts, that no one has ever seen the beginning
of cancer of the breast, but the changes just enumerated seem to form a com-
mon preliminary to the onset of true cancer, which on such a basis develops
rapidly and is accompanied as a rule with fatty degeneration in the affected
cells.

In rare cases of Hodgkin's granuloma the proliferation of large mono-
nuclear cells and of giant-cells, originally of inflammatory origin, takes on more
autonomous and sarcomatoid qualities. The cells become more numerous,
the stroma less, the nuclei larger, mitoses more abundant, metastases com-
posed of large round-cells without stroma occur, and the process has many of
the qualities of a blastoma. Yet the true neoplastic properties of these cases
must be doubted, although they exhibit a certain progress toward a genuine
autonomous newgrowth.

The abnormal physiology associated with the precancerous state will be
discussed under General Etiology.

Beginning thus either in isolated embryonal cell groups or in tissues
long subjected to the influences of the precancerous stage, tumors grow,
always chiefly, sometimes exclusively, from their own resources, i.e., from the
original cells involved in the process.

Modes of Origin. — Four modes of the origin and extension of tumors may
be discerned:

1. Growth is unicentric and exclusively from the original cell group
involved in the tumor process. In the large class of blastomas arising from
embryonal cell groups, the originating cells are isolated from the first, and the
tumor-cells remain isolated during their entire history. Thus hyperneph-
roma may begin in a small group of cells misplaced in the renal cortex,
produce a large tumor of the kidney, invade the renal vein and produce
metastases in many organs, the cells in all situations being the direct descend-
ants of those composing the original cell complex.

2. Multicentric growth is observed in many tumors. In multiple epithe-
lioma of the skin, rr-ray cancers, cancers of the gastro-intestinal tract
following multiple polypi, fibrosarcoma of nerve trunks, and others, several
centers originating tumor-cells appear simultaneously or at intervals. These
centers may gradually coalesce producing one large tumor area or they may
long remain discrete.

Petersen by reconstruction in wax has shown that certain cancers of the
breast arise from several discrete centers of proliferation, and a similar
multiple origin in an adrenal tumor is described by Woolley; and for carcin-
omatosis of the liver, by Von Heukelom and Oertel.

A remarkable case of multiple angiosarcoma or endothelioma, involving
nearly the entire skeleton, is described by Marckwald.

Of such cases some must be referred to the wide diffusion of the inciting
factors as in #-ray cancers; others to multiple foci of embryonal displaced or
superfluous cells as Hauser would explain the multiple cancers of the intes-
tine; while the conditions in a few cases suggest some complex influence of an
existing tumor upon neighboring cell groups predisposed to tumor growth.

Multiple tumors of the same type in paired organs is a special case of
multicentric growth. Carcinoma arises in both breasts, teratoma in both
ovaries, lymphosarcoma in both testes. In each such case different influ-
ences seem to be concerned but in all the influence both of local and of con-
stitutional factors is suggested.

The occurrence of multiple tumors of different types in the same organ
or in different organs of the same subject is also observed.

In some instances a second tumor may result from conditions brought

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 37

about by the presence of the first, as when a submucous fibromyoma causes
ulceration followed by cancer of the uterine mucosa.

Tumors have been observed simultaneously in the uterus, ovaries and
breast, a combination suggesting the influence of the functional relation
existing between these organs. The rather common occurrence of two or
more tumors in different organs of the same subject suggests nothing more
than the accidental coincidence in several organs of the general etiological
factors in the genesis of tumors.

Many cases illustrating several groups of multiple tumors have been
collected by Walter and Woolley. Among 1000 autopsies on tumor cases
Hansemann found five with multiple primary growths, and in 1225 cases
collected by Redlich 14 showed more than one primary tumor. When a
minute search is carefully conducted and all forms of tumor growth included,
the proportion of multiple tumors is much greater.

Symmers in 215 autopsies found tumors in 55, in 22 of which more than
one type existed. Getting observed three cancers of different organs,
several adenomas of bile ducts, and an angioma of liver, in a man of 58 years.

3. The question whether a tumor process may gradually extend from an
originating focus over the surrounding normal cells cannot at present
be determined. Such a possibility is commonly denied. Borst argues
that it is impossible to conceive how such an influence can be transferred
from one cell to another. Ribbert, after strongly opposing the idea of
transference of the tumor tendency from a tumor-cell to normal cells, admits
that there may be widespread multiple foci of origin which exhibit neoplastic
growth one after the other, thus simulating the lateral diffusion of the tumor
process. Unless one assumes as White actually does, that tumors develop
from single cells, it is necessary to assume some such gradual implication of
the several cells in the originating group, so that Ribbert has practically
admitted the gradual extension of a tumor by progressive involvement of
normal cells, not by transfer of influence from one cell to another, yet by
the effects of underlying factors upon one cell after another. It is not
necessary to attribute this influence to the mere contact of tumor-cells or
to suppose that it involves a parasite.

Increased vascularity, mechanical displacement, disordered function,
chemical stimuli and toxic agents, may all be included among the factors
resulting from the presence of tumor-cells. There is also a certain complex
tropism observed in the growth of tissues in lower animals, whereby processes
at work in one tissue induce similar tendencies in contiguous cells. There
appears to be adequate theoretical basis for the extension of a tumor process
over normal cells, and observation indicates that in some cases such extension
actually occurs.

First, in the neighborhood of many epithelial tumors the contiguous
cells show a peculiar increase in number, size and chromatin content.

This collateral hypertrophy is more common about primary tumors but
may be seen in metastases. Usually it does not reach a neoplastic grade,
but it is sometimes difficult to distinguish from an advance of the tumor.

In adenoma of the sigmoid such transformations may occur, the outlying
cells first increasing in size, then becoming opaque and granular, while the
nuclei become hyperchromatic. Some extensive superficial adenomas of the
sigmoid appear to have developed in this manner.

Hauser depicts definite stages in the transformation of normal glands
into hypertrophic forms which he believes precede the development of
cancer. Haaland has described a neoplastic transformation of the pulmonary
cells in metastatic carcinoma in the mouse, an observation which needs to

38 N EOF LA STIC DISEASES

be confirmed, but the sarcomatous transformation of the stroma of trans-
planted cancers of the mouse, if genuine, is probably a sufficiently attested
instance of the tropism exerted by tumor epithelium upon adult connective
tissue.

In adenocarcinoma of the human ovary is sometimes seen a sarcomatoid
proliferation of the stroma.

Yet these instances of lateral extension of tumor processes, if they eventu-
ally stand the test of criticism, are rare and it should be emphasized that
the great majority of tumor-cells are isolated in origin and throughout their
history.

4. The systemic round-cell sarcomas present a difficult problem in
the analysis of their mode of origin and extension. Multiple myeloma arises
simultaneously at numerous widely distant foci in the bone-marrow and
may early show a diffuse tumor process throughout many bones. Hence
one must assume the existence of so many foci of origin as to suggest the
simultaneous involvement of the entire bone-marrow system.

Multiple metastases cannot satisfactorily explain the course of these
tumors, and it would seem probable that there occurs a lateral extension
of the tumor process over adjacent normal areas as well as infiltrative growth
from the multiple foci. In the group of lymphocytomas there are examples
very strongly indicating simultaneous tumor growth originating in a large
portion of the lymphatic system. In some intestinal cases (Wells, Symmers)
there is a diffuse lymphadenomatous hyperplasia involving the entire lym-
phoid apparatus, from the cardiac orifice to the anus, the superficial, the thor-
acic and the abdominal nodes, and the bone-marrow. Leucocytosis is
absent and the spleen is little affected. A rapid lateral extension from very
many foci or a primary involvement of the entire system seems to be the
only reasonable explanation of such cases. There are systemic highly
malignant large-cell sarcomas of equal extent. Chloroma, with or without
leukemia, occurs as a multiple or diffuse tumor process affecting wide areas
of marrow and lymphatic system for which a lateral extension from many
foci or a primary diffuse origin seems a necessary assumption. In thyroid
tumors of fish the hyperplasia which seems to result from exaggerated re-
sponse to functional stimulus, is felt in all the widely disseminated alveoli
of the gland. Some of these hyperplastic glands may regress (Marine),
but beyond a certain stage they become autonomous.

Cell Division in Tumors. — Normal and many abnormal types of cell
division occur in tumors, including mitosis, direct nuclear division, and
direct and indirect fragmentation.

This subject has been very fully investigated by Stroebe, Vit. Miiller,
Cornil, Arnold, Pianese, Galeotti, Hansemann, and many others, who agree
that the chief mode of cell division in tumors is by mitosis. In the benign
tumors in which the growth is comparatively slow the scanty mitotic figures
usually appear normal, but degeneration, inflammation and very rapid
growth are marked by increasing irregularity in the mitotic process.

Pianese classifies the irregularities occurring in cancer as follows:

A. Relatively typical mitosis, which may be bipolar and symmetrical,
hyper- or hypochromatic, and giant.

B. Atypical mitosis, either asymmetrical or multipolar.

C. Abortive mitoses, marked by suppressed or atypical polarization of
chromosomes, by aberration of chromosomes, by loss of polar bodies, and by
degeneration of cytoplasm.

As a rule he found the first two types in comparatively intact cells, while
abortive mitoses occurred chiefly in degenerating cells. Irregularities in

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 39

all the phases and elements of the mitotic process occur in malignant tumors
and bear a certain relation to the morphological and physiological variation
of the tissue from the normal (Hansemann). The number and size of the
chromosomes, the structure of the spindles, the coordination of the division
phases, the position of the elements in the cell, contribute numerous abnor-
malities in the process. Hyperchromatic cells may arise from asymmetric
mitosis. Hypochromatism results from asymmetric mitosis and loss of
chromosomes.

Asymmetric mitosis has been referred to secondary subdivision of cen-
trosomes, one of which may divide into as many as four parts, each forming
attraction spheres. Under these conditions the migration of chromosomes
is often delayed and unequal (Galeotti).

The results of abortive mitosis give rise to a great variety of structures
which have been elaborately illustrated by Pianese. In this class of struc-
tures have been found many of the pseudoparasites of cancer. Thus abnor-
malities in the mitotic process have been observed rather more abundantly
in carcinoma than in sarcoma, but many of them have been seen in inflam-
matory and regenerative hyperplasia (Stroebe).

Striking peculiarities in such a fundamental process as cell division
may well suggest that here is disclosed the essential nature of tumor growth.
Hansemann has interpreted the studies in this field in such a manner,
holding that asymmetrical, multipolar and abortive mitoses mean unequal
distribution of cell potencies, loss of cell differentiation, freedom from normal
restraints to growth, and exaggeration of growth over functional capacities.
These physiological properties he includes in the conception of anaplasia,
the morphological side of which is illustrated in resting and dividing tumor-
cells. To a considerable extent this interpretation may be valid, and yet
the majority of tumor-cells divide by normal mitosis (Pfitzner, Hauser),
and the minute study of the conditions favoring abnormal mitoses indicates
that these changes are secondary results of tumor growth and not primary
and essential.

Abnormal, asymmetric and multipolar mitoses are readily produced
experimentally, by heat, and by many chemicals (Galeotti, O. Hertwig).

Gametoid Mitosis. — In the maturation of sex cells the mitotic nucleus
exhibits only one-half the number of chromosomes of the somatic or general
body cells, and these chromosomes instead of assuming a V shape and radial
arrangement and splitting lengthwise in the monaster, are ring-like or loop
shaped, or composed of coarse granules arranged in the long axis of the
spindle. This type of division with reduction of chromosomes is called
gametogenous or heterotype.

Farmer, Moore and Walker have found that this type of division, here
called gametoid, is common in the growing edges of epithelioma and other
tumors. On this ground they at first assumed that tumor-cells possess the
physiological significance of sexual cells, but this view has been abandoned
since gametoid mitosis is by no means constant in tumors, and the peculiar
mitoses may not signify the properties of sex cells. Yet, I think the obser-
vation remains suggestive, since tumor-cells may show three properties of
sex cells, gametoid mitosis, increased growth capacities, and remarkable
altruistic relations.

Amitosis is frequently observed in rapidly growing tumors and in some
cases it may be the chief mode of cell division. According to Nedjelsky
it begins with swelling of the nucleolus -followed by elongation, budding or
cleavage of the nucleus. It results in the formation of giant-cells with pale
nuclei which may later undergo budding or mitotic division, or by division

40 NEOPLASTIC DISEASES

of the cell body it often leads to rapid regeneration of viable tumor-cells
(V. Mtiller).

Flemming and Trambusti hold that amitosis always results from degenera-
tive changes in the cell and may yield giant-cells but not fully viable tumor-
cells. Marchand and most observers believe that mitosis contributes,
as does amitosis, to the rapid regeneration of tumOr-cells, but fails to convey
to the progeny all the properties of the parent cells. Pianese in his elaborate
study of cancer-cells could not find that amitosis was ever followed by cell
division, but was always abortive, leading to the formation of multinucleated
giant-cells.

Howard has endeavored to trace in the nuclear changes of tumor-cells
many processes parallel to those observed in the protozoon nucleus.

The impression that tumor-cells must owe their exaggerated growth
capacities to some form of fertilization has led to an interpretation of certain
nuclear changes suggested by this point of view but now abandoned. Klebs
once thought that the nuclei of englobed leucocytes fused with the nuclei of
tumor-cells. Recklinghausen saw appearances suggesting the fusion of
the nuclei of endothelium and fibroblast.

Auerbach and Bashford pictured the fusion of the nuclei of adjoining
tumor-cells, and Schleich thought that endogenous cell formation consti-
tuted a form of cell infection which accounted for overgrowth.

Neoplastic vs. Inflammatory Hyperplasia. — Neoplastic hyperplasia is
usually more rapid than the multiplication of cells in inflammation, or re-
generative growth. Lymphosarcoma of a few months' growth may reach
a bulk constituting a large portion of the bodyweight. Carcinoma of the
liver may largely replace the tissue of this organ in a brief period. In the
terminal stages of many malignant tumors growth is much accelerated so
as to divert much nutriment from the other tissues. This rapid growth is
associated with a great abundance of mitotic nuclei in the tumor-cells which
often far exceeds that seen in any inflammatory process.

Yet rapidity of growth is not an essential distinguishing feature of
tumor processes. Few tumors grow as rapidly as the fetus in utero.

Leucocytes multiply with great rapidity in pneumonia; and epithelium
covers denuded skin far more actively than the growth of such cells in many
epitheliomas.

A more important distinction of tumor growth is found in its progressive
tendencies. Tumors commonly grow to a bulk far exceeding the limits
of any inflammatory or physiological process affecting the same area, and
they continue to grow to whatever extent nutrition is provided. Physiolog-
ical regeneration observes a certain adaptation to the function of the
organ; inflammatory overgrowth is measured by the intensity and duration
of certain irritants and ceases when these irritants are removed; tumor
'growth ignores all these limitations and ceases only with the death of the
patient or the curtailment of blood-supply. Yet there are cyclic variations
in the growth of tumors, periods of activity being followed by standstill or
regression.

Indeed there appears to be a natural limit to the growth of some tumors
in some subjects. Progressive fibrosis brings some cancers of the breast
to comparative quiescence in an innocuous scirrhus form, and the meno-
pause marks the acme of growth of some uterine myomas, and has been
followed by the spontaneous regression even of cancer of the breast (Watson-
Cheyne).

The frequency of tumor regression in lower animals, the increasing number
of spontaneous regressions in human} tumors (Czerny), and observations of

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY

the unhindered growth of tumors over many years in old persons, indicate
that limitless growth is not a power possessed by all malignant tumors. The
universal employment of surgical measures renders this fact less obvious
than it might be.

The morphology of neoplastic hyperplasia differs from inflammatory
overgrowth and physiological regeneration. A productive inflammation
is usually a diffuse process involving a whole organ or tissue area and it grades
off insensibly into normal tissue (chronic mastitis), while a neoplasm is
usually circumscribed on account of its origin from an isolated group of cells
(fibroma mammae). Productive inflammation involves all the elements of a
tissue; tumor processes usually reside in a single-cell type. Inflammatory
neoplasia is confined by narrow limits, which in tumors are very wide.

1 •' -.' *

FIG. 5. — Mammary cancer. Spontaneous local regression, with formation of fibrous tissue,
calcific granules, and fatty crystals.

Tumor-cells show the features of anaplasia, loss of specific form, and of
polarity, variation in size, nuclear hyperchromatism, multiformed nuclei
and atypical mitoses, all of which are absent or less marked in inflammatory
hyperplasia.

Yet inflammatory overgrowth passes by insensible gradations into neo-
plastic hyperplasia. This significant principle of pathology has an important
and yet a limited application. As a rule tumor growth differs sharply from
any inflammatory hyperplasia affecting the same tissue, but there are excep-
tions to this rule.

(a) There are inflammatory hyperplasias of the bone-marrow cells,
leukemic processes with some of the features of a neoplasm, and chloromas
which are true tumors of marrow-cells. Most cases fall clearly into one

42 NEOPLASTIC DISEASES

of these categories but others are intermediate in type and it is difficult to
determine whether they are strictly inflammatory or truly neoplastic.
Similar intermediate grades of hyperplasia, difficult to classify, are occasion-
ally encountered with nearly every tissue cell in the body.

(b) A process beginning as a simple inflammatory hyperplasia may in
the same individual gradually assume neoplastic properties.

In the thyroid gland of goiter, especially in fish, in the prostate gland of
hypertrophic prostatitis, in the uterine mucosa of a glandular endometritis,
in the mammary gland of chronic mastitis, and in the lymph-nodes of Hodg-
kin's granuloma, are occasionally seen transformations of a functional or
inflammatory hyperplasia into a more or less typical neoplasm. Here it
would appear that a hyperplastic process incited by external irritants may
continue and increase long after the removal of the irritant. As with certain
chemical reactions so with pathological processes the importance of momen-
tum must be recognized.

It may be objected that when a neoplasm appears in the course of in-
flammatory hyperplasia something new is added.

This objection may be valid for certain cases where the neoplasm appears
suddenly and in widely different form from that exhibited by the preexisting
hyperplasia, but not for other cases in which observation shows the change
to be gradual. Since with every increase in quantity there is a change in
quality it is reasonable to expect that gradually accumulating tendencies
in the life of the cell may express themselves at times in quite sudden and
radical changes in morphology and behavior. All these considerations
strengthen the view that the "precancerous condition" is of wide occurrence
and of much theoretical and practical importance in oncology. In this condi-
tion one finds tissues and cells in a state of overgrowth intermediate between
inflammatory and neoplastic hyperplasia, exhibiting certain tumor characters
which must be judged from different standards for each tissue, and which
experience shows are often followed by genuine and usually malignant
tumors.

The theoretical distinctions which a general survey establishes between
neoplastic and inflammatory hyperplasia are sharp and fundamental but
these distinctions fail us when we have to search for them in processes of
doubtful nature. Here we assume them to exist from our general knowledge
but we cannot prove their presence.

Thus as Borst assumes, inflammatory overgrowth results from exagger-
ated response to external irritants while neoplastic growth arises from loss of
normal restraints to growth. The one is purposeful, organized, self-limiting,
typical, accelerated hyperplasia, while the other is baneful, lawless, pro-
gressive, atypical degenerative growth excess. But this is a composite
picture and the practical problem is to decide how much it is reflected in
individual doubtful cases. Virchow recognized this difficulty and some ob-
servers, finding it insurmountable, have concluded that there is only a differ-
ence in degree between healing of wounds, inflammatory hyperplasia and tumor
formation (Brosch, Fabian).

This view cannot be accepted. Inflammatory hyperplastic processes
pass by insensible gradation into neoplastic growth according to our present
Analysis. Syphilitic leukoplakia becomes epithelioma, and Hodgkin's
granuloma may take on a sarcomatoid character. Yet these are complex
processes and although we cannot detect when growth from external stimula-
tion is succeeded by growth from loss of growth restraints, yet theoretical
considerations require us to assume that at some point such a change actually
occurs. I have elsewhere suggested that some hyperplastic processes, owing

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 43

their inception to the influence of parasites, become at length established
and progress without the stimulus of the parasite. Here one may suppose
that the declining stimulus is replaced by progressive loss of growth
restraints, but the reasoning would still show that inflammatory hyperplasia
passes into neoplastic growth.

On the other hand I do not believe that growth restraints are fully main-
tained in some inflammatory hyperplasias. In proud flesh mechanical
restraints seem obviously defective and in hypertrophic endometritis several
signs of lowered tissue tension are visible. External stimulus and loss of
growth restraints are here combined, and it cannot be said that neoplastic
hyperplasia is wholly different in nature from inflammatory overgrowth.

Thus, however closely the processes are analyzed, the conclusion remains
that inflammatory hyperplasia passes into neoplastic.

Regressive Changes in Tumor-cells. — Tumor-cells in general suffer the
same degenerative changes as occur in other tissues but some special interest
attaches to this field, on account of the frequency and extent of these changes
in tumors, and also from the very minute analysis which has been required
because of the former interpretation of many intracellular structures as
parasites. The presence of degenerative changes in tumors is the direct result
of the activity of growth, the accelerated metabolism, and the uncertainty
of blood-supply.

Fatty degeneration is nearly constant in cancer, less common in sarcoma.
It contributes a light opaque color to tumor cords which is one of the earliest,
gross diagnostic signs of many cancers. It seldom reaches an extreme degree,
the fat being commonly limited to fine droplets which first appear about the
nucleus.

It is most prominent in tumors of glands which normally secrete fatty
substances as in adenoma sebaceum, adrenal tumors, and cancer of the
breast. In rapidly growing, well-nourished tumors the active metabolism
is unfavorable to the deposit of visible fat, which appears chiefly in areas of
necrosis.

The chemical nature of the lipoids of tumors is no better known than is
that of the fats in other conditions. In a series of cancers Pianese could find
no fat blackening with osmic acid.

Stains by Sudan III and Scharlach R commonly reveal many fine fat
droplets in such tumors. To what extent the fatty degeneration of tumors
belongs in the class of lipoid or myelinic degenerations has not been deter-
mined, but Kaiserling and Orgler found myelin droplets in the cells of many
cancers and sarcomas.

White has described several varieties of fatty crystals occurring in frozen
sections in and about the cells of carcinoma, sarcoma, and adenoma. Some
of these were large plates or needles which did not melt readily and which
he regarded as cholesterin.

Smaller needles which melt and solidify into globules on cooling he identi-
fied as fats. Other small needles and anisotropic crystals were classed as
mixtures of cholesterin with lecithin and as myelin forms. The crystals
seem to be associated with cell-growth rather than with degeneration and
White suggests that they are in some way concerned in the regulation of
cell-growth.

Hydropic degeneration occurs in the edematous portions of both benign
and malignant tumors, and affects both nuclei and cell bodies.

It is seen in marked degree in the lining cells of cystic adenoma and in the
cells of any tumor that is constantly bathed in fluids as in papillary epithe-
lioma of the bladder. Exfoliated cells lying in tissue spaces are commonly

44 NEOPLASTIC DISEASES

ballooned out with imbibed fluids. Virchow's "physaliden" were in part
hydropic vacuoles in nuclei or cytoplasm which in the fresh condition
appeared hyaline but on hardening yielded a central granular or homogene-
ous mass.

Glycogenic degeneration of tumors has been carefully studied by several
observers. According to Gierke it appears in tumors under the same condi-
tions as in other cells. These are mainly as a primary physiological con-
stituent of actively growing or embryonal cells and as a secondary result of
disturbed nutrition and degeneration. In the former class it would naturally
characterize malignant, rapidly growing and embryonal tumors, and in the
latter it would be associated with and have much the same significance as
fatty changes. Observation has shown that glycogen is commonly found in
most rapidly growing tumors (Best), but in very variable quantities, and
some malignant growths as breast cancer are usually free from it. In endothe-
lioma it is very constant and abundant (Gierke). In 1544 tumors Lubarsch
found glycogen in 477, 29 per cent. Fibroma, osteoma, glioma, and heman-
gioma were constantly glycogen-free; lipoma and lymphangioma and ade-
noma nearly always so. The more certain the embryonal nature of the
tumor the more constant was the presence of glycogen. Thus in teratomas,
hypernephromas, and choriomas it was present in all cases and usually
abundant. It was about equally common in sarcomas (50.7 per cent.) and
carcinomas (43.6 per cent.); in squamous cell epithelioma 70 per cent.

Four factors seemed to Lubarsch to chiefly determine its occurrence.

1. An origin of the tumor from embryonal cells.

2. An origin from cells normally containing glycogen.

3. The absence of mucous and colloid degeneration, and frequent presence
of fatty changes.

4. The presence of numerous delicate blood-vessels in intimate relation
to the parenchyma.

Secondary glycogen deposits appear in necrotic areas and about the
inflamed edges of tumors which are elsewhere free from it (Best). Brault
thought that glycogenic degeneration sometimes preceded mucous changes
in mucoid carcinoma.

Miiller concluded that actively growing, well-nourished cells contain
no glycogen, which appears in cells with feeble metabolism. The relation
of glycogen content to the prognosis of tumors was considered by Brault,
who states that in sarcomas there is no parallel between glycogen content
and malignancy, while with carcinoma the glycogen holding tumors are
regularly the more malignant. Best and Gierke, however, did not find this
rule to hold.

Mucous degeneration is a widespread and important regressive change
in many tumors. It may be a primary and essential feature of the neoplasms,
arising from exaggerated development of the mucous constituents or from
increased secretion, or it may overtake tumors whose cells have no original
tendency toward its production.

It represents the matrix of primary myxoma, the secretion of many
adenomas, and a degenerative product in chondroma, sarcoma, and carci-
noma. It is readily recognizable by the homogeneous luster and viscid
quality which it imparts to the tissue. True mucin is found chiefly in
connective tissue tumors, pseudomucin in epithelial growths. Certain
tumors are characterized by a remarkable production of mucus. Primary
myxoma of the skin consists of spindle- and star-shaped cells lying in a
matrix of homogeneous finely fibrillated material which infiltrates the sur-
rounding tissues and doubtless contributes to the local recurrence of these

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 45

growths. Some gelatinous cancers of the colon early invade the peritoneum,
spread through the cavity and produce immense quantities of firm gelatinous
material which distends the abdomen. In such cases it may be difficult
to discover any remnants of living tumor-cells, and some such tumors seem
to reach a standstill through excessive production of mucus. Cancer of the
stomach may yield a localized growth or diffuse infiltration of the stomach
wall in which are found scanty groups of tumor-cells widely distended by
mucus.

Adenoma of the ovary may yield cystic tumors of very large dimensions
composed of cysts distended by fluid containing large quantities of pseudo-
mucin. Mixed chondroma of the parotid commonly shows areas of cartilage
verging into myxoma, and recurrences of the tumor may eventually assume
the type of pure myxoma. Actively growing lipomas are occasionally over-
taken by diffuse mucoid degeneration.

Intracellular mucous globules are observed in a wide variety of tumors
in which the process fails to make headway. As a rule, when mucous
degeneration overtakes a tumor, while a rapid increase in size may follow,
the tumor has reached the acme of its cellular activity and its malignancy
is reduced. Since the nuclear constituents of the cell are chiefly concerned
in mucus production, the appearance of intracellular mucous degeneration
usually indicates a process intimately affecting the vitality of the cell.

Hyaline changes in cells, vessels and stroma, are the most common forms
of regressive process occurring in tumors. Firm, homogeneous, acidophile
material arises from the connective tissue elements and vessels of the stroma,
from the tumor-cell cytoplasm, and from exudates and secretions. Pro-
nounced grades of the first type are seen in keloids, fibroma, fibrocarcinoma,
endothelioma, and angiosarcoma.

It may strongly influence the course of the neoplasm, usually appearing
in slowly growing or regressing tumors to which qualities it contributes.
Atrophy of cells usually keeps pace with the progress of hyaline changes,
so that large tumors may be converted into nearly stationary growths com-
posed largely of hyaline masses.

In some angiosarcomas the walls of vessels are converted into hyaline
rings sheathed by ill-nourished tumor-cells. Calcification of these hyaline
vessels produces the sand grains of psammoma.

Intracellular hyalinosis produces a wide variety of intracellular structures
which have been studied and elaborately depicted by Pianese. A some-
what special variety is the keratinization of squamous cell epitheliomas,
in which group the appearance of hyaline globules, rings, and vacuolated
bodies, within or about the nucleus, in the cytoplasm, or involving the cell
borders, produces bizarre structures, many of which were once interpreted
as parasites. Exudates and secretions becoming inspissated contribute a
large portion of the hyaline material in some tumors. "Mulberry cells"
containing small nuclei and many large acidophile globules resembling red
blood-cells occur in certain tumors and in other conditions. Their appear-
ance suggests an origin from englobed red cells or from intracellular hyaline
degeneration. Weber depicts them in a case of myeloma, and I have found
them very abundant in cancer of the stomach. True amyloidosis has been
described by many authors in a variety of tumors, as carcinoma of esophagus
by Wagner, tumor of the bladder (Billroth), carcinoma and sarcoma of
larynx (Burow), carcinoma of lung (Langhans), chondroma of lung (Siegert),
carcinoma of breast (Aoyama) and endosteal sarcoma (Hildebrandt). Some
fibromas or sarcomas of the larynx are characterized by the development of

46 NEOPLASTIC DISEASES

large masses of amyloid. Usually the amyloid masses have a concentric or
radial striation.

Colloid Degeneration. — Homogeneous, semisolid, acidophile material occurs
in many tumors in large intercellular masses and in small intracellular
globules. The largest collections are seen in ovarian adenomas, in which the
ordinary 'mucin may present the qualities of firm colloid. Thyroid tera-
tomas containing little else than thyroid tissue with distended alveoli are
frequent in the ovary, and some ovarian adenomas, not of thyroidal nature,
may show considerable masses of colloid substance. Carcinomas in various
situations may present cylindrical intra-alveolar masses of colloid approach-
ing the appearance of thyroid tissue. Colloid appears in the cells of many
tumors in the form of globules of rather dense strongly acidophile material.
These structures are one of the chief sources of Russell's fuchsin bodies.
Colloid droplets may appear in well-nourished mitotic cells or in cells showing
advanced stages of other forms of degeneration.

Miscellaneous Peculiarities of Tumor-cells. — Besides the well-defined
types of degeneration tumor-cells exhibit a wide variety of alterations which
have been subjected to close scrutiny but which it is difficult to interpret
and classify.

These changes affect both nucleus and cytoplasm.

In the highly developed tumor-cell nucleus may be distinguished five
elements:

1. Nuclein, a nucleoproteid, composing the chromatin which appears
in densely basic staining clumps, normally arranged along the periphery of
the nucleus or as an intranuclear network.

2. Paranuclein, an acidophile substance composing the nucleoli.

3. Linin, or plastin, an achromatic substance forming an intranuclear
network.

4. Amphipyrenin, which some authors describe as constituting the
nuclear membrane. It is distinguishable from linin. According to Albrecht
the nuclear membrane is a lipoid substance.

5. Nuclear fluid, filling the meshes of the nuclear network.

As compared with normal cells all of these nuclear structures may.be
much more abundant in tumor-cells. In giant-cells especially those of
myogenous origin, and in various sarcomas and epitheliomas, the nuclei
reach astonishing proportions from hypertrophy chiefly of nuclein. In
epitheliomas great excess and multiplicity of paranuclein bodies is somewhat
characteristic, while in endotheliomas the nucleoli are relatively small.
Shrinkage and pyknosis of nuclei occurs in degenerating and necrosing areas
of many tumors. Wide distention from imbibition of fluids may accompany
hydropic degeneration of the cytoplasm. Rarefaction of nuclein masses
may result in a pale diffuse stain of the thickened chromatin network. Or
the chromatin may appear in very thin strands eventually disappearing in
complete karyolysis. A common appearance in carcinomas is the presence
of several discrete blocks of chromatin lying irregularly in a nucleus devoid of
chromatic membrane. The various stages of karyorrhexis may be followed
in degenerating or necrosing cells. The fragments of chromatin thus result-
ing may be scattered in the cytoplasm and remain pyknotic or become
vacuolated or surrounded by cytoplasmic vacuoles or become dissolved.
Extrusion of chromatin into the cytoplasm may result in the appearance of
many basophile granules in the cell. The chromatin or linin may break up
into many fine rings within the nucleus and these be discharged into the
cytoplasm, as observed by Schuller and interpreted by him as the forms of an
intranuclear parasite.

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 47

Under the term pseudo-adipose and cystic degeneration of nucleus
Pianese described the appearance of homogeneous spheroidal, brownish,
achromatic globules in the nucleoplasm, occurring especially in tumors of
the liver. This author also describes a hyalinosis of the nucleoplasm which
results in a transformation of part or the whole nucleus into a hyaline mass.

Fragmentation of the nucleus with formation of pseudonuclei occurs
in many giant-cell tumors. In melanoma the nuclei often contain large
masses of homogeneous material in which appear all stages of the formation
of granular pigment.

In the cytoplasm of tumor-cells the early stages of degeneration, hydropic,
mucous, lipoid, fatty, glycogenic, colloid, hyaline and calcine yield a great
variety of distortions of the cell structure and abnormal granules, rings,
globules and complex masses most of which are identified by appropriate
technics. The complex morphology of these products is illustrated in the
extensive literature on the pseudoparasites of cancer, especially in the work
by Pianese. Many of the bodies, especially those of epithelioma, I have found
duplicated by diphtheria toxin necrosis of the corneal epithelium.

FIG. 6. — Bird's eye inclusions in cancer-cells. (After Le Count.)

Phagocytosis by tumor-cells yields many intracellular bodies as from
red blood-cells, leukocytes, other tumor-cells, bacteria, pigment, and foreign
bodies, all in stages of degeneration. Meser found throughout a deep cancer
of the breast lycopodium seeds which had penetrated the tumor from the
dressing and had been englobed in the cells.

Multiplication of centrosomes with their surrounding archoplasm may
yield a number of cytoplasmic bodies containing a central chromatic point,
and a rim of condensed protoplasm more or less separated from the remaining
cytoplasm. Hansemann found as many as twenty centrosomes in one can-
cer-cell with multipolar mitosis. In normal cells the occurrence of multiple
centrosomes has been abundantly shown by many histologists; Heidenhain
counting as many as one hundred in a giant-cell of the rabbit's marrow.

Comparing the centrosomes of the guinea-pig's spermatocytes with
structures in cancer-cells, Borrel has shown that multiple centrosomes are a
prolific source of the peculiar bird's-eye inclusion of Leyden which he and
many others have regarded as a parasite. He finds that the centrosomes of
cancer-cells may appear as chains or congeries of chromatin granules without
special protoplasmic mantle or as multiple chromatic granules with well

48 N EOF LA STIC DISEASES

segregated and somewhat differentiated cytoplasm, or as single swollen
chromatin bodies with large cytoplasmic masses lying in cell vacuoles.

LeCount's observations support Borrel's interpretation of a large class
of intracellular bodies in cancer. Benda in dissenting from this view was
able to show the presence of normal centrosomes in cells containing the bird's-
eye inclusion, possibly from some other source than centrosomes.

Accumulation of secretory products greatly modifies the appearance of
many tumor-cells and produces some structures which have been interpreted
as parasites. Since the secretory activities of glandular epithelium are
closely associated with that portion of the cell containing the centrosome, the
presence of chromatin in many cancer bodies is perhaps not an argument
against the origin of these bodies from secretory processes. That such an
origin accounts for many of the peculiar structures in cancer-cells has been
maintained by many observers. Pianese thus explained the majority of
the bodies of the Thoma-Sjobing type which were small perinuclear bodies
with relatively large chromatin granules. According to Greenough the
characteristic bird's-eye inclusion of cancer-cells is practically limited to
glandular carcinomas and is chiefly the result of secretory processes.

He found them nearly constantly in breast cancers, but absent in sarcomas
and epitheliomas.

Somewhat similar conclusions have been reached by Nosske, Honda and
Klimenko. As a rule these authors found the typical inclusions in slowly
growing cancers in which secretory function may be assumed to persist.
In position they usually lie between the nucleus and the alveolar lumen
(Greenough). They vary in size from minute globules to masses distending
the cell. Stains show a central basophile portion which may be of large size
or may be absent, and a rim of protoplasm which may be granular, or radially
striated, or surrounded by a condensation capsule. While Plimmer stated
that these bodies occur in enormous numbers in rapidly growing cancers,
chiefly in the growing edges, later observers have not confirmed this state-
ment but have found them in moderate numbers, chiefly in slowly growing
tumors, and well within the edges. Apolant and Embden noted very few
inclusions in mitotic cells, an observation which accords equally well with
the secretory origin as with the centrosome theory.

Thus the specific bird's-eye inclusions of cancer-cells, first described by
Virchow, suggested by Foa as a possible parasite, appropriated and variously
described by Thoma, Soudakewitsch, Leyden, Plimmer, Ruffer and Walker,
and finally defended by Feinberg, must be ascribed to two main sources,
multiplication of centrosomes and secretory processes in which centrosomes
are probably concerned. The chromatin element of these bodies favors their
origin from centrosomes, while the location in the cell and the morphology
and occurrence chiefly in glandular carcinoma support the theory of retained
secretion.

STRUCTURE AND GROWTH

The composition of tumors and the characteristics of their growth present
many variations from the normal standards.

Some tumors, called histioid, reproduce simple tissues and are composed
of a single and uniform parenchyma.

Others, called organoid, are of more complex architecture consisting of
tumor-cells supported by normal stroma and blood-vessels, and reproduce
the structure and preserve more or less the function of organs. The extremes
of these types are well defined, as lymphosarcoma versus adrenal adenoma,
but the great majority of tumors reveal some organoid characters.

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY

Homotypic or homologous tumors reproduce the structure of the tissue
in which they arise (adenoma of breast) ; heterotypic or heterologous growths
differ in structure from the tissue in which they grow (chondroma of breast).
Tumors may reproduce the structures of adult organs, and tumor cells
may preserve the characters of adult cells, as in epithelioma of the lip, and
these may be termed adult tumors. Others arise from groups of embryonal
cells whose adult characters they never reproduce and these are conveniently
termed embryonal. Examples are the socalled fetal adenoma of thyroid,
and many teratomas of testicle and kidney. Such embryonal tumors are
to be distinguished from those which, because of extreme metaplasia, differ
widely from the originating structure. The organoid homotypic and adult
characters tend to disappear as growth proceeds more rapidly and in meta-
stases and recurrences, or in different parts of the same tumor. In ordinary
cancer of the breast there may be wide variations in these. qualities.

FIG. 7. — Peritheliomatous structure assumed by

curettage.

adenocarcinoma of uterus following

Adamantinoma in successive recurrences may change from an adult
acanthoma through an adenomatoid growth to a highly malignant tumor
composed of closely packed, indifferent round and polyhedral cells.

Chondro-epithelioma of the parotid of comparatively adult type may recur
as pure atypical myxoma. Recurrences after operation may differ widely
from the original structure. I have observed typical perithelioma after
the removal of adenocarcinoma of testis, and in a uterus removed shortly
after curettage for typical adenoma malignum I have found a spindle-cell
tumor of perithelial type.

Wholly spontaneous changes are illustrated in adenocarcinoma of adrenal
which may invade the liver under the form of diffusely growing large cell
carcinoma.

In normal growth cells maintain a certain quantitative relation to the
other elements of the tissue of origin, and they have an orderly arrangement

50 NEOPLASTIC DISEASES

and a polarity toward each other and to contiguous structures, but in tumors
there is a progressive loss of these relations. Even in benign tumors as in
chondroma, the cells are in excess over stroma and their relation and position
are altered.

Some adenomas, as of thyroid and stomach, show a remarkable preserva-
tion of normal structure even while proving malignant, but in most pro-
nounced blastemas cells increase enormously over stroma, eventually
relations between individual cells and between cells and stroma are lost,
and the cells grow diffusely. Several notable characters of tumors are
dependent upon the gradual development of these tendencies. Benign
tumors retain much of the tissue organization, grow from their own resources,
provide themselves with their own stroma and vessels, and push surrounding
tissues before them and remain encapsulated.

In malignant tumors the cells increase in number and size, become dis-
placed from natural connections, lose their polarity and invade and destroy
surrounding tissues.

Lining cells grow outward into polypoid projections, drawing blood-
vessels with them, or downward forming compressed pearls or convoluted
cords; gland alveoli elongate and widen, or sacculated projections from sides
or fundi produce simple tubules, or cystic or cofnplex adenomas; diffuse
masses of cancer or sarcoma cells disorganize the normal structure and force
their way into neighboring spaces, alveoli and vessels. The demands for
nourishment lead to formation of elongated vessels sheathed with tumor-
cells producing the arrangement of perithelioma, which may appear in many
varieties of tumors where the cells are pressed for food.

Necroses arise where nutrition fails. Finally, the disordered cells pene-
trating lymph- and blood-vessels, become loosened and pass into the circula-
tion, lodging into adjacent lymph-nodes or distant organs, giving rise to sec-
ondary tumors.

Many of these characters of tumor growth must be referred to mechanical
crowding of cells, and the demands for nutrition, influenced by whatever
remnant of tissue organization the tumor may retain.

The local extension of malignant tumors gives rise to many changes in the
invaded tissue and reveals many specific qualities of tumor-cells.

Local extension involves the passage of tumor-cells first into tissue spaces
and lymph radicles. Whether tissue spaces directly communicate with
lymph radicles (Recklinghausen), or lymph radicles form a series of closed
anastomosing channels (Ranvier), there is no doubt that inflammatory and
degenerative processes soon open the lymphatic vessels to the tumor-cells.
From this point the ameboid properties of the cells (Klebs, Waldeyer),
mechanical pressure, and the natural course of fluids facilitate the progress
of the tumor toward the larger lymph-vessels and nodes. Invasion of the
terminal vessels occurs through the communication between the lymph and
blood capillary plexuses (Sabine).

Through gland ducts, renal tubules, bile ducts, bronchioles, and tubular
structures also, as well as through vessels, local extension may occur.

In muscle, extension of tumor-cells is affected by the muscular contrac-
tions, and especially in pyloric cancer the extension may be widespread before
any local tumor develops. Blumenthal attributes the invasive properties
of tumor-cells to their proteolytic enzymes which he conceived as dissolving
the tissue barriers, but neither the histology of the process nor the known
capacities of tumor ferments support such a view.

Inflammatory reaction frequently meets the invasion of tumor-cells.
This is usually of a low grade, causing the appearance of lymphocytes, large

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY

mononuclear leukocytes, plasma-cells, and in certain cases polynuclear leu-
kocytes. It is a highly significant feature of malignant tumor growth and
must be regarded as a defensive process. Well-marked reaction signifies a
pronounced capacity to limit the tumor growth but not that the effort will be
successful. Yet about many epitheliomas which are making little progress
one finds a thick barrier of lymphocytes. In carcinoma o.f the breast one
may find islands of tumor-cells inclosed in masses of lymphocytes and
presenting clear signs of degeneration.

It is probable, as Orth concludes, that some degeneration of tumor-cells
always precedes the tissue reaction.

Very actively growing malignant tumors and their late metastatic
deposits often fail to show any inflammatory reaction, but the majority
of infiltrating growths elicit considerable cellular response from invaded

FIG. 8. — Diffuse lymphocytic infiltration in a rapidly growing carcinoma of breast.

tissues. Degeneration and calcification of tumor-cells, formation of macro-
phages from fibroblasts, endothelium, and leukocytes, and appearance of
giant tumor-cells, accompany the process.

Besides the general inflammatory reaction, which fails only in very rapid
invasion, the different tissue cells exhibit interesting reactions against
tumor-cells.

Striated muscle-cells exhibit a relative immunity to many cancers which
infiltrate the perimysium while long sparing the muscle-fibers. Eventually
the sarcolemma is penetrated and the tumor-cells pass rapidly along the
sheaths, absorbing the muscle substance, hollowing out central portions of
fibers, causing fatty and hyaline degeneration, fragmentation, swelling of
ends of fibers with formation of giant-cells, and exciting proliferation of
nuclei of sarcolemma and muscle-cell (Fujinami) .

52 NEOPLASTIC DISEASES

Smooth muscle-cells also are rather resistant but are frequently destroyed
chiefly with simple atrophy.

Specialized gland epithelium is usually passive before the attack of
invading tumors. The cells degenerate and atrophy, the membrana propria
often persisting to inclose pseudo-alveoli of tumor-cells. Gland ducts are
often rilled or distended with tumor-cells which replace the lining cells or
stimulate them to feeble multiplication.

Squamous epithelium tends to hypertrophy when invaded by alien
cells, with thickening of the Malpighian layer, formation of new papillae
and hyperkeratosis. With melanoma the swollen hyperchromatic and pig-
mented epithelium is often difficult to distinguish from the tumor-cells.

Endothelium usually degenerates, exfoliates and disappears, or forms
macrophages. In blood-vessels it may proliferate and assist in the formation
of stroma.

In connective tissues where the changes are not obscured by inflammation
the invasion leads to degeneration, compression, and atrophy of fibroblasts,
swelling, edema, fragmentation and solution of fibrils and matrix, and de-
struction of elastic fibers.

In many organs preexisting stroma, vessels and trabeculae, may long
persist, as in the lung where the air vesicles may be passively filled with
invading tumor-cells. Strongly encapsulated organs as testis, kidney,
lymph-nodes, spleen, may long resist invasion and rupture by tumor-cells.

Reactive growth of invaded connective tissue plays an important
part in the course of desmoplastic tumors. In scirrhus and metastatic
carcinoma it may far exceed the bulk of tumor-cells and may eventually
lead to complete scarring of large quiescent areas once the seat of active
proliferation.

In fat tissue cells penetrate readily, replace the fat in the tissue cell
envelops, incite mucous degeneration, form foreign body giant-cells about
free fat, and sometimes induce proliferation of fat-cells.

Periosteum and perichondrium may successfully resist invasion from
without, but when the element of pressure is added they yield to the invading
cells. From within the attack on bone is more rapid. The matrix is
absorbed, the tumor-cells forming lacunae like osteoclasts, dissolving cancel-
lous tissue, and in many cases of myeloma, sarcoma and metastatic hyper-
nephroma and carcinoma, perforating the shaft. New blood-vessels accom-
pany these inroads and new fibroblasts act as osteoclasts, facilitating the
absorption. Formative osteitis accompanies many tumor processes in bone.
Located in periosteum it may lead to bony encapsulation on the periphery
keeping pace with bone absorption within. Epithelial tumor-cells invading
bone are usually free from new bone formation but in a group of carcinomas,
especially of the prostate, bone-cells are excited to extensive proliferation
possibly even to the extent of a secondary tumor growth. Such cases are
wholly different from the tumors originating in bone-cells and yielding the
extensive group of bone sarcomas. In certain very vascular tumors the bone
is passively absorbed and replaced by large sinuses lined by giant-cells.

Nerve-trunks owing to their rich lymphatic sheathing are extensively
invaded, especially by epithelial tumor-cells. The medullary sheaths
atrophy from pressure, the axis cylinders being the last element to disappear;
while the nuclei may feebly multiply.

In a few instances the nerve-trunks seem to lead the way in local exten-
sions especially of epidermoid carcinoma. Brain tissue is quite passive to
the invasion of tumors, suffers pressure atrophy with degeneration of all the
specific elements, while necrosis often occurs from occlusion of vessels.

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 53

In the local extension of malignant tumors the inherent momentum of
cell-growth is doubtless the chief factor. As this property constitutes the
great distinction between normal regeneration and malignant neoplasia,
its analysis is of first importance, and will be discussed under general etiology.
Here it may only be mentioned that the histological study of invaded tissues
leads to the conclusions above stated, and offers little basis for the theories
of attraxins drawing the cells deeply into the tissues, or of special toxic agents
preparing the tissues for invasion, or for the belief that inflammatory changes
greatly influence the invasive properties of the cells of an established tumor.

Functional activity in tumors may be retained in part cr exhibited in
exaggerated form. Geotropism, the quality of living cells to cover and grow
along surfaces, is shown in epithelioma, endothelioma, and adenoma. Phago-
cytosis of bacteria, leukocytes, red cells, fragments of organ cells, other
tumor-cells, even in mitotic division, bile, fatty material and foreign bodies,
is exhibited in great variety. Many tumor-cells may exhibit slow ameboid
properties, as first observed by Virchow in chondroma.

The abundant matrix in many osleo- and chondrosarcomas, the mucus of
myoma, fat-cells in liposarcoma, and the rigid alveolar structure of adenoma
destruens even in metastases, are familiar indications of functional activity.

Clear examples of overfunction of tumor tissue are seen in mucous
carcinoma of the colon and in melanoma of the skin. Some tumors of the
hypophysis seem to be followed by overactivity of the influence of this gland
on growth.

While tumors destroying the adrenal, pancreas or thyroid may not be
followed by Addison's disease, diabetes, or myxedema, yet the functional
capacities of such tumor tissue have not been demonstrated by chemical
and physiological tests, and the absence of specific disease with these tumors
may be referable to the wide limit of safety of the organs involved or the
presence of aberrant glands. Hansemann reports complete destruction of
the pancreas by carcinoma without diabetes although diabetes is common
with cancer of the pancreas. The early bilateral adenomas of the adrenal
may very well fail to give Addison's disease, but I have seen complete destruc-
tion of both adrenals by diffuse hypernephroma with bulky metastases but
no signs of Addison's disease. The disease was rapid and no search was made
for aberrant adrenals.

Tetany followed extirpation of one-half of the thyroid for cancerous goiter
by v. Eiselsberg, but disappeared on the development of a metastatic focus.
When this focus was removed the symptoms of tetany recurred, in spite of
new metastatic growths, these, Hansemann suggests, being more anaplastic.
Since a large portion of the thyroid was not removed and since the symp-
toms suggest involvement of the parathyroid rather than the thyroid T
think the interpretation of this case is very uncertain. Many thyroid
adenocarcinomas contain colloid and functionate, but it is difficult to find
any histological traces of functional activity in true cancer of the thyroid.

Adenoma and primary carcinoma of the liver usually fail to show traces
of bile formation, yet Heller observed bile in the cells of a pulmonary metas-
tasis from liver cancer. Hansemann found bile in the adenomatous portion
but none in the carcinomatous areas of an adenocarcinoma of the liver.

Chemical studies in general support the view that many tumors retain
some of the function of their parent cells, as shown by the high content and
qualities of lipoids in hypernephroma (Wells) and the considerable content
of iodine in thyroid cancer (Beebe, Ewald). As a rule, functional activities
diminish with increasing anaplasia, and original overactivity may be sue-'
ceeded by complete failure, as in the pigment-free metastases of melanoma.

54 NEOPLASTIC DISEASES

Stroma.- — benign or encapsulated tumors provide themselves with a new
stroma, while infiltrating growths appropriate and alter the preexisting
stroma of the invaded tissue. In sarcoma it is usually much less abundant
than in carcinoma and may consist entirely of blood-vessels, while in cancer
it is more abundant and fails only in very anaplastic growths. In sarcoma
a fine intercellular stroma is in some degree constant but may be difficult
to demonstrate. In carcinoma the cells are in immediate apposition without
intervening fibrils. Endothelioma reveals its close embryological relation to
sarcoma by fine fibrils which imperfectly penetrate the cell masses (Woolley).

In benign organoid tumors the neoplastic process is usually limited to
one type of cell, in adenoma to epithelial cells, and the new stroma results from
a formative influence on the cells of the connective tissue and vessels asso-
ciated with cells originating the tumor.

Mechanical influences may be prominent in the behavior of this stroma
or the cells may show active mitosis, and even participate in the tumor growth.
Thus stroma may have adult characters, or as in fibro-adenoma it may be
difficult to determine whether the epithelium or the stroma cells dominate
the neoplastic process. In certain ovarian adenomas the periacinar stroma
may be extremely cellular, as in sarcoma.

It seems necessary to sharply distinguish between those tumors whose
stroma is clearly not neoplastic and those in which it constitutes a part of
the tumor and which must therefore be regarded as mixed tumors. In
chondro- and osteosarcoma the stroma is a combined product, consisting
of intercellular substance derived from the tumor-cells and new vessels
derived from the tumor or from peripheral tissues. In teratomatous cancer
of the testis the stroma may be richly infiltrated by lymphocytes and even
contain lymph follicles, yielding a type of stroma not seen in any other car-
cinoma. In veins the stroma of an invading tumor may consist of capillaries
arising from the vessel-wall.

Elastic fibers are seldom reproduced in the stroma of tumors and if
present belong chiefly to the preexisting tissue (Williams).

According to Bonney they disappear in all areas of connective tissue
proliferation and cellular exudation, but in isolated areas in breast cancer
he found bulky periacinar masses.

The stroma of an original growth may fail to be reproduced in metastases
with increasing anaplasia, but often reappears in typical form, as in scirrhus
carcinoma, or in the overdeveloped vessels of fungus hematodes.

The stroma of surrounding tissues may be (i) passive during the increase
of tumor-cells, or it may be incited to (2) reactive growth, and there is
considerable evidence to show that this reaction may reach almost if not
quite to a (3) neoplastic grade.

Most highly organized tissues are passive during tumor invasion, as the
liver in cancer. Very active growth of tumor-cells usually fails to excite any
reaction even from simple tissues, as in lymphosarcoma in the skin.

Apart from collateral hypertrophy as previously discussed, epithelial
tumor-cells exert a notable formative influence on connective tissue; they
are desmoplastic.

So marked is this influence that many carcinomas are composed of much
new connective tissue and relatively few cells both in primary tumors and
in metastases. Originally this action is the result of a formative stimulus of
epithelium upon connective tissue, but eventually it proves protective and
some cancerous areas undergo complete regression from overgrowth of
fibrous tissue.

An osteoplastic influence is exerted on bone tissue by some cancers,

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 55

and active budding and proliferation of muscle-cells is occasionally seen with
rare myoplastic tumors.

That the presence of a tumor may excite its stroma or surrounding tissue
to neoplastic growth has never been demonstrated. While improbable, such
an action is not impossible and has been suggested by several appearances
encountered with spontaneous and transplanted tumors. Langhans con-
sidered the possibility that teratoma testis might incite the spermatoblasts
to tumor growth in certain complex tumors of this organ.

In certain lymphocytomas it is difficult to distinguish between the
infiltrative growth, multicentric origin, and the contact influence of tumor-
cells. Haaland thought he observed the transformation of pulmonary cells
into tumor-cells about metastatic carcinoma in the mouse. Ehrlich, Loeb,
and others have observed the sudden appearance of sarcoma in the course
of transplantations of carcinoma in mice and rats, and Murray has strongly
substantiated the belief that this sarcoma arises from the stroma and not
from the altered cancer-cells.

The influence of transplantations renders these observations inapplicable
to human tumors, and several uncertainties still surround the interpretation
of this remarkable change of structure. No such stroma reaction has been
observed in spontaneous tumors, although the reactive overgrowth of invaded
tissues may at times exhibit some of the qualities of a neoplasm.

Regressive changes occur in tumor stroma very similar to those observed
in the parenchyma. In some cases these changes greatly influence the
character and course of the tumor. In progressive keloids the hyaline
stroma is the chief portion of the tumor.

Cylindroma or syphonoma, are terms applied to a tumor structure in
which the stroma appears in the form of elongated twisted thickened cords
of hyaline material. This structure is most often seen in basal cell carcino-
mas. In old regressing carcinoma large areas of tissue may show very few
tumor-cells in a mass of quiescent hyaline stroma.

Edema, mucous degeneration, and calcification of stroma are frequent
factors influencing the course of tumors.

In cancers, fatty degeneration often affects not only the parenchyma but
also the stroma. Calcification may begin in the stroma and gradually
involve the entire substance of myomas, or it may form a hard shell about
this or other growths. Solid or lamellated concretions of hyaline material
of uncertain nature are occasionally seen in the stroma as in the parenchyma.
Experimental Analysis of Slroma Reactions. — Much light has been thrown
on the meaning of the cellular reaction to invading tumors by experimental
studies on transplantable tumors.

^ The inoculation of susceptible animals with a tumor graft is usually followed by a
brief local polynuclear leukocytosis incited by diffusible products of tumor-cells, red cell
detritus, and traumatism.

An excessive degree of this reaction may prevent the graft from surviving. With
successful grafts there is later a gathering of lymphocytes in moderate number and these
may form rich foci which interfere with the growth of the tumor-cells. The graft then
becomes successfully implanted by inciting the growth of fibroblasts and capillaries about
which the cells adhere. Often the vessels of the graft are appropriated and reopened.
From this point the growth proceeds by multiplication of the transferred cells about the
new stroma derived from the host's tissues. In its further progress the tumor may become
encapsulated and thus be shielded from cellular attack, or it may early show infiltrative
tendencies unopposed by any cellular reaction.

In some conditions animals become immunized by the temporary growth followed'by
spontaneous regression of the tumor (Gaylord, Clowes). In such cases one of the earliest
changes observed is a focal degeneration of the tumor-cells accompanied by an accumula-
tion, probably from chemotactic influences, of ameboid large and small lymphocytes,

56 N EOF LA STIC DISEASES

mononuclear leukocytes, and often many plasma cells. Minute hemorrhages may occur in
the tumor about which eosinophile cells gather. These cells surround the tumor and
penetrate within it, sometimes richly infiltrating the stroma.

Then follows contraction of the tumor mass, multiplication of spindle-cells, growth of
new vessels and encapsulation of the regressing tumor. During the absorption process
the endothelial macrophages appear and giant-cells result from fusion of tumor elements.
Even to a late stage mitosis may persist in such encapsulated regressing tumors and
section of the capsule may excite renewed growth.

In immune animals the implantation of cancer excites a more active emigration of
polynuclear cells, the degeneration of parenchyma cells appears earlier and is more pro-
nounced, and the lymphocytic reaction is less marked, plasma-cells being absent (De Fano).

With a sarcoma of the hare transplanted into rabbits v. Dungern and Coca obtained
in the rabbit hypersensitization followed by complete immunity by successive implantations
of the tumor. The second or third graft excited a rich production of endothelial macro-
phages which promptly surrounded and englobed the degenerating tumor-cells, and formed
macrophage thrombi in the small vessels. Leukocytes were not prominent in this reaction.
In the adjoining lymph-nodes were many similar endothelial macrophages.

With Jensen's mouse cancer Russell found that grafts in resistant mice^ suffered ex-
tensive degeneration and the peripheral rim of surviving cells failed to excite a stroma
reaction.

Working with Japanese mice Burgess observed that in both susceptible and non-
susceptible animals tumor grafts established themselves by exciting a stroma reaction,
after which in the immunized mice the nutrition of the tumor was cut off by overgrowth of
fibroblasts with much intercellular substance.

In the interpretation of these results one may conclude that in highly immunized and
hypersensitized animals the reaction is pronounced, immediate, and exudative, preventing
the growth of new stroma or by thrombosis (v. Dungern-Coca) shutting off blood-supply.
In spontaneously immune or in alien animals the reaction is less pronounced, new stroma
forms, but later degeneration of the graft leads to strangulation by connective tissue
overgrowth.

Analyzed in the light of experimental studies, the processes connected
with the growth of tumors signify as follows:

Infiltrative growth without stroma or cellular reaction indicates absence
of protective forces in the body.

The development of vascular stroma from the host's tissues, up to a
certain degree, is favorable to the growth of the tumor.

Overgrowth of stroma with much intercellular substances is a menace to
the tumor.

Polynuclear leukocytes gather about the tumor as the result of necrosis,
trauma, bacterial processes and actively chemotactic tumor products, and
signifies a sharp response against the tumor.

Lymphocytes and large mononuclear leukocytes signify a reaction of
immunity, limiting the growth of cells, establishing local tissue immunity,
and conveying immune forces to a distance. Plasma-cells are a later factor
in the same process.

Eosinophile cells gather about hemorrhages.

Endothelial proliferation, if slight, figures as a part of the stroma reaction,
but if excessive, macrophages form and oppose cell-growth.

Degeneration of tumor areas, fusion giant-cells, and necrosis, may result
chiefly from withdrawal of nutriment.

It is obvious that most of these conclusions have been warranted by
previous study of human material, but it must be claimed that the experi-
mental studies have rendered them more precise.

Blood-vessels. — The relation of blood-vessels to tumor growth presents
two highly important aspects, first in connection with the beginning, of
cancer, and second in the channels of nutrition in the progressive growth of
tumors.

Franz Boll from a study of early epithelioma and of the growing edges
of such tumors concluded that changes in the blood-vessels determined

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 57

the proliferation of epithelium. He found the walls of capillaries thickened,
opaque and varicose. The adventitia of veins and arteries was invaded
by cells, and the vessels lost their sharp demarcation from the surrounding
tissue which took on an embryonal character.

These changes were found throughout the tumor and preceded the exten-
sion of the growth. An extensive disease of the vascular system of the whole
area involved was in Boll's opinion an essential part of the cancerous process.
The later study of the vascular system of malignant tumors, while not fully
demonstrating the prime influence of vascular lesions, has yet emphasized
the importance of the blood-supply in the origin and growth of many
neoplasms.

Theilhaber, among recent writers, has emphasized the importance of
arteriosclerosis in the origin of many cancers in elderly persons. He con-
cludes that the local predisposition of aging tissues to cancer results from a
diminution of the cellular elements and a contraction of the blood-vessels
in the connective tissue. On the other hand Warner reports a study of the
blood-vessels of 206 cancerous organs, finding that 105 (51 per cent.) showed
obstructive arterial changes, 118 (57 per cent.) fibrosis, and 85 (42 per cent.)
lymphocytic infiltration. Since normal vessels were present in almost half
the cases endarteritis could not be considered a necessary factor in the
production of the disease.

Possibly a very close analysis by various methods of the circulatory
conditions about beginning carcinomas would show a more constant relation
between this factor and carcinoma in elderly persons. On the contrary side,
increased vascularity has been demonstrated in the beginnings of many
carcinomas, and has been assumed to account for the awakening of many
cell rests. Evidently the exact relation between blood-supply and the
inception of carcinoma has not yet been elucidated.

Since the demands for nutrition in tumors exceed those of normal tissues
the significance of the vascular system is correspondingly increased. In the
older literature S. von der Kolk stated, as a result of injection experiments,
that only arteries formed anew in tumors, the veins being those which became
inclosed in the tumor.

Extensive lesions of the blood-vessels have been described by many
authors as a significant feature of tumor growth (Eberth, Belapolsky).
Virchow pointed out that the circulation in many tumors is to some degree
independent of and different from the general circulation, a fact according
with the parasitic nature of tumor growth. The difficulty of passing injec-
tion material from arteries through veins he attributed to compression,
invasion, and thrombosis of the veins and to an indirect connection of veins
with arteries.

The "saber-sheath" flat veins on the surface of many tumors result
chiefly from compression. The turgescence of enlarged veins leading out
from malignant tumors was one of the gross features giving rise to the term
cancer. Compared with the affected organ the vessels of actively growing
tumors are more numerous, dichotomous branching of the arterial system is
absent or irregular, and the main vessels are often tortuous and spirally
wound.

The vascular system may be studied by corrosion preparations, by .v-ray photographs
of specimens injected with bismuth and oil, and by Hill's method of injection with India
ink with subsequent clearing of tissues by alkali and glycerine.

From results obtained by the two latter methods Goldman observed the marked increase
in vascularity in the periphery of growing tumors, while in quiescent cases the central
portions were nearly devoid of vessels and those of the periphery reduced. The new vessels

58 NEOPLASTIC DISEASES

were usually of small size, tortuous, irregularly distributed, and the arteries rapidly broke
up into capillaries.

In the growth of blood-vessels in tumors one may distinguish two factors,
direct irritation by tumor products and a formative influence exerted by
tumor-cells. Along the growing edges of advancing carcinoma there is often
a zone of hyperemia and section shows many new capillaries and round-
cells, producing at times a structure which is equivalent to granulation
tissue. Such changes, which soon regress, may be referred to inflammatory
reaction. In the artificial implantation of tumor grafts, in the organization
of intravascular tumor thrombi, in the natural growth of angiomas, and in
the recurrence of many varieties of cellular tumors, new vessels develop
apparently as a result of a formative influence centered on the vessels of
surrounding tissues.

In many endotheliomas and some angiomas the vessels constitute the
unit of the tumor; elsewhere they are devoid of neoplastic qualities. The
structure known as perithelioma may develop solely as an expression of a
formative influence of tumor-cells upon blood-vessels, and has been observed
in angiosarcoma, fibroblastic sarcoma, hypernephroma, epithelioma, and
teratoma.

The structure of the blood-vessels varies greatly.

In some benign growths the large arteries exhibit all three coats in pro-
portions approaching the normal. In most malignant tumors muscle-
tissue is deficient in walls of arteries, and the main type of vessel is composed
of adult fibroblastic tissue lined by endothelium. In many endotheliomas
the vessels are chiefly spaces lined by tumor-cells. In adenoma of thyroid
and some primary carcinomas of the liver widely dilated capillaries lined by
endothelium produce highly vascular growths. In telangiectatic sarcoma
the capacious sinuses may be lined by endothelium backed by connective
tissue. In bone-sarcoma widely dilated sinuses are lined by tumor giant-
cells, as in the pulsating sarcomas of tibia and humerus. Finally a feeble
circulation may be maintained in intercellular tissue spaces without definite
lining cells.

Lesions of blood-vessels are frequent and important for both the tumor
and the organism. Functional inadequacy or compression of vessels is
chiefly responsible for the degeneration and necrosis of the parenchyma of
tumors.

Rupture from degeneration or trauma gives rise to hemorrhage and
infiltration with blood. Strangulation of pedunculated ovarian cystomas
or uterine myomas, cutaneous sarcomas, and even breast cancer may lead
to complete hemorrhagic infarction, necrosis, and sloughing.

Hyaline degeneration of vessel-walls yields a characteristic structure in
certain sarcomas, as in the ovary.

The vessels of invaded tissues are passively compressed or react with
periarteritis and round-cell infiltration or the walls are invaded by tumor-
cells by way of the vasa vasorum, and the perivascular lymphatics form a
channel directing the course of invading cells. Arterial trunks long resist
the attack of most tumors, but fall a ready prey to squamous epithelioma
whose cells penetrate the adventitia, split up the muscularis, occlude the
lumen, and thus cause necrosis of the invaded tissues. In such vessels the
tumor-cells may largely disappear with fibrous organization. In the veins
tumor-cells readily penetrate to the intima producing nodular swellings,
endophlebitis carcinomatosa, and eventually rupturing into the vein.

It has often been noted that very vascular tumors may long fail to develop

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 59

metastases, yet the invasion of tissue veins is the chief source of metastatic
growths in sarcoma and with many carcinomas. An intravascular position
characterizes the growth of certain tumors throughout most of their history.
Chorioma of the uterus and testis is remarkable for its limitation to pelvic,
vaginal, abdominal, and pulmonary veins. According to Marchand and
Risel other rare tumors growing in or invading the blood-vessels may imitate
the hydatidiform appearance of chorioma. Hypernephroma often passes
up the renal vein, and distends the vena cava and the hepatic veins before
generalizing. An adenocarcinoma of the liver regularly appears as a circum-
scribed growth distending the large branches of the portal vein in this organ.
Course and Rate of Growth.- — Many variations are observed in the course
and rate of growth of tumors.

1. Rapid and progressive multiplication of tumor-cells without notable
intermission or hindrance is characteristic of most highly malignant
neoplasms.

Lymphosarcoma in adult or young subjects may run its course in a few
weeks with extensive metastases in many organs. Cancer of the liver in
elderly subjects may terminate with steadily progressive symptoms in three
months. Some melanotic tumors after becoming established run a very
rapid course. Children are especially susceptible to such forms of fulminant
blastomatosis.

Pregnancy usually accelerates tumor growth. I have observed cancer
of the breast arising after gestation prove fatal, with widespread metastases,
before term. With experimental tumors pregnancy sometimes accelerates
but at others retards growth (Moreau, Loeb).

2. Intermittent periods of relative or complete quiescence occur in the
course of many malignant tumors. It is probable that such quiescence is
often more apparent than genuine. The progress of the edges of carcinomas
and the involvement of lymph-nodes often appear to be sudden and the
growth reaches certain dimensions in a few weeks after wrhich progress is
much slower. Exhaustion of growth capacities may partly account for
such cases, but usually it is referable to pressure on a distended capsule or
hindrance to the increased blood-supply. The onset of edema, hemorrhage,
retention of secretions, inflammatory complications, or central necrosis,
fibrosis, contraction, and evacuation of fluids, simulate changes in the rate
of growth. Or a primary tumor may be at a standstill while internal meta-
stases are active.

Yet apart from these conditions there appears to be a frequent tendency
in certain tumors to grow steadily to a certain bulk and then to remain sta-
tionary until trauma or other external factors initiate a new period of growth.
A definite form of intermittent growth is observed in cancer of the stomach
and epithelioma of mucous membranes which remain localized ulcers for a
time, but suddenly extend more rapidly upon the invasion of liver or lymph-
nodes. Malignant change in a benign tumor is marked by sudden accel-
eration of growth, as when myosarcoma develops on a uterine myoma.

3. A natural limit exists to the course of some tumors and the rule of
endless increase is by no means invariable. Myomas of uterus may cease
to grow at the climacteric. Warts and lipomas may be self-limiting. The
relative bulk is in part an indication of the general momentum of growth of
tumors. Thus squamous epithelioma does not as a rule produce a bulky
growth, and seldom yields bulky metastases. Epithelioma of skin or even
of esophagus may produce ulcers which after steadily growing to certain
dimensions long remain practically quiescent, and on section one finds a
firm basis of connective tissue beneath the ulcer and few or no mitoses in

60 NEOPLASTIC DISEASES

the tumor-cells. Martland has reported a mixed tumor of a salivary gland
of 20 years' duration and long stationary. The same numerous and com-
plex factors which interrupt growth may succeed in establishing a perma-
nent limit. It is also beginning to appear that a local or general immunity
may be slowly established and effectually prevent growth.

4. Spontaneous cure is observed with certain tumors under peculiar
conditions.

There is a considerable series of polypoid tumors of skin and mucous
membranes where nutrition is cut off by constriction of the pedicle and which
are either completely extruded or regress without detachment. Fibromas
and chondromas may accidentally compress their nutrient vessels with
regression or sloughing.

Within the tumor hyaline degeneration of vessels and mucous degenera-
tion of stroma and parenchyma usually retard growth and may completely
exhaust the capacity for growth. Calcification of parenchyma and capsule
may incarcerate the tumor.

Inflammation about the borders and in the body of the tumor seems to
cause the occasional extrusion of certain sarcoid growths of the skin (Ran-
dolph, Watson). Accidental infection by erysipelas has been followed by
spontaneous regression of sarcomas.

For somewhat uncertain reasons benign tumors have been known to
regress, as exostoses (Nasse, Starck) and papilloma of the bladder (Nitze).
A local or general immunity seems to be the only explanation of an increasing
list of spontaneous cures of highly malignant tumors.

Most of these cures are only partial. Among them are sarcomas, squa-
mous epitheliomas, and glandular carcinomas (Czerny).

Tripier records a case of multiple round- and spindle-cell sarcomas of
wide distribution with pulmonary hemorrhages which disappeared after the
condition seemed hopeless. The exact nature of this case is uncertain.
Kaposi has recorded the disappearance of lymphosarcoma of the upper jaw
while internal metastases were in progress, and Reichel, of a spindle-cell
sarcoma of forehead.

Some of the cures have followed persistent recurrence after operation.
(Shepherd, Watson). In dermatological literature there is a considerable
list of reported spontaneous cures of cutaneous sarcomas. While the true
nature of many of these processes is uncertain, I do not believe that they
can properly be rejected, as Williams would, from the field of neoplasms.

Spontaneous recovery from chorioma belongs in a special category owing
to the peculiar relations of this tumor. In 15 cases this process has been
known to regress after the occurrence of pulmonary or vaginal metastases,
in three of which neither uterus or vaginal nodules were removed. In 7
other cases recovery followed partial removal (Ewing).

Recovery after partial removal of ovarian adenocarcinoma is not infre-
quent. Rotter has described a case of complete cure of an original malignant
adenoma of the rectum, although after 3 years a metastasis of the iliac
bone was found at autopsy. Here a complex form of local tissue immunity
seems to have existed.

With cancer of the breast there is a group of cases in which the disease
becomes locally extensive and internal metastases form, the patient becoming
greatly debilitated, but at this stage the picture changes and very marked
improvement sets in attended with regression or even disappearance of
many tumors. Although these patients usually die of the disease they may
enjoy good health for many years. General debility cannot account for such
a course, and there seems to be no other explanation than the development

DEFINITION. CLASSIFICATION. GENERAL PATHOLOGY 61

of a relative general immunity. In MacKay's case improvement was coinci-
dent with absorption of a pleural exudate, and I have followed several very
resistant cases which were marked by continuous ascites, sometimes chyli-
form (Hodenpyl).

Somewhat similar are those cases in which primary tumors disappear
and the patient long enjoys fair health, during the very slow progress of
internal metastases (Bryant, Gould, Broca, Hutchinson).

FIG. 9. — Almost complete replacement of liver by metastatic fibrosing carcinoma of breast.
The external tumors in this patient had notably regressed.

The self-limiting tendencies of certain epitheliomas seem to have resulted
in spontaneous cure in cases reported by Sanger. Many interesting cases
of this general type are collected by Williams.

The morphology of spontaneous regression presents special characters
with each type of tumor, among which are the calcification and giant-cell
formation in epithelioma (Petersen), giant-cell degeneration in chorioma
(Teacher) (Ewing), extreme hyalinosis in cancer of the liver, and simple
atrophy of parenchyma in the large cell tumor of the testis.

CHAPTER III
MALIGNANCY AND ITS EFFECT ON THE ORGANISM

The Significance of Malignancy. — The distinctions between benign and
malignant tumors involve questions of great interest from both the theoret-
ical and the practical sides. If malignancy were a purely clinical conception
it would be impossible to draw any rigid distinctions "between benign and
malignant tumors since nearly all tumors may occasionally prove fatal. Yet
the tendency is to restrict the term to tumors which exhibit certain features
which are essentially deleterious to the host. The most important of these
features are infiltrative growth, local destructive properties, recurrence after
removal, formation of metastases, local interference with function and
general toxic action of absorbed tumor products. These elements involve
both anatomical and clinical effects.

Infiltrative growth is the most important of the anatomical factors in
malignancy. This property facilitates local and general extension, renders
removal difficult, is responsible for many recurrences, and is a constant
preliminary to the local destruction of tissue. The controlling influence
of encapsulation is seen in the harmless course of many very cellular tumors
which may readily be enucleated while circumscribed but which on rupture
of the capsule take on infiltrative and malignant properties. It is also
demonstrated in transplantable tumors which upon incision of the capsule
may be transformed from regressing into malignant infiltrative growths
(Loeb). .

During experimental increase of growth Bashford and others have shown
that originally circumscribed mouse tumors take on infiltrative qualities.
Yet Borst notes that early fibroma of the kidney showing infiltrative
growth later becomes encapsulated and the same observation applies to
myomas.

Rapidity of growth is usually associated with infiltrative qualities and
deleterious effects and if carefully separated from simple increase in size
from other causes is a nearly constant sign of a dangerous tumor. Local
destruction of tissue is a variable feature prominent only in certain types of
tumors, appearing early in squamous epithelioma, and constituting the sole
malignant quality of rodent ulcer. In benign tumors destruction of tissue
is a secondary effect of pressure. Hemorrhage from destruction of vessels
may be the chief instrument in the cachexia which marks the course of many
ulcerating tumors as in the stomach and uterus. Pain from involvement
of nerves is often the first and even the last clinical problem in the course
of a lethal neoplasm.

Formation of metastases may be held to constitute any tumor malignant.
Being usually the result of infiltrative growth, invasion of vessels, and cel-
lular character, and signifying dissemination and collapse of defensive
powers, it is the most impressive external sign of malignancy. It is, however,
by no means constant in lethal tumor processes, as in glioma, rodent ulcer,
etc., and certain tumors otherwise benign may occasionally yield distant
secondary growths, as chondroma and myoma.

Local interference with function is the chief dangerous feature of many

MALIGNANCY AND ITS EFFECT ON THE ORGANISM 63

gliomas, epitheliomas of larynx, esophagus, cardia, and cancer of the pylorus
and rectum, and many benign tumors become serious chiefly from effects
of pressure.

The general intoxication resulting from tumor growth is a complex subject
which has long been recognized as one of the most obscure and important
problems in the natural history of malignant tumors. Hemorrhage, mechan-
ical interference with nutrition, pain, the psychical condition, abnormal
secretions, destruction of important tissues, the toxic action of products
absorbed from degenerating and ulcerating areas, and bacterial infection
combine to produce the cachexia of tumors and require consideration in a
separate chapter. When the clinical signs of malignancy declare themselves
the conditions exciting them often belong to the past history of the disease
and are often irremediable.

Diagnosis of Malignancy. — The prediction of the course that a given
tumor will take is based upon two sources of information, anatomical and
microscopical diagnosis and accumulated experience regarding the usual
behavior of tumors of known histological structure. Fortunately a parallel
exists to a very marked degree between the histological structure and the
usual clinical course.

The main subdivisions of tumors into benign and malignant is accom-
plished at once and as a rule only by microscopical structure. Under some
circumstances the microscopical structure may stand alone and override
all other considerations. Far more usual is it to find the interpretation of
structure to be greatly influenced by clinical information regarding the exact
location of the tumor, its attachments, the presence of a capsule, and the
age and condition of the patient.

Pathologists and surgeons alike commonly ignore these essential condi-
tions of accurate diagnosis, a delinquency which is responsible for the wide
and firm differences of opinion regarding the relation of microscopical struc-
ture and prognosis. It must also be urged that tumor diagnosis is commonly
assigned to the relatively inexperienced, whereas the correct interpretation
of structure in the light of clinical data requires a very wide experience not
only with the general tendencies of specific structures but with the observed
clinical courses of different tumors.

A somewhat general estimate of the malignancy of tumors may be based
on the distinctions between adult, and embryonal or anaplastic growth. It
has long been recognized that the greater the variation in type between a
tumor and its originating tissue the more malignant the tumor, and Hanse-
mann has effectively emphasized this principle pointing out that the morpho-
logical evidences of anaplasia have a physiological significance indicating the
degree to which the process is freed from growth restraints and the control
of the organization. Yet here is encountered the difficulty of distinguishing
between original embryonal qualities and signs of acquired anaplasia. One
group of tumors arises from embryonal cells which have lagged behind in
development and such tumors bear an embryonal stamp. The histological
signs of this embryonal character are often difficult to distinguish from the
signs of anaplasia, and if they are wrongly interpreted an erroneous impression
may be drawn of the malignancy of the tumor. The great theoretical value
of the distinction between embryonal and anaplastic cells is not, however,
equalled in practical importance, since both types of tumors, especially the
latter, are usually quite malignant. The histological signs of anaplasia are
a cellular character, marked variations in size in either direction from the
originating cells, increase of chromatic nuclear substance, abundance and
abnormality of mitoses, and loss of polarity and diffuse infiltrative growth

64 NEOPLASTIC DISEASES

of cells. In many instances lack of reaction of the tissues against the
infiltration of tumor-cells is a significant feature. Equally important are
the general signs of exalted nutrition and vitality of the cells. Upon these
features one may safely base the estimate of growth capacity and potential
malignancy of tumors.

The clinical course does not always accord with the signs of growth ca-
pacity. Many factors besides the surgeon's knife influence the progress of
growth. One must distinguish between the potential malignancy and the
clinical course of tumors. The histological signs of malignancy measure
the potential malignancy of a tumor but the clinical course is subject to
wide variations from the position of the tumor, hemorrhage, trauma, changes
in rate of growth, bacterial infection, etc., any one of which influences may
greatly alter the course. With these important limitations it may be asserted
that there is a close parallel between histological structure and the malig-
nancy of a tumor.

In practice the most frequent source of discrepancy between histological
signs of malignancy and clinical course arises from the confusion of embry-
onal with anaplastic qualities. Some of the most malignant looking tumors,
as the congenital sarcoma of the kidney, teratoma testis, sarcoma of skin,
adenoma of thyroid, gastro-intestinal tract and other organs, and large cell
epithelioma of the skin, long remain localized and spare the lymph-nodes.
These tumors are of embryonal origin, and the growth capacities of their
abundant atypical undifferentiated cells are much below those of other tumors
whose cells show true anaplasia and increasing loss of growth restraints.
Recurrent adult and highly malignant squamous epithelioma yields cells
with little trace of pavement character, which closely resemble those of a
benign embryonal epithelioma. Here and in many other fields it is neces-
sary to know the history and to divine the origin of the tumor in order to
construct the prognosis.

Different standards apply to different tissues in estimating the significance
of cell-growth. The thyroid, liver, uterine mucosa, and lymph-nodes re-
spond readily to various stimuli and the gross and microscopical criteria
applicable to those organs cannot be employed for the breast, kidney, or
stomach.

The nature and origin of many round-cell growths are obscure and
difficult to recognize, while their natural history is imperfectly known, so
that in this group there are many apparent discrepancies between structure
and prognosis. Finally, there is a natural limit to the onward growth of
many malignant tumors and it should occasion no surprise if in advanced
stages certain malignant tumors should advance more slowly, become
stationary or even regress. Further knowledge may possibly show that
under some conditions the presence of tumor tissue is a safeguard rather
than a menace to the organism.

The transformation of a benign into a malignant tumor occurs in rare
instances. To be separated from this category are those cases in which
one element of teratoma gains the upper hand and eventually outstrips the
relatively benign portions. Apparently this event may occur at any stage
of the growth of teratomas. In a case which 'I have reported a teratoma of
the testicle containing adult thyroid, epidermoid cysts and diffuse carcinoma,
the malignant process was delayed for years. In an ovarian dermoid which
had broken into the colon, I have seen epithelioma developing from the irri-
tated epithelial surface. In another group of cases, a pigmented mole or
adrenal rest in the kidney after growing slowly for years may suddenly,

MALIGNANCY AND ITS EFFECT ON THE ORGANISM 65

perhaps after trauma, take on malignant qualities. Here the neoplastic
nature of the originating cell group may be doubted.

When an encapsulated nearly stationary but potentially malignant
tumor breaks through its capsule and grows rapidly there is no ground for
assuming a change in the quality of the tumor. Different portions of many
tumors differ widely in structure, and many apparent changes in type of
tumors rest on the mistaken conclusions of a biopsy.

The impression that the tissue of a well-established benign tumor may
after a long period take on diffuse malignant characters is based chiefly
upon observations of uterine myomas. About 3 per cent, of such tumors are
said to become sarcomatous, but the exact significance of this change has
always been subject to doubt and discussion. In the great majority of such
cases the impression that a malignant change has occurred is based on the
discovery of a myosarcoma by operation on a tumor of which the previous
history has been imperfectly traced. In a smaller proportion a very slowly
growing fibroid has been known to exist for years when it suddenly begins
to grow rapidly and on removal one portion of the tumor is found sarcoma-
tous. This portion is often connected with an ulcerated surface of the endo-
metrium, an observation which justifies the conclusion that the ulceration
and the sarcomatous change are in some way related. In other cases the
myoma has been cystic or angiomatous. Sarcomatous change of this sort
has occurred in several authentic cases (Piquand). The true interpreta-
tion of this change remains uncertain. It may be that the sarcoma results
from a new tumor process arising in the stroma; or a sarcomatous process
becomes established in the stroma of the endometrium subsequently in-
vading the myoma (W. Williams); or the more rapid growth and the cell
changes represent the natural course of the original tumor which has not
thereby acquired any new powers of growth (Borst). The enumeration of
these possibilities suffices to reveal some of the complications of this subject.

Carcinoma has been known to develop from the epithelial elements
present in many uterine fibroids, as in cases recorded by Klob, Roily, and
others. More often uterine fibroids are invaded by malignant tumors of
adjacent or distant organs, as by cancer of the endometrium, lung (Schafer),
or breast (Bender).

In the breast, cancer and sarcoma have been found in connection with
fibro-adenoma, and it appears that the malignant tumor has arisen from the
tissues of the benign. In the case of ovarian cystomas there is no evidence
to show that varying grades of malignancy exhibited by these usually benign
tumors constitute a definite change in type.

While therefore the transformation of certain benign tumors into malig-
nant forms has been shown to exist, this event is among the rare occurrences
in the natural history of tumors. In the fields where it is supposed to be most
frequent, R. Williams has shown that benign tumors are much less liable
to change of type than are the normal tissues to develop cancer. This
conclusion accords with the rule that a tumor process becomes established at
a certain momentum which it tends to maintain throughout its entire course.

EFFECTS ON THE BODY

The emaciation accompanying tumor growth has long been recognized as
one of the most significant and obscure of its many features. It may be said
to be a constant effect of both very malignant and relatively benign tumors.
It occurs early or late, with or without anemia though probably always with
diminution in the total volume of blood, sometimes with preservation of the

66 NEOPLASTIC DISEASES

fat deposits, and is preceded by distinct muscular weakness. It affects
chiefly the muscular system but also all cellular organs and tissues. Inani-
tion is undoubtedly the chief factor in the loss of weight. Mental depression
leading to distaste of food, the lowering of digestive capacity, and mechanical
obstruction to the alimentary passages, reduce the amount of food absorbed.
In six cases of uterine cancer v. Noorden calculated the voluntary ingesta at
300-1200 calories. The importance of starvation is strikingly emphasized
by the rapid increase in weight following relief of esophageal and pyloric
stenosis.

Abnormal loss of proteins figures in many cases, by hemorrhage, exudation,
albuminuria, and diarrhea. A febrile destruction of proteins occurs very
often and is a somewhat neglected factor especially in low forms of infection,
and the difficulty of securing bacteria-free tumor tissue suggests that bacterial
poisons may often be at work when not suspected. The influence of ac-
tively regenerating tissues upon the general organism has been generally
overlooked in discussions of the tissue atrophy of cancer. The exalted ca-
pacity of tumor-cells to absorb nutriment may long be successfully met by
physiological processes but there is a point, as mentioned by Cramer, when
the general body tissues begin to yield their food supply to the tumor. That
this process may actually lead to atrophy of normal tissues has been shown
experimentally by Stockard who observed marked diminution of the re-
maining arms of Medusa during the normal regeneration of amputated
arms. The restored individuals were sometimes only half as large as the
original.

The conception of a toxic destruction of protein tissues emanated from the
observations of F. Miiller, 1889, upon seven febrile cancer patients. In two
of these, pancreatic, and mammary, a toxic destruction was not apparent
but in four gastric cases the nitrogen loss was excessive and in a case of
cancer of penis with metastases, an intake of 21 gm. N., 3064 calories, failed
to balance the loss. These observations support the general belief that the
products of degenerating necrosing and infected tumors cause toxic destruc-
tion of tissues in cancer as in other diseases.

Yet the belief in a specific toxic destruction of protein tissues in cancer
has never been fully accepted. It is worth noting that Wilks in 1868 from
the study of 2000 autopsies at Guy's hospital concluded that cancer as such
does not cause cachexia. This conclusion has steadily gained support.

Many observers have failed to detect the toxic nitrogen loss described by
Miiller and verified by Klemperer. Many cases with entirely normal protein'
metabolism have been observed by Widal, Setti, Braunstein, Clowes, and
Lewin, and even a nitrogen retention has been found in cases studied by
Schopp and Moraczewski. It is possible that a correct interpretation of
these cases must consider such factors as masking of a nitrogen loss by inade-
quate excretion by the kidneys, or by the sparing action of carbohydrate diet.
Schmidt points out many resemblances between the supposed toxic destruc-
tion of cancer and that of fever, as the sparing of fat, and the high oxygen
consumption, which is yet not in proportion to the protein catabolism. Yet
these objections merely emphasize the difficulty of securing a suitable subject
for investigation, among which gastric, hepatic, intestinal, and ulcerating or
infected cases must not be included. In a case of mammary cancer which
seemed to meet all obvious requirements Benedict and Gorslin at New York
Hospital readily maintained nitrogen equilibrium and found no abnormality
in the partition except marked increase of creatin over a terminal period of
10 days. Our present knowledge derived from careful clinical study,
from observation at autopsy, and finally from chemical investigation, seems

MALIGNANCY AND ITS EFFECT ON THE ORGANISM 67

to warrant the conclusion that a peculiar toxin secreted by cancer-cells
and leading to cachexia does not exist.

This conclusion does not seem to need revision in the light of various
chemical analyses of cancer tissue (Petry, Wolf, Beebe, Schaffer), since
no new and abnormal toxic substances have been shown to exist in tumor
tissue, although quantitative variations in their split products may occur.

Tumor Ferments. — It is everywhere agreed that cellular tumors are very
prone to degenerate and that their products may cause intoxication. This
subject appears in a new phase in the study of tumor ferments. Petry
emphasized the well-known rapid autolysis of tumor tissue which he referred
to autolytic ferments. Buxton found quantitative but no qualitative dif-
ferences between tumor and normal tissue ferments.

A heterolytic action of tumor ferments has been actively claimed by Neu-
berg, Jacoby, and Blumenthal and Wolff, but I think on insufficient grounds.
None of these authors has considered the influence of bacterial or leukocytic
ferments, factors which seem to me to influence their results and to explain
their inconstancy, and warn against the hasty acceptance of the compre-
hensive deductions drawn from them. Kepinow has pointed out the obvious
defects of this work and with Miiller has shown that when free from leukocytes
and bacteria cancer tissues do not accelerate autolysis in other organs. Petry
also was unable to find evidence of specific ferment activities in the aseptic
blood of cancer. Abderhalden and his associates have endeavored to show
that the splitting of optically active polypeptids in the presence of tumor
juice follows a different course than with extracts of normal tissue, but their
results were inconstant.

The study of experimental tumors in lower animals has given additional
support to the belief in the innocency of well-nourished tumor tissues.
Especially in mice it is observed that tumors nearly as large as the animal
itself may be well borne until the moment when ulceration, infection or
necrosis occur.

The Blood in Cancer. — Changes in the blood are of interest to the student
of tumors chiefly in their relation to cachexia and to the problems of immunity.

Benign tumors exert little or no influence upon the blood and the very
slight change of the early stages of malignant tumors may be cited in support
of the view that in the beginning cancer is a local disease. Likewise in the
established stages of many malignant tumors the blood remains practically
normal in quality, and even in advanced stages there are many records
showing normal cells and hemoglobin. Cabot collected 19 cases of
gastric cancer with over five million red cells. Laache noted the same immu-
nity of the blood against the effects of a bleeding uterine carcinoma and con-
cluded that there is an individual insusceptibility to the effects of malig-
nant tumors. In some gastric cancers there may be a concentration of the
blood, probably from diminished fluid ingesta which maintains the quality.
Leichtenstern, Patrigeon, and the writer have observed cases of gastric
cancer with increase of Hb. to 100 per cent., shortly before death. Even
when marked emaciation occurs the blood may fail to deteriorate in quality,
so that Hampeln, Neubert and others speak of a marantic as opposed to the
usual anemic type of malignant disease.

Yet the great majority of malignant tumors are associated throughout
most of their course with progressive deterioration in the quality and quan-
tity of the blood. Usually this anemia takes the form of a secondary chlo-
rotic process, with loss of Hb exceeding the reduction of cells, low Hb index,
and slight leukocytosis. In a notable group of cancers of the stomach the
anemia dominates the clinical picture, and takes a secondary pernicious form.

68 NEOPLASTIC DISEASES

The sources of the anemia of malignant tumors are numerous and complex
and being variously combined must be estimated separately for each case.

Hemorrhage is the most obvious source of deterioration of the blood,
but occasional escape from its natural effects has been recorded as above.
It is quite as capable of causing emaciation as anemia. Interference with
ingestion of food leads to anemia and emaciation in cancer of esophagus and
stomach. The absorption of hemolytic agents from ulcerating and infected
surfaces and from necrosing areas of closed tumors is a chief factor in pro-
ducing anemia. Maragliano, Kullman, Bard, Polk, and many others have
demonstrated the presence of hemolytic properties in the blood of cancer.
Elsberg found that normal red cells injected beneath the skin of cancerous
subjects were soon hemolyzed yielding a characteristic discoloration of the
skin and he proposed this method as a diagnostic test for carcinoma. In
extracts of degenerating and necrosing tumors Weil demonstrated thermola-
bile and thermostabile hemolysins not differing from those obtained from
necrosing normal organs. Clinical effects of the action of such hemolysins
were observed by Bard who pointed out that in cancerous pleuritic exudates
the red cells are often hemolyzed while in other bloody pleural fluids the
red cells are intact. The presence of these circulating hemolysins may render
transfusion of cancer patients with normal blood a dangerous procedure.
Against their own serum the red cells are resistant and since the specific
gravity of the blood is usually low the red cells are resistant to hypotonic
solutions. Since hemolytic agents and variations in the resistance of red
cells are commonly present in other diseases these properties have not been
found reliable in the diagnosis of cancer.

The specific gravity of the blood in most cases does not differ from that of
other forms of secondary anemia, but in well-established cachexia the gravity
has often been found remarkably low. Dieballa, Peiper, and Moraczewski
found lower . specific gravity, 1012-1032, in cancer of stomach, than in
pernicious anemia of equal grade. The albumins of both plasma and serum
are distinctly low in such cases (Grawitz). In a case of gastric cancer
Wendelstadt and Bleibtreu found 0.79 gm. instead of the normal 2 to 2.25
gms. in 100 gm. blood-serum.

Rieder believed that the lymphocytosis of cancer resulted from accelerated
flow of lymph and Grawitz attributed the dilution of the blood to the same
factor, finding that watery extracts of cancer tissue when injected into
rabbits produced a marked increase of lymph flow.

Leukocytosis was early recognized as a very frequent condition in cancer,
having been described post-mortem by Andral in 1823, and in the circulating
blood by Lucke and Virchow about 1867. The leukocytes were long regarded
as derivatives of the tumor. Virchow referred their presence to increased
flow of lymph.

Although some disturbance of the leukocytes is very frequently observed,
the uncomplicated tumor process seems to have no capacity to attract
leukocytes to the circulation. This conclusion accords with the fact that
tumors excite no uniform local reaction. The cause of leukocytosis must
therefore be sought in some other factor than the presence of growing tumor
tissue.

Ulceration or other inflammatory complications are the most definite
causes of leukocytosis in cancer, and the resulting hemorrhage adds to the
increase of white cells seen in bleeding and necrosing tumors. Bacterial in-
fection, local and general, may intensify the effects of absorption of tissue
toxins and loss of blood.

Degeneration and necrosis of tissue and foci of cells must account for

MALIGNANCY AND ITS EFFECT ON THE ORGANISM 69

the leukocytosis of many large cellular and rapidly growing tumors. The
inflamed lymph nodes in the vicinity of malignant tumors indicate absorption
of irritants but these nodes seem to furnish few new cells to the blood since
the leukocytosis is usually polynuclear.

As a reaction of immunity may be considered the lymphocytosis asso-
ciated with certain tumors about whose edges round-cells gather in masses
but there seems to be no ground in the human subject for assuming the same
interpretation of polynuclear leukocytosis. With the onset of cachexia
the way is open for the action of many causes of leukocytosis which are as
numerous as the elements in the cachexia itself.

With these theoretical principles the results of leukocyte counting in
tumor patients offer only a partial parallel. The temptation is often strong
to assume some specific chemotactic influence residing in the tumor process
to account for pronounced leukocytosis observed in certain cases. Hayem
observed marked leukocytosis with scirrhus of the breast which subsided
after operation only to return with recurrence of the growth. In many
rapidly growing but apparently uncomplicated tumors especially in children,
pronounced leukocytosis has been observed without satisfactory explanation.
In the extensive series of blood reports of Alexander, Price-Jones, Cabot,
and others, it is not always possible to refer the leukocytosis to definite factors
apart from the tumor process. In fulminant carcinosis of breast and other
organs the disease may be actively febrile and associated with marked poly-
nuclear or mixed leukocytosis. Renal carcinoma is very frequently marked
by intermittent fever and leukocytosis. Satisfactory explanation of these
peculiarities is wanting.

Certain specific events in the course of malignant tumors may be marked
by definite changes in the leukocytes. Severe cachexia with anemia is usually
attended with the presence of myelocytes, and myelocytes with nucleated
red cells are often seen with marrow metastases. Kurpjuweit collected
13 cases in which considerable numbers of myelocytes were associated
with bone metastases. Eosinophilia is regarded by Neusser as diagnostic
of bone-sarcoma. In general, sarcoma affects the blood and leukocytes earlier
and more than carcinoma, and in many cases of sarcoma the increase has
reached the higher limits of inflammatory leukocytosis (Martin, Matthew-
son, Alexander). In certain cases of systemic lymphosarcoma, myeloma,
and in leukemic chloroma, it is probable that numbers of tumor-cells reach
the blood and may be found in stained specimens. In two cases of localized
sarcoma Loeper and Loeste claim to have found specific tumor-cells in the
centrifuged sediment of the blood. The many details of differential diagnosis
by the blood may be left to the special treatises upon this subject.

The total quantity of blood in cases of malignant tumor varies greatly but,
as Louis showed in 1846, it is usually much diminished. The distinction
between the anemic and the marantic cases is here quite pronounced, the
vessels in the former type showing at autopsy a considerable volume of
watery blood, while the others may give a much reduced quantity of con-
centrated blood of fair quality. The cases with arterial hypotension observed
by Janeway must usually fall in the former class.

The regeneration of the blood in cancer has been found by Bierfreund to
require much longer than in other surgical conditions, and in progressive
cases the Hb seldom reaches the ratio existing before operation. Yet it is
impossible to establish any general rule in this matter. In a woman who in
four years underwent six operations for recurrent adamantinoma of the
superior maxilla, I found the highest Hb (85 per cent.) and good general
health, although the tumor had again recurred.

70 NEOPLASTIC DISEASES

The resistance of the red cells to various destructive agents has been found
about normal in early stages of cancer but in advanced cases it is much in-
creased, probably as a result of reaction to hemolytic factors (Schmidlech-
ner). So marked may the increased resistance become that Conte regarded
this property as of diagnostic significance.

Alkalescence of Blood. — Determinations of the alkalescence of the blood
have yielded results which differ with the method employed and the particular
factors brought into consideration. Klemperer found a reduced amount of
CO2 in the blood of advanced cancer. Peiper titrating the whole blood
found very low grades of alkalescence in advanced cachexia, and Rumpf,
Limbeck, and others, dealing with the whole blood, obtained uniform dimi-
nution of alkali in advanced cases. It is clear that the chief factor in these
results was anemia, although as claimed by v. Noorden, liberation of acids
from destruction of proteins and acidosis may occasionally be present
(Herter). Yet H. Strauss titrating laked blood found marked variations,
some cases showing normal and some increased alkalescence.

Methods dealing with the serum yield directly opposite results. In 1906
Moore and Wilson found that the serum alkalescence to dimethylamido-
azobenzol showed a striking increase in cancer as compared with healthy
subjects and other hospital patients, while the basic capacity of the inorganic
salts after removal of proteins by incineration showed a small but distinct
increase. Gamble, Royle and Watson secured similar results by the same
methods in both carcinoma and sarcoma, but in very advanced cachexia
the alkalinity was barely above normal. Neither extirpation nor #-ray
treatment produced any change. Sturroch improved the di-methyl tech-
nic and found an average alkalinity of the serum of 0.190 N and often more
than 0.200 N in cancer, while non-malignant cases gave an average of 0.173 N.

Hyperglycemia with a percentage of glucose reaching 0.33 was regularly
found in the blood of cancer by Freund and again in many cases by Trinkler.
Yet Matrai could not find that the anemia of cancer varied in this respect
from other forms. Lewis and Benedict found quite variable relations
between sugar content of the blood and the progress of malignant tumors,
but usually an increase in the later stages.

A retention of chlorine and phosphorus, especially the former, was ob-
served by Moraczewski to be earlier and more pronounced in the anemia of
cancer than in other forms.

Influence of Cancer on Digestion. — Gastric Digestion. — The absence of
free HC1 in the gastric contents of cancer of the stomach, discovered by Van
der Velden in 1879, and thoroughly investigated by many later writers,
stands as a prime factor in the anemia and malnutrition of this disease. In
all but 10-13 Per cent- °f sucn cases free hydrochloric acid is missing (Rich-
ter). When cancer is grafted on simple ulcer the early stages of the process
may be marked by the excess of free HC1 belonging to the former condition,
but as a rule this excess declines and eventually disappears, sometimes
suddenly as the disease progresses (Rosenheim, Schneider). In most
cases the loss occurs early in the disease (Riegel).

Several factors appear to be combined in determining the loss of free HC1.
In most cases of gastric cancer one finds a general chronic catarrhal inflamma-
tion, in some cases there is atrophy of the mucosa, and in one group a diffuse
infiltration of mucosa and muscularis is observed. There is every reason
to attribute to these anatomical lesions a loss of functional capacity partly
accounting for the loss of HC1. Yet the failure of free acid occurs in many
early cases, and is relieved after excision of the cancer (Rosenheim). In
other cancers not involving the stomach a similar deficiency of HC1 occurs,

MALIGNANCY AND ITS EFFECT ON THE ORGANISM 71

so that it seems necessary to assume that malignant disease exerts some gen-
eral influence which affects gastric secretion, even in the absence of severe
anemia and cachexia.

Reissner showed that in gastric cancer the total chlorides secreted are
not below normal, that decrease of free acid is nearly always associated with
increase of fixed chlorides, and that the acid is promptly combined in the
stomach with alkalis of the blood and serum exuded from the tumor. Since
an increased supply of NaCl from the tumor juices can probably be elimi-
nated, it would appear that the loss of free acid in early cases results from
its neutralization by alkalis and not from any functional deficiency of an
apparently normal mucosa. This explanation can hardly apply to late and
cachectic cases and to other forms of cancer in which the total chlorides are
diminished. That the tumor yields such free alkalis is further indicated by
Stahelin's observation that free HC1 introduced into the cancerous stomach is
actively neutralized; by the neutralization of HC1 by cancer tissue in artificial
digestive mixtures (Rosenberger) ; and by the increased quantity of protein
found in the stomach juice after previous washing (Salomon).

Moore and Palmer from the study of a series of cases of carcinoma,
sarcoma, and non-malignant tumors, found in nearly all a diminution of HC1,
which they attribute to reduction of hydrogen ions of the blood. In many
of these cases it is evident that they have to deal with the effects of cancerous
cachexia, but in others which were not cachectic Parker suggests that the
general unhygienic hospital surroundings were at fault. Copeman and Hake
with Cramer, secured the interesting result from observations on 500 mice
that the implantation of cancer in these animals is followed by decided
increase in the physiologically active HC1.

There are therefore a specific influence of tumor juices neutralizing
secreted HC1 of the gastric juice, a diminished functional capacity of an organ
damaged by an extensive tumor, and an effect of cachexia in reducing the
hydrogen ions of the blood and impairing the secretion of acid, all to be
considered in the relation of cancer to the acid of the gastric juice.

The gastric ferments persist long after the disappearance of free HC1
(Oppler) . According to Glassner both rennet and pepsin are diminished with
tumors of the f undus in which there is considerable destruction of the mucosa,
whereas pepsin alone is diminished with cancers of the pylorus in which
region it is principally secreted. Emerson found that one hour after a test
breakfast 16.9 per cent, of the proteins in the normal stomach has been hydro-
lyzed to the stage in which they are not precipitable by phosphotungstic acid,
while in cancer of the stomach 27.6 per cent, reached this stage. In a diges-
tion mixture containing a piece of fresh cancer tissue he found proteolytic
digestion to proceed further than in mixtures of pepsin — HC1. These
experiments indicate that cancer tissue contains a ferment similar to that
found in other autolyzing tissues. Whether this ferment is specific of
cancer tissue; to what extent the advanced proteolysis observed in cancerous
stomachs is the effect of this ferment; and the part played by leukocytes and
bacteria, are matters yet to be elucidated. Rosenberg has verified these
results and the method has been found of value in the diagnosis of gastric
cancer.

Neubauer and H. Fischer have found in the stomach washings of gastric
cancer and in the expressed juice of carcinoma and sarcoma a ferment which
splits glycyl-tryptophan and this test has been extensively employed in diag-
nosis with satisfactory results. Lately it appears to have been shown that this
ferment is ptyalin from saliva. Fischer points out that amino-acids appearing
in the abnormal digestion of cancer of stomach unite with free HC1 through

72 NEOPLASTIC DISEASES

the amino-group, while the total acidity may remain normal on account of
the acid reaction of the free carboxyl group.

Disturbance of motility of the stomach dominates the clinical signs in
cancer of the pylorus, leading in many cases to dilatation of the stomach and
stagnation with abnormal fermentations of the contents. Of the influence
of cancer on absorption by the stomach little is definitely known. With
diffuse infiltration of the wall and contraction of the cavity, evacuation of the
organ may be accelerated and absorption must be greatly reduced.

As a result of diminished digestive capacity, disturbance of motility,
and retarded absorption, abnormal fermentative processes become established
and various bacterial species find a favorable soil. The products of fer-
mentation include lactic, butyric, and acetic acids, alcohol, and protein
decomposition products. Boas at one time claimed that the presence of
lactic acid in the gastric contents was specific of carcinoma and appeared at
an early stage when stagnation and loss of free HC1 did not exist, but it has
since been shown that the presence of lactic acid is dependent upon impaired
motility and deficiency of HC1 (Strauss, Wagner, Seelig). Since these
conditions are present very early in cancer and since, as Sick has shown,
formation of lactic acid is favored by decomposition products of cancer
tissue, the test for lactic acid is of considerable diagnostic value.

Intestinal digestion suffers in many ways from malignant tumors of the
gastro-intestinal tract and its accessory glands. With gastric cancer the
discharge of abnormal digestive putrefactive and bacterial products into the
intestine tends to incite disorder throughout the entire course of digestion,
and Wasbutski, Kast and others have shown that intestinal decomposition
occurs especially in cases with loss of free HC1 and active fermentation in
the stomach. Rarely there is severe diarrhea in the terminal stages of
such cases. The main effects of tumors of the intestinal tract are the result
of stenosis and ulceration and either of these conditions in pronounced form
has a prompt influence on general nutrition. Detailed studies in this field
are meager. Excessive indicanuria tells of absorption of putrefactive prod-
ucts in stenosis, and formation of fistulous tracts may complicate and
terminate the course without much influence on the extent of this absorption.

Blood in the stools offers a means of diagnosis in ulcerating tumors, and
constitutes a serious source of anemia. Acholic stools result from can-
cerous stenosis of the common duct, and impaired digestion of fats follows
destruction of the pancreas and occlusion of its duct.

Tumors of the liver, bile passages, pancreas, cecum, and rectum, produce
various important clinical types of disease the full discussion of which may
be left to works on special pathology. Here it may only be said that all
of these conditions tend to produce cachexia through the combination of
very numerous factors which must be analyzed for each case and the variety
of which reveals the very complex nature of tumor cachexia.

Changes in the Urine. — Specific alterations in the urine of cancer have not
been demonstrated, but its composition varies greatly according to general
rules. Specific substances appear in the urine with melanoma and myeloma.
The entire subject invites further study by improved methods.

The total nitrogen varies with the diet throughout the main course of the
disease, while at the termination may be observed the increased nitrogen
output which Miiller interpreted as a sign of toxic destruction of proteins,
or the diminished excretion of starvation. The distribution of the urinary
nitrogen fails to show any specific characters. The percentage of urea is
influenced mainly by starvation, falling to a very low figure in extreme cases.

Uric acid may be increased without relation to leukocytosis (Cario).

MALIGNANCY AND ITS EFFECT ON THE ORGANISM 73

The course of this substance in cases of various cellular tumors has not been
determined. Brandenburg and Blumenthal found the nitrogen of alloxur
bodies relatively high in most of their cases, while Setti failed to find any
uniform increase.

Ammonia nitrogen has not been found to show any variations other than
those dependent on digestion and nutrition. Herter found high ammonia
in the coma of gastric cancer.

Creatinin excretion has been found low in cachectic cases by Benedict
and Gorslin, an observation which accords with Shaffer's view that the
creatinin coefficient is a measure of muscular efficiency. Creatin appears
in moderate amounts in cachexia.

Rest nitrogen, chiefly amino-acids, is higher than in some other abnormal
states and increases with the progress of the disease (Setti). Salkowski has
drawn attention to an increase in the colloidal nitrogen precipitable by alco-
hol, in cancer. This fraction corresponds partly to the amino-acids (Wolf).
Later Salkowski estimated the nitrogen precipitable by lead acetate after
removal of phosphates by alkaline barium chloride, finding that this nitrogen
fraction is greatly increased in cancer. The nitrogen estimated by Salkowski
probably includes the oxyproteic acids and polypeptids.

An increase in unoxidized sulphur has also been observed by M. Weiss
and others, and Salomon and Saxl have demonstrated such a notable and
uniform increase in oxidizable neutral sulphur as to indicate its value in
diagnosis. Lehman points out that the results of this test depend largely
on the diet without the control of which the examination is useless. From
observations in this field Saxl concludes that various analytic methods
demonstrate the occurrence in notably increased amounts of protein deriva-
tives, chiefly oxyproteic acids, which escape the normal transformation
into urea. In general he finds a somewhat specific disturbance of metab-
olism in cancer marked by a nearly constant excess in total metabolism,
relative reduction in urea formation, increased ammonia excretion and
increase of protein derivatives which fail of oxidation into urea. In no
other disease except certain special intoxications is the internal oxidation of
protein so much disturbed as in cancer. Saxl goes on to show that the
disturbance of oxidation is probably due to accumulation in the system of
rhodan an oxidation product of hydrocyanic acid, since this substance is
increased in the urine in cancer and when administered to man reproduces
the typical metabolic disturbance of cancer. The basis of this theory remains
to be verified.

The urinary chlorides show no specific relation to cancer. Although
Beneke supposed that the cancerous constitution was marked by deficiency
of alkaline chlorides, observation shows that these urinary principles depend,
as in other diseases, chiefly on the diet, the presence of disintegrating protein
tissues, and, the activity of the kidneys. In severe inanition the chlorides
fall very low (Miiller, Braunstein), but an increased excretion has often been
observed (Schopp). Chloride retention may occur with cardiac or renal
insufficiency and may be associated with anemia and edema (Laudenheimer).
Chlorine loss may result from active destruction of tumor or other tissues.
Marked disproportion between urinary nitrogen and chlorine in favor of the
latter occurs in states of inanition with little protein intake and much destruc-
tion of tissue, as in cancerous stenosis of esophagus. Schopp concluded that
NaCl might be retained in the building up of tumor-tissue in cancer of the
liver, but Laudenheimer found the same proportion of NaCl in liver tumor
and normal liver tissue. Royle finds retention of both Na and Cl in cancer,
that of Na being greater than CL He concludes that extra Na combines with

74 NEOPLASTIC DISEASES

phosphoric acid and that the retention of chlorine seems to counterbalance
the alkaline phosphates of the blood and maintain the proper relation of
salts in the plasma. In 10 cases of carcinoma Braunstein found no changes
in the urine which could be regarded as specific. In three cases the excretion
of Na and Cl was practically normal and the loss of P ran parallel with that of
N. Phosphoric acid excretion is increased in most cases both absolutely
and in proportion to the nitrogen with which in general it runs parallel. The
P : N ratio runs i : 4 or i : 5 : 6 instead of the normal i : 7 (Braunstein) . Its ex-
cess suggests a source in tissues rich in P, as the bones, glandular organs, or the
tumor tissue itself. Sulphuric acid excretion is parallel with that of nitrogen
but Cario observed somewhat increased proportions in two cases of cancer of
esophagus. The partition of the sulphur has not been determined, but high
percentages of ethereal sulphates may be expected with ulcerating tumors, and
intestinal disturbance.

Urobilin. — Considerable urobilin was frequently observed and regarded
as somewhat characteristic of cancer especially of cachectic and hepatic cases,
by F. Muller and Gerhardt. Yet Hoppe-Seyler had previously found little
urobilin in several cases, and B lumen thai who observed an excess in gastro-
intestinal and ulcerating cases, often found it absent in others. Braunstein
from the study of 22 cases concludes that urobilin is missing in cancer so
long as fever and complications are absent, but appears with metastases
especially in the liver; with necrosis and decomposition of the tumor; and
with complicating pneumonia. In cancer of the liver when the bile ducts
are closed he found that bilirubin replaced the urobilin.

Products of putrefaction of proteins are found in increased quantities
in the urine of advanced cancer but the exact source of these substances has
not been fully determined. Indican, phenol, aromatic oxyacids, and ethereal
sulphates, have been estimated by several observers who attribute their
presence to intestinal putrefaction, to decomposition of secretions and to
destruction of tumor-tissue. That intestinal putrefaction is not the sole
source is indicated by the considerable quantities of such substances observed
with decomposing tumors of breast and uterus (Brieger, Haberlin, Hennige).
Lewin finds excess of aromatic acids in patients with N loss, but not with
those showing N retention and concludes that these substances are derived
from the toxic destruction of tumor and tissue proteins and not wholly from
intestinal putrefaction. Yet it still remains uncertain whether aromatic
oxyacids, indol and phenol, may arise in the course of nitrogenous metabolism,
and it is clear that patients laying on nitrogen are not likely to be suffering
from excessive intestinal disturbance.

A cidosis of Cancer. — The acetone bodies in cancer follow the same rules
as in other conditions. Their presence in the urine bears no relation to the
growth of cancer as such, and these substances are absent in the early stages
of the disease and when the patient is well fed (Waldvogel). With the
advent of protein loss and cachexia acetone and diacetic acid commonly
appear in the urine and beta-oxybutyric acid is added in severe inanition.
Hirschfeld relieved the acidosis by giving sugar.

In cases chiefly of esophageal, gastric and hepatic cancer v. Jaksch,
Riess and Senator described a form of cancer coma in which the dyspnea,
acidosis, and diminished alkalescence of the blood were present as in diabetes.
In two such cases Klemperer observed a daily N loss of 5 to 9 gms. which he
interpreted as signifying toxic destruction of tissues. The coma he referred
not to the acidosis but to the general toxic process, v. Jaksch also stated that
these patients were not always suffering from starvation but that the appear-
ance of acetone bodies ushered in a severe type of general cachexia. It is not

MALIGNANCY AND ITS EFFECT ON THE ORGANISM 75

entirely clear that cancer coma is purely an acid intoxication, and it seems
probable that the rapid burning of tissue fats and proteins of which acidosis
is only one result may be responsible for some of the sudden terminations of
malignant tumors.

Von Noorden's observation of considerable quantities of lactic acid in the
urine of two cases suggests that the acidosis of cancer may involve hepatic
disturbance as well as pure acidemia.

Demineralization occurs in cancer cachexia as in other conditions and is
associated with nitrogen loss with wh'ich it maintains a parallel. Of n
cases Lewin observed loss of mineral salts, 1.36 to 8.9 gms., and of nitrogen, in
seven, and slight retention of both in four. One important source of these
mineral salts is probably the bones which become increasingly fragile in
many wasting diseases. The shafts become thinner, the cancellous spaces
and Haversian canals larger, and Campbell has shown that the breaking strain
is greatly reduced. In some cases of cancer the calcium depots become
greatly disturbed and extensive deposits of calcium salts are found frequently
in the tumor, occasionally in the lung.

Alluminuria occurs in most cases of cancerous cachexia but is absent in the
early stages of the disease. According to Miiller it occurs in 35-72 per cent,
of all cases of carcinoma. In cancer of the intestinal tract albumoses are
very often present (Ury, Lilienthal), either by direct absorption of digestive
products through the ulcerated surface (Maixner) or from the disintegration
of tumor tissues (Pacanowski). In many cases of myeloma a peculiar pro*
tein, Bence- Jones body, appears in the urine.

CHAPTER IV
METASTASIS

The formation of secondary tumors is a cardinal property of malignant
tumor growth. The appearance of a secondary tumor at some distance
from the primary growth may represent one of several events. It may mean
a multiple origin, and a new tumor; or a continuous extension from the
primary growth; or a true metastatic growth arising from tumor-cell emboli.
Only a critical estimate of the known tendencies of particular tumors can
determine which of these events has occurred. Melanoma and multiple
fibroma both produce very numerous tumors of the skin, the one from cell
emboli, the other by multiple growth of new tumors.

Multiple origin of new tumors is observed with a considerable list of
neoplasms, already considered, including fibroma molluscum, myeloma,
epithelioma of skin, sarcoid growths of skin, adenoma and adenocarcinoma
of mucous membranes, chondroma of spine, myoma, lipoma, etc.

Lymphatic Permeation. — By continuous extension of primary infiltrating
tumors through the lymphatics, apparently discrete tumors often appear
at points widely distant from the original growth. In multiple carcinoma
of the skin continuous chains of cells may extend through convenient lym-
phatics until the cells reach a locality favorable for growth and there mul-
tiply, producing discrete tumors connected with the primary growth only
by a thin strand of cells. It is conceivable that accidental breaks may occur
in this chain of cells completely separating the secondary from the primary
growth. There are many tumors in which this process leads to formation
of secondary growths. At what remarkable distances secondary tumors may
arise by this method has only recently been demonstrated.

In cancer of the breast Handley has shown that there may be continuous
extension of tumor-cells through the lymphatics of the deep pectoral fascia
to the axillary and supraclavicular nodes: thence to overlying skin and to
humerus: through the deep lymphatics to the ribs, pleura, lung and spine:
across the chest wall to the opposite breast: downward through the abdom-
inal wall to the epigastric region and thence by the falciform ligament to the
liver; and further to the inguinal region with involvement of lymph-nodes,
skin and femur. Extension through superficial lymphatics is much less
wide. Invasion of the humerus occurs at the deltoid insertion and of femur
at the trochanter, where these bones are closest to the skin, through the
deep lymphatics of which the bone invasion follows. The leg and arm bones
escape infection, which is inconsistent with a free embolic origin through the
blood-vessels. Passing through the deep lymphatics of chest or abdominal
wall the cells enter the pleura and peritoneum and become implanted on
the serous surfaces and produce superficial infiltrations of the lung, liver,
intestines, and ovary. Or the viscera may be invaded through their main
lymphatic vessels giving central tumors. The liver is involved through the
lymphatics of the falciform and round ligaments, or by transperitoneal im-
plantation, or by way of portal nodes; the lung by transpleural implanta-
tion or through bronchial nodes and hilus. Abdominal invasion by the epi-
gastric route is earlier and more frequent than the thoracic, occurring without

METASTASIS 77

thoracic lesions in 1 2 per cent, of all cases. The diaphragm is invaded by
the epigastric peritoneal route, and through the descending lymphatics of
its crura the retroperitoneal nodes and kidneys are attacked. This process
of lymphatic permeation rfandley believes is the master process of general
dissemination in cancer. Lymphatic embolism he would reduce to a very
secondary factor. Handley bases his conclusions on the study of long
slices of thoracic and abdominal parietes in advanced cases of mammary
cancer. In such material he finds the lymphatics continuously filled by
tumor-cells. The only breaks occur as the result of perilymphatic fibrosis,
an inflammatory reaction excited by the tumor process and resulting in
complete atrophy of tumor-cell cords at many points.

While recognizing the value of Handley's studies it must be considered
that the condition at autospy may not clearly indicate the manner in which
the lymphatics have become filled. It is conceivable that cell emboli lodging
at different points in a lymphatic chain may grow in both directions and
after a time fill the lymphatic completely. Many observers believe that
lymphatic embolism is commonly associated with continuous permeation
in most mammary and in many other cancers. However, the result of these
processes is practically the same, ending, in prolonged cases, in very wide-
spread and nearly continuous invasion of lymphatics.

The theory of continuous permeation is of fundamental importance in
surgical procedure. To what extent this process prevails in different forms
of cancer can be determined only by careful study in each case. Such
studies are not yet available and are essential before this theory can safely
be adopted. In epithelioma of esophagus Borrmann has found that the
metastatic tumors in the stomach wall, which have long been regarded
as implantations through the esophagus, are connected with the primary
tumor by an unbroken chain of cancerous lymphatics. Bloodgood believes
that successful extirpation of cancer of the tongue and infected lymph-nodes
may be accomplished only by removal of all lymphatics joining ulcer and
lymph-nodes.

Yet the majority of observers fail to find in early cases such uniform and
continuous connection between primary cancers and infected regional lymph-
nodes and are agreed that such infection is usually by means of cell emboli.
I have repeatedly failed to find any trace of invaded lymphatics connecting
carcinomas in the breast with infected axillary nodes, and have been equally
unsuccessful with cancer of tongue and penis. Metastases from lingual
cancer often appear first in rather distant nodes, sometimes on the opposite
side of the neck. The metastases from melanoma of foot and other regions
are usually incompatible with the theory of continuous permeation. In
general it appears probable that the rapidly growing epidermoid and glandu-
lar carcinomas disseminate chiefly by lymphatic embolism, while slowly
growing and recurrent tumors, especially in the skin often extend by continu-
ous permeation. This belief is strengthened by such observations as those
of Gussenbauer who found cancer-cells in the cervical lymph-nodes in 29
of 32 cases, and of Kuster who found the axillary nodes free from cancer-cells
in only two of 117 operative cases of breast cancer. Since definite growing
tumors of the lymph-nodes are much less common it is clear that embolic
cancer-cells are frequently present in lymph-nodes and that they are prob-
ably destroyed there under some circumstances. Yet it is extremely rare
to find in lymph-nodes any appearance suggesting the destruction of small
groups of embolic tumor-cells. On the other hand evidences of retardation
of growth by fibrosis and encapsulation are relatively common.

The frequency of lymph-node metastases varies with different tumors,

78 NEOPLASTIC DISEASES

with different varieties of the same tumor, and with different positions of the
tumor in the same organ, and must be separately considered for each case.

Cancer of breast probably stands high on the list, very few fully malig-
nant cases of this disease failing to involve the nodes if allowed to remain
more than a few months. Williams found the nodes involved in 86 (73 per
cent.) of 118 cases at first examination, and in 40 (90 per cent.) of 44 autop-
sies. The variety of the cancer is here of paramount importance, and is
a factor often underestimated.

Epithelioma of the tongue or tonsil very early and nearly constantly
invades the lymph-nodes but here again the type of the tumor is the deter-
mining factor. Williams recorded 86 (83 per cent.) of 104 lingual cases
infected at time of first examination, and 56 of 57 cases coming to autopsy.
Epithelioma of the lower lip invades the lymph-nodes more slowly but
eventually in almost all cases. In 186 cases of cancer of stomach examined
at autopsy by Moore, Cuneo, and Colwell, lymph-nodes were involved in 149.

The lymph-nodes escape in many cases of uterine cancer, especially with
tumors of the fundus. Epithelioma of the skin is slow in reaching the lymph-
nodes, and rodent ulcer and adenoid cystic epithelioma are remarkable
for the long or permanent immunity of adjacent lymph-nodes. Of 34 malig-
nant tumors of the testis Butlin found the lymph-nodes free in only three,
but in a series of 19 cases I found several which had not attacked the inguinal
nodes. The tumor usually first affects the epigastric nodes.

The value of available statistics, however, is very limited since most
authors fail to distinguish between the different types of cancer, although
it is well known that some are very prone to invade the lymphatics while
others long remain circumscribed. It is little help to know that 75 per cent,
of the cancers of the breast involve the lymph-nodes within a year of their on-
set when the surgeon might learn that his case is an adenocarcinoma which
long spares the nodes.

For the same reasons available statistics regarding the period at which
lymph-node invasion occurs appear to be of uncertain value. Thus Fink
observed it in breast cancer as early as the sixth and always after the thir-
teenth months, yet I have examined a mucoid breast cancer of 10 years'
duration, service of Dr. Hartley at Roosevelt Hospital, without invasion of
the nodes. Similar variations are observed with many other tumors, while
it should be noted that some cancers show general dissemination without
palpable enlargement of regional nodes.

Changes in lymph-nodes draining malignant tumors show that the im-
plantation of metastases is preceded by a period of preparation of the soil.
For weeks or months before actual tumor invasion the regional lymph-nodes
may be moderately swollen. During this period many new lymph-nodes may
develop in the course of the vessels. On section the swollen nodes show
diffuse hyperplasia with catarrhal exfoliation of sinus endothelium, or multi-
plication of follicles. It is not uncommon also to find the nodes atrophic
and fibrous, or extensively invaded by fat tissue, conditions which reduce
their effectiveness as filters. Owing to a variety of causes old changes of
this latter class may permit the passage of cancer-cells through or around
a given group only to lodge in a more central area. The former class of recent
alterations must be referred to the absorption of toxic products from the
tumor, autolytic and bacterial. There are no specific histological features
of the precancerous condition of the lymph-nodes, but there are reasons to
believe that regressing tumor-cells may be found in the sinuses before definite
implantation has occurred. As previously noted, Kuster found that in
only two of 117 cases were the axillary nodes removed with breast cancer

METASTASIS 79

free from invasion. Yet the proportion of lymph-node recurrences when the
nodes are not removed is very much less. Nevertheless it is extremely rare
to find any metastatic focus in a lymph node which does not appear to be
safely implanted and capable of growth.

The earliest nodules appear in the sinuses from which they invade and
compress the pulp with complete atrophy of lymphoid tissue. From this
point, the cells may invade the capsule and the peripheral lymphatics,
blood-vessels, fat, or fibrous tissue.

When the metastatic period is established lymph-node invasion may
follow rapidly. In a case of cancer of breast a swollen axillary node examined
in March showed only inflammatory hyperplasia with no demonstrable
tumor in the breast, but in June the entire breast was infiltrated by a flat
diffuse growth and some axillary nodes were completely replaced by cancer.
Since many tumor metastases long remain confined to the regional lymph-
nodes and fail to make any headway through the blood-stream it may be
assumed that there is a regional and a general immunity against implantation.
Yet in not a few cases cancer skips the regional nodes and yields distant
metastases. According to Gross this occurred in one out of 7 cases of
breast cancer. With some rapidly growing tumors both local and general
susceptibility to metastasis exists at a very early period, and in most cases
one must conclude that the growth capacities of the cells are of chief impor-
tance in determining the fate of cell emboli.

Invasion of the Thoracic Duct.- — In not a few cases of advanced cancer
the .thoracic duct is invaded, an event which commonly leads to widespread
dissemination by lymph and blood-stream.

One of the striking results of invasion of the thoracic duct is the appear-
ance of enlarged nodes in the supraclavicular region. Troisier in 1886
first emphasized the diagnostic importance of this symptom in cases of
abdominal and especially of gastric and uterine cancer, and similar cases
have since been reported by many observers (Lit. in Williams, p. 425).

It has also been observed with cancer of pancreas (Raw), testis (Poncet),
prostate (Hurlemont), adrenal (Troisier). Nevertheless it is a late and,
with improving diagnosis, a rare symptom of diminishing importance, and
must be distinguished from other affections of the nodes, and according to
Williams, from VernemTs "pseudolipome sus-claviculare." According to
Rousseau, in 37 cases presenting Troisier's symptom, the left nodes were
involved in 29, the right in four, both sides in four.

Inguinal lymph-node invasion is also associated with and occurs without
involvement of the thoracic duct, with abdominal cancers, especially of
the uterine fundus, prostate (Viannay), bladder, rectum, chorion, and occa-
sionally with many other primary tumors. Among other symptoms resulting
from occlusion of the thoracic duct are chylous ascites (Leydbecker), chylo-
thorax, and lymph varices which may lead to cysts of considerable size. The
results of invasion of the blood-stream from the duct with multiple tumors
of the lung are frequently observed.

Winkler has given a full description of 27 cases (12 original) of cancer and
one of round-cell sarcoma of the thoracic duct. The invasion followed most
frequently cancer of the stomach, then of uterus, while other cases arose
from the gall-bladder, testis, colon, and kidney. In all these cases the abdom-
inal nodes were enlarged and adherent to the duct, offering abundant oppor-
tunity for the invasion by this means. The duct presented one of three
conditions, (i) Free masses of tumor-cells lying in a coagulum, with throm-
bosis or occlusion (2) Papillary masses of tumor growth adherent to the wall
and organized from it, usually at the valves, with numerous varices often

80 NEOPLASTIC DISEASES

resembling a string of pearls. (3) Complete thrombosis by tumor masses
invading the wall and mingled with fibrin.

Invasion of Serous Cavities. — The large serous cavities are penetrated
by many pathways and in the course of a considerable number of tumors
chiefly those of the contained organs. The most frequent source of free
peritoneal growths is the ovarian adenocarcinoma which at any period may
rupture its covering and be disseminated throughout the cavity. Its cells
readily become implanted on the peritoneum, producing many miliary or
large solid papillary or cystic tumors with a tendency to ascites. One of
the most remarkable forms of peritoneal cancer arises from small adeno-
carcinomas of colon or appendix, which early perforate the peritoneum,
spread rapidly throughout the greater sac and, retaining the large alveolar
structure, produce enormous quantities of mucus greatly distending the
abdomen. In very large tumors of this sort, several liters of gelatinous
material may be evacuated and it may be extremely difficult to discover any
trace of living tumor-cells. I have seen gelatinous cancer of the rectum,
following an extraperitoneal route, fill the pelvis inclosing rectum and bladder,
pass up the abdominal parietes in front and retroperitoneal tissues behind,
separating liver from diaphragm, inclosing the entire abdominal cavity in
a rigid shell 3-5 cm. in thickness, and eventually invading the mesentery
and subserous intestinal lymphatics, but without any trace of intraperitoneal
growth. This condition may be designated as abdominal cancer en cuirasse.

Peritoneal invasion is a very common late complication of breast cancer,
and occurs as Handley has shown, often by way of the epigastric lymphatics.
From the subperitoneal lymphatics and along the falciform and round liga-
ments of the liver he has found cancer nodules opening into the peritoneum.
Loose cells often become implanted first in Douglas sac or on the ovary.
More frequently there is a widespread permeation of the subperitoneal
lymphatics, which may become nearly universal. It is associated with active
growth of hard fibrous tissue, producing nodules and adhesions. Eventually
the entire peritoneum becomes thickened, leathery and opaque, and the
omentum shrinks to a firm globular infiltrated mass. Such patients show
marked resistance to cachexia and may suffer for months or years from increas-
ing ascites which gradually drains their strength or suddenly terminates
life by asphyxia.

The peritoneum seems to have very little capacity to destroy cancer-
cells, so that the invasion once accomplished is usually progressive. Gravity
and the muscular contraction of stomach, intestine, diaphragm and parietes
assure a general dissemination of cells. These movements also may cause the
separation of tumor masses which have been found free in the peritoneal and
pleural cavities, while the aspirated fluid nearly always contains exfoliated
cancer-cells.

Intrapleural and intrapericardial cancerous invasion occurs chiefly by
direct invasion from cancer of breast, bronchi, and lung, with results very
similar to those produced by breast cancer in the peritoneum.

Penetration of the cerebrospinal membranes occurs in rare cases of carci-
noma chiefly of the breast, and may lead to a universal cerebrospinal carci-
nomatosis resembling meningitis. In a breast case observed at New York
Hospital, service of Dr. Conner, isolated cells, small groups of cells and thin
plates were found from the vertex to the cauda equina, infiltrating the pia,
and penetrating many sulci, with little cellular or serous exudate.

Lymphatic Invasion by Sarcoma. — It is a somewhat important dis-
tinction that lymphatic invasion by carcinoma is frequent, by sarcoma rare.
Not a few epithelial tumors violate this rule and travel through the blood-

METASTASIS 81

vessels, but sarcomas that tend to invade lymphatics are much less numerous.
The lymphosarcomas are the only sarcomas that frequently travel by the
lymphatics and the origin of these tumors within the lymph-nodes fully
accounts for this tendency. The blood-vessels also serve as channels for the
dissemination of lymphosarcoma, so that certain forms of this tumor yield
the most abundant and widely disseminated metastases seen with any type of
neoplasm.

Most statistical reports of lymph-node invasion in sarcoma are of doubtful
value owing to the uncertainty connected with the diagnosis of sarcoma.
Most of the sarcomas reported of the testis and thyroid are probably epithe-
lial tumors, and commonly invade the lymph-nodes. Melanoma declares
its specific nature by frequently (41.7 per cent. Williams) affecting lymph-
nodes. Of the bone-sarcomas the spindle-cell and giant-cell types rarely,
the round-cell or lymphoid-cell types frequently involve the adjacent nodes
(Gross). The frank spindle-cell sarcomas of the parietes and its contained
structures, and those of the internal organs affect lymph-nodes in 5-15 per
cent, of cases. As a rule the blood-vessels as well as the lymphatics may be
the route of entry.

The comparative immunity of lymphatics against invasion of sarcoma
is probably to be explained chiefly by the greater local fixation of sarcoma-
cells as compared with the mobile and sometimes amebiod cancer-cell.
It is in accordance with this view that the lymphosarcomas behave much
like carcinomas. At the same time sarcomas are usually more vascular
than carcinomas so that cells rapidly break into the blood-vessels whose
walls are thin or deficient. The growth of most sarcomas is more expansive
than with carcinomas and more often encapsulated, so that lymphatic
channels are closed and only the nutrient blood-vessels remain pervious.
I do not think that the original relations between lymphatics and epithelium
or connective tissue cells have any influence on the character of tumor metas-
tases, since at the period when dissemination begins these relations are
greatly altered.

Dissemination by Blood-vessels. — The blood-vessels are the chief
channel of the extension of sarcomas, they are frequently invaded by carci-
nomas, and several epithelial tumors show a remarkable capacity to flourish
in and travjel through the veins. The abundance of thin- walled blood-vessels,
the presence of naked sinuses, and the tendency toward necrosis and hemor-
rhage rather than fibrosis, may largely explain the predominance of blood-
vessel invasion by sarcoma as compared to carcinoma. In many cases, as
in fascial myxosarcoma, the tumor-cells appear to be mechanically forced into
the veins by the presence of rapidly growing and swollen tumor-tissue.

The entry into the veins is accomplished through the defective vessels
within the tumor, or by invasion and rupture of adjoining vessels, or by infil-
tration along the vasa vasorum and intima, with gradual erosion of the wall.
Carcinoma often penetrates the wall via the perivascular lymphatics.

The result of such invasion is at first a thrombosis complete or partial,
at the point of entry. The tumor-cells may then be destroyed by organi-
zation and fibrosis of the thrombus with subsequent canalization (Schmidt),
or the cells continue to grow within the vein, they become attached to the
wall, produce flat or polypoid outgrowths, many cells or cell masses become
detached from the wall or from the original tumor and are carried to the
first zone of capillary vessels, usually the lungs, where they lodge as emboli.
Here again they are exposed to destructive agencies and may perish, but
more often develop secondary tumors.

If the detached masses are large they regularly lodge in the lungs, or

82 NEOPLASTIC DISEASES

become arrested in the right heart. Direct transport of emboli or continuous
growth in the veins is by far the most important mode of dissemination in
blood-vessels, and several well known tumors offer striking illustrations.
Chorioma originates in the uterine sinuses and maintains throughout its
intra vascular and hemorrhagic tendencies, producing retrograde vaginal and
renal metastases, honeycombing the uterine wall, and yielding forward metas-
tases in the lungs. Portions of the stroma of villi as well as tumor-cells have
been found in the pulmonary emboli of chorioma. Hypernephroma regularly
perforates the renal vein and* may extend in a solid column of tumor-tissue
into the heart. Adenoma of the liver is commonly found distending the
portal veins. The intravascular hydatid growths of teratoma testis are
among the oldest observed forms of intravenous extension. When a sarcoma
or carcinoma ruptures into a pulmonary vein widespread dissemination
results and very numerous tumors appear rapidly in different tissues and
organs.

The form assumed by tumors growing within vessels is sometimes influ-
enced by the existing mechanical and nutritional conditions. Freedom from
pressure allows the cells to reveal their natural tendencies, and the intra-
vascular tumor may be more " typical" than the original. Or a more rapid
and diffuse growth is assumed. In the axillary vein the cells of breast
cancer may become larger and more anaplastic, and I have seen evidence of
multiplication of loose cells in this situation and in the thoracic duct. The
organization of a tumor thrombus with fibrosis and reopening of the lumen
occurs rarely. The advancing mass of hypernephroma in the renal vein is
usually very edematous and the cells hydropic. Fuhrmann and Risel believe
that some tumors, especially myxoma, tend to assume an hydatidiform growth
when invading blood-vessels and they would attribute the chorion-like form
of certain testicular teratomas to the influence of the intravascular position
and not to any intrinsic chorionic character.

Are vagrant tumor-cells destroyed in the blood or lymph stream or their
associated organs, and if so by what mechanism? To this fundamental
question only a very incomplete answer can be given.

The scope of the conditions to which the question applies is very wide,
including many different forms of tumors and cells, involving the natural
life span of the cells and the facility with which they may reach the circu-
lation. It must be assumed at once that in many systemic sarcomas and
other rapidly growing neoplasms, cells are constantly reaching the circulation
and perishing there at least by natural autolytic processes. It is a very
prevalent belief however, that cells of most carcinomas from an early period
of their growth frequently reach the blood and lymph and are actively
dissolved by antagonistic substances in the blood. Many general considera-
tions favor this view. The active infiltration of capillaries and lymphatics
by rather loose tumor-cells suggests an easy and frequent passage into the
moving current. The list of observed emboli even of normal cells is quite
large. The experimental cultivation of tumor-cells by Burrows shows that
they are regularly capable of growth in the isolated state, and in many human
tumors, as in thyroid adenoma, it has been shown that blood-clot may be
penetrated by loose tumor-cells much as in an artificial culture. In several
well-known tumors cited elsewhere, as chorioma, hepatic carcinoma, and
mammary carcinoma, tumor masses and loose tumor-cells are observed
within the vessel lumen.

The belief that such loose tumor-cells are destroyed in the blood- or
lymph-stream is based on rather scanty evidence. Usually wide dissemina-
tion is observed to follow the invasion of blood-vessels. M. Schmidt,

METASTASIS 83

however, has shown that tumor-cell emboli are much more frequent in the
lungs than are secondary tumors of these organs. In 28 cases he found
emboli in the pulmonary arterioles in all, but definite metastases in only
13. From the study of the lungs in these cases Schmidt concludes that
in carcinoma of the abdominal organs there is frequently and repeatedly a
discharge of cancer-cells which lodge in the small arteries of the lungs.
Only a small portion of these cell emboli produce metastatic tumors or grow
into the perivascular lymphatics. Most of them are inclosed in fibrin,
organized, encapsulated, and in spite of retained vitality, rendered harmless.
Some of them grow through their capsule into the capillaries and small
veins whence they may form the source of late general metastases. All
of these processes may occur without macroscopical changes in the lungs.
The chief source of these emboli he believes to be through the pervious
thoracic duct. The endophlebitis carcinomatosa which Goldmann finds to
be nearly constant in generalized carcinoma, he regards as a sequel of pul-
monary emboli. In chorio-adenoma it has been shown that pulmonary
emboli occur in cases which recover after hysterectomy, but the mechanism
of destruction of the embolic cells, if they exist, has not been followed. In
many hepatomas the growth is from the first into the veins, but pulmonary
or other metastases are almost unknown with this tumor.

In the lymph-nodes while it has been shown that microscopic invasion
is more frequent than growing metastases, actual observation of late regress-
ing cell emboli in the nodes is not satisfactorily reported. The lymph-nodes
seem to retain and retard the growth rather than destroy the cells.

Experimental research has suggested the existence of a premetastatic
period during which the organism is incapable of developing metastatic
tumors. Gay found that he could not successfully reinoculate tumor-bearing
animals until a certain period had elapsed after the first implantation.
Yet these results are not uniform. Tyzzer by manipulating his grafted
tumors was able to cause numerous metastases apparently without regard to
the period of growth.

Serological studies have in general failed to demonstrate in the blood
serum of natural or immune animals any substances capable of destroying
tumor-cells. The most direct evidence favoring the existence of cytolytic
powers of the blood is contributed by Freund and Caminer. These observers
claim to have shown that normal blood dissolves cancer-cells in vitro, while
the blood of cancer patients has lost this property. With many others I have
been unable to verify these observations, and believe that Freund was dealing
with erratic autolytic and bacterial effects and not with true cytolytic agents.
In any case Freund's studies would not encourage the view that tumor-cells
are destroyed in the circulating blood of cancer patients.

Retrograde transport was first emphasized by v. Recklinghausen as an
important process in the dissemination of tumors through both blood- and
lymph-vessels. The basis of his conclusions had been laid in many previous
observations on the fate of insoluble particles injected into the veins. Retro-
grade transport occurs chiefly in those organs in which there is a normal
venous pulse, lungs, liver, kidneys, heart, and brain, and in which violent
expiration or increase of intrathoracic pressure from any cause may trans-
form the weak forward into a backward current. When the main lymphatic
or vein is occluded the flow is entirely disordered and backward transport
is facilitated. Occlusion of the trunk vessel is probably essential for back-
ward metastasis in lymphatics but not in veins. In either case the backward
progress is probably slow and intermittent although wide distances seem at
times to be traversed (Arnold, Ernst). In the organs retrograde metas-

84 NEOPLASTIC DISEASES

tases arise from tumors originating in these organs and from distant tumors.
Thus a large tumor thrombus lying in an arched vein of the kidney in primary
sarcoma of tibia could originate only by backward passage through the renal
vein of an embolus traveling from below. Emboli in a cerebral sinus with
cancer of breast (Arnold), in an hepatic vein from intestinal or thyroid cancer
(Heller, Bonome), and in cerebral, cardiac, pulmonary, and hepatic veins
with hypernephroma (Ernst), are not infrequent examples. Backward
passage through obstructed lymphatics may be assumed in cases of advanced
cancer of bronchial nodes with subpleural lymphatic invasion but without
involvement of pulmonary parenchyma. Cases of gastric cancer with
involvement of portal, lumbar, and inguinal nodes, v. Recklinghausen referred
to retrograde passage of obstructed lymphatics. Metastases in supra-
clavicular nodes from tumors of abdomen and testis, with invasion and
occlusion of thoracic duct have been explained by several observers as retro-
grade lymphatic growth (Troisier, Poncet, Most). A cancer of gall-bladder
with retrograde metastases in renal lymphatics, the veins being free, has been
described by Vogel. With cancer of pancreas is sometimes found continuous
lymphatic invasion down the aorta to the pelvic nodes and discrete nodules
along the mesentery. In many of these cases it may be difficult to eliminate
backward permeation, as Handley has shown, and some writers, especially
Ribbert, doubt or deny the occurrence of retrograde lymphatic embolism.
Yet there seems to be good reason for holding that such embolism frequently
occurs especially when a lymphatic trunk is occluded.

That tissue and tumor-cells pass through the pulmonary capillaries
has frequently been demonstrated and in certain tumors, especially the
lymphosarcomas, general metastases develop in this way. Passing the lungs
the embolic cells tend to lodge in organs with feeble circulation, as liver,
bone-marrow, and subcutaneous tissue. Or being arrested in the lung the
embolic cells may grow through the vessels and break into the pulmonary
veins (secondary embolism). Zahn speaks even of a tertiary embolism,
metastatic tumors of the liver producing pulmonary emboli which grow
through the lung.

Abnormal communications between the cardiac chambers may permit
the passage of larger emboli into the aorta. In a case of sarcoma of the
seminal vesicles and in one of thyroid cancer, metastases were found in the
kidneys but not in the lungs, from which Zahn concluded that emboli had
passed through a patent foramen ovale, a process which he termed paradoxic
embolism. Finally the blood-vessels are reached by way of the thoracic
duct.

Thus invasion of the blood-stream may occur by: (i) Direct invasion of
vessels in primary or secondary tumors, (2) secondary embolism, (3) tertiary
embolism, (4) retrograde transport, (5) paradoxic embolism, (6) passage
of single cells through pulmonary venules, (7) through the thoracic duct.

Metastasis of a benign tumor was first claimed by Cohnheim for thyroid
adenoma, and similar observations have since been reported by many
writers. The great vascularity of this gland, the immediate contact of
epithelium with capillary endothelium, and the extreme hyperplasia which
may follow functional stimuli, offer unusual conditions in the thyroid favor-
ing the dislodgment of adenomatous alveoli and even of simple hyperplastic
cells. The occurrence of such metastases has been accepted by the majority
of observers (Borst), but Williams and many others believe that in all such
cases a small malignant tumor exists in the thyroid which gives origin to the
metastases. The question is further complicated by the great difficulty
of estimating from their morphology the growth capacities of thyroid cells.

METASTASIS 85

It is a fact, however, that thyroid cells have unusual powers of proliferation
and growth, and it would seem necessary to admit that under rare conditions
thyroid adenoma and hyperplastic thyroid cells may give rise to distant
benign tumors. Definite proof of such an event requires minute search of
the main and any accessory thyroids, which has been lacking in my own and
many other reports.

Similarly for the benign hydatid mole and even for the normal placenta
there is a very suggestive group of facts which has led Marchand and others
to believe in the occurrence of malignant metastases of normal chorionic
epithelium.

Pure chondroma not infrequently enters veins and its ameboid cells
produce distant metastases. In the notable case of Ernst's a chondroma
of the vertebral column advanced through the lumbar, adrenal, spermatic,
azygos, and cava inferior veins into heart and lungs. Discontinuous metas-
tases usually in the lungs have often been observed from chondroma of pelvis,
scapula, fibula, etc. (Lit. Ernst). The metaplasia of undifferentiated tumor-
cells derived from teratomas or sarcomas must account for some chondro-
matous metastases from tumors of testis and probably from other organs.

Metastases have been observed with leiomyoma of the uterus (Klebs,
Langerhans, Beetson, Schlagenhaufer) ; of the stomach (Hansemann, Moser,
Borrmann); and jejunum (Ribbert). In some cases the structure of the
tumor has not varied from the usual benign myoma, but in others the cells
were larger and nuclei large and oval. Some were cystic and vascular.
Birch-Hirschfeld speaks of the invasion of uterine lymph-vessels by
myoma. Williams denies that the simple uterine myoma ever produces
metastases.

Contact Infection. — Contact of a cancerous surface with an opposed,
abraded or inflamed mucous surface is a rare source of transfer of tumors.
The best known example is the infectious lymphosarcoma of dogs which is
commonly transferred by coitus. This and other tumors of lower animals
may sometimes be transferred by rubbing a granulating surface with a portion
of tumor.

The cases of cancer a deux in man have figured prominently at times but
in none has the actual transfer by coitus been proven. Demarquay collected
134 cases of cancer of penis in only one of which transfer by coitus appeared
possible. Of 27 such cases collected by Gueillott none seems to me beyond
question. Yet the genuineness of some of these cases cannot be denied.

Transfer of epithelioma of lower lip to upper is difficult to establish but
seems to have occurred in a few cases (v. Bergmann). In a case reported by
Hartmann and Lecene a cylindrical cell cancer of the cervix seems to have
become implanted on the squamous epithelial surface of the vagina.

Implantation of epithelioma of esophagus in the stomach has been
widely accepted as a fact (Borst), but Borrmann has found continuous per-
meation of the lymphatics connecting such tumors. Similar evidence has
not been adduced" against implantation of renal tumor fragments in the ureter
(Butlin). Likewise the contact transfer of carcinoma has been reported
from one point to another in the urinary bladder, vagina, vulva (Thorn,
Walter), cheek (Lucke), thighs (Williams), stomach (Klebs), vocal cords
(Semon), and from hand to conjunctiva (Kaufmann). In most of these
cases it is difficult to eliminate lymphatic extension and primary multiple
tumors so that the doctrine of contact infection has always excited a legiti-
mate scepticism. Bucher, Kaufmann, and others have fully stated the
many grounds for this scepticism and it is obvious that the evidence must be
very complete before any case can be accepted. The transferred tumor

86 N EOF LA STIC DISEASES

should be of different structure from that arising in the implanted surface
and the lymphatics should be free from invasion.

"Genius loci," or the particular susceptibility of a tissue to develop
secondary tumors is an interesting phase of the study of metastases. Fa-
miliar examples are the predominance of pulmonary metastases in chorioma,
which is simply explained by the intra vascular position of this tumor; the
bone-marrow metastases of hypernephroma and cancer of prostate; and the
multiple cutaneous tumors secondary to lymphosarcoma testis. The mech-
anism of the circulation will doubtless explain most of these peculiarities,
for there is as yet no evidence that any one parenchymatous organ is more
adapted than others to the growth of embolic tumor-cells. The spleen, how-
ever, seems to escape with peculiar frequency.

Virchow observed that organs frequently originating cancers are rarely
the seat of metastatic cancer. Yet Zahn collected 16 metastatic cancers of
the stomach, and 26 invasions of the ovary in 366 cases of mammary cancer.

The preservation of structural type in metastatic tumors is often remark-
able, yet as a rule there is increased anaplasia and more rapid growth in
metastatic tumors and especially in recurrences after operation.

Adenocarcinoma of the alimentary tract invades the lymph-nodes and
the peritoneum, and produces distant metastases while rigidly maintaining
its large alveolar type. Adenocarcinoma of the stomach has been recognized
in a metastasis over the scapula. The metastases of benign tumors are
always typical in structure. The bone metastases of hypernephroma are
usually recognizable. Metastatic melanoma is usually but not always
pigmented. On the other hand the general metastases of chorioma tend to be
overgrown by Langhans cells with loss of syncytium. Sciuamous epithelioma
may yield spindle-cell tumors in the liver.

In general there is a gradual loss of structure in metastatic tumors.
The liver metastases of mammary cancer, hypernephroma, and chorioma
may be indistinguishable. The more anaplastic the original tumor the less
is the room for change in its metastases. Mixed tumors tend therefore to
become simple and certain elements may be eliminated in metastases and
recurrences. This rule is best illustrated in the great variety of simple
metastatic growths arising from teratoma testis. A peculiar form of elimi-
nation of epithelium is seen in the regional metastases of mixed tumors of
the parotid which are often purely myxomatous or chondromatous.

Tridermal metastases which rarely arise from teratoma of testis or ovary
indicate either that all three tissues are contained in the cell embolus, or
that undifferentiated cells unfold their potencies after lodging in distant
organs.

The osteoplastic carcinoma of the prostate offers a remarkable change of
type and tendency in its pulmonary metastases. Here osteosarcoma ap-
pears to accompany the carcinomatous elements. A satisfactory explanation
of this process cannot be given but Schmorl supposes that the original
bone metastases incite osteosarcomatous growth from which embolic cells
yield osteoid tumors in the lung.

It is characteristic of certain cases of several tumors that a very small
original focus gives rise to very bulky secondary growths. This course is
followed by some cancers of the breast with large tumors in the axilla, by
melanoma of the skin or cancer of gall-bladder invading the liver, by mucoid
cancer of colon involving the peritoneum. On the other hand squamous
epithelioma rarely produces bulky metastases.

Recurrence. — After apparently complete removal of malignant and of
some otherwise benign tumors the growth may recur. The recurrence is

METASTASIS 87

usually in the operation wound or its immediate neighborhood (local re-
currence), or in adjacent lymph-nodes (regional recurrence), or it may appear
in distant organs from metastatic emboli. Sarcoma often recurs at a distance
from the original growth while local and lymphatic recurrence is the rule
with carcinoma.

Recurrence by implantation from abdominal tumors in the laparotomy
wound or in the peritoneum is a well recognized hazard of operations. The
return of many malignant tumors is prompt and local but many years may
elapse between the removal of choroidal melanoma and its reappearance in
widely distant regions.

The very wide variations in the periods of recurrences are the result of
many complex factors so that statistical reports in this field are of limited
significance. Yet Williams has gathered a very interesting collection of
such records. Among the most striking of these reports are the long inter-
vals sometimes elapsing between operation and recurrence, in cancer of
breast, 30 years (Heurteaux, Verneuil); rectum, 21 years (English); of tongue,
18 years (Guinard); choroidal sarcoma, 14 years (Fischer and Box); uterine
cancer, 15 years (Poniard). The records of repeated recurrence are also of
interest as encouraging the surgeon. Thus Gross performed 22 operations
in 54 recurrent tumors in a case of sarcoma of the breast during four years,
the patient finally recovering.

Recurrent tumors may reproduce exactly the structure of the original
or follow the rules already stated for metastatic growths. Local recurrences
usually show increasing malignancy and anaplasia, and at times the recurring
tumor shows an astonishing variation from the original type. Clinical
observation is here supported by the results obtained with transplantable
tumors which by repeated passage may be considerably heightened in activity.
Squamous epithelioma is comparatively stable in type, as is also adenoma
destruens. Most alveolar carcinomas tend to lose the alveolar form and
recur diffusely. Myxoma of the skin recurs repeatedly with the same struc-
ture, while melanoma may retain or lose its pigment. Recurring mixed
tumors tend rapidly to become simple. One sees pure chondroma in the
returns of parotid tumors. In the second to fourth recurrences of a complex
tridermal teratoma testis I found pure angiosarcoma. In a case of ada-
mantinoma originating as squamous epithelioma, L'Esperance, in this
laboratory, has recorded progressive changes through plexiform epithelioma,
glandular carcinoma, diffuse small spindle-cell structures, alveolar round-
cell sarcoma, and finally in the sixth operation, diffuse round-cell "sarcoma."

There appear to be no indications that a recurrent tumor may be less
anaplastic than the original, but Apolant claims to have reduced an alveolar
carcinoma to an adenoma by transplantations in immunized mice.

Recurrent tumors in the great majority of cases arise from cells or portions
of the tumor which have escaped removal. Microscopic section of the edges
of specimens removed at operation often reveals that the knife has passed
through strands of tumor tissue or vessels containing tumor-cells. There
can be little doubt that the rough manipulation of cellular tumors in the
preparation of the patient and in the excision of the growth widens the field
of infection by forcing cells through vessels and tissues spaces. Or, viable
cells are scattered through the wound by piece-meal removal from inaccessi-
ble regions. The practice of removing a portion of the tumor for diagnosis
may add to the dangers of local dissemination. With myxoma, a tumor
which is characterized by persistent local recurrence, the semi-fluid tissue
may very readily be forced into the surrounding fat tissue.

Arising from remnants of the original growth recurrence is usually

88 NEOPLASTIC DISEASES

prompt, multiple, in the line of incision or near by, and of the same type as
the original growth or more malignant. Yet there are many records of cases
in which recurrence in the line of incision has been delayed for years. Such
cases require the conclusion that displaced cells may long remain dormant.
The many instances in which partial removal of malignant tumors has been
followed by regression of the remnant, as in ovarian carcinoma and in
chorioma, indicate that the mechanical disturbance of nutrition, or removal
of local sources of growth stimulus, or the general relief of the organism
from toxic products, turn the balance in favor of the patient, and lead to
absorption of tumor-cells. Thus tumors in rats sometimes regress after
hemorrhagic infiltration following crushing trauma. The same factors may
be assumed to retard the growth in more malignant tumors which spring up
at varying periods after incomplete removal.

As a second source of recurrent tumors it has been suggested by v.
Rindfleisch, Beneke, and others that tumors exert a pervasive formative
influence leaving the surrounding tissues in a state of excitation and with a
momentum toward neoplastic growth, so that after the removal of the tumor
the adjacent tissues give origin to a new tumor. This somewhat vague
conception is vigorously rejected by Ribbert and is quite irreconcilable with
the theory of origin from isolated cell groups. Yet there are several considera-
tions which render it inadvisable to discard such a theory of recurrences.
This question is closely related to that of the influence of tumor growth upon
surrounding tissues and to that of the multiple origin of tumors in the same
organ.

Attention has already been called to the fact that some tumors advance
by gradual lateral extension over previously normal cells, so that removal
at one stage of this extension may leave other cells which later reveal their
momentum toward tumor growth. The local recurrences of some lingual
and laryngeal cancers seem to accord with this view. Further, the local
predisposition to tumor growth which figures distinctly in many phases may,
as Borst points out, extend over a considerable area in all of which the tumor
growth does not reveal itself at once but develops in separate stages or foci.
Such conditions seem rather clearly revealed in neurofibromas, and, according
to Hauser, with various carcinomas, especially those of the gastro-intestinal
tract.

Ovarian cystomas recur in the opposite ovary or in fragments of the
first ovary or in misplaced ovarian structures in the neighborhood, showing
the influence of local predisposition (Velits). Many authors have pointed
out the great frequency of cancer after ovariotomy and have endeavored to
show, without 1 think complete success, that loss of the ovaries greatly
increases the local disposition of many tissues to cancer (Wells, Kratzenstein,
Neugebauer, Williams).

A third source of recurrence is found in the multiple origin of many tumors.
The removal of a small cancerous nodule from the breast with chronic mastitis
may readily be followed by the appearance of a new tumor in an adjacent
portion of the gland or in a supernumerary gland. One seldom hears of
recurring uterine myomas since these are so clearly multiple tumors, but
multiplicity while less obvious is perhaps equally common with epithelioma
and sarcoma of the skin where the new tumor is often regarded as a recurrence.

New tumors following operation differ from the true recurrences in not
appearing in the scar, developing usually after an interval, reproducing the
original growth without great change in malignancy, and often being solitary.

CHAPTER V
CHEMISTRY OF TUMORS; SEROLOGY

Constitution of Tumor Proteins. — The conception that tumor proteins
must differ in essential respects from those of normal tissues has not been
demonstrated by chemical methods. The nature of the problem involved
appears to have presented itself in different forms in the minds of investi-
gators who have attacked the problem.

A different distribution of normal proteins from that of normal tissues
has been demonstrated in tumor tissue by Petry, Wolff, and Beebe, who found
a higher content in nucleoprotein, more uncoagulable protein, and less
globulin and albumin. It is probable that these results depend on the over-
growth of cell nuclei, degenerative and autolytic processes, and edema.
Nucleohiston is present only in lymph-nodes among normal tissues and its
presence in lymphatic metastases of tumors originally free from this protein
indicates that metastatic tumors receive chemical impress from the tissue
in which they are growing. Although nucleohiston is absent in primary
carcinoma of breast and in the testis, Beebe found this substance in lymph-
aode metastases of mammary cancer and Bang in the lymphatic metastases
of testicular carcinoma. Nucleohiston gives a precipitate when CaCla is
added to a watery solution of the tumor.

Direct chemical analysis of the split products of cancer proteins by Wolff
yielded a high proportion (35 per cent.) of glutaminic acid, while Bergell
and Dorpinghaus found excess of alanin, phenylalanin, asparaginic acid and
diamino acids. Yet these results conflicted with those of Petry, Neuberg,
and Beebe.

Resistance to peptic and susceptibility to tryptic digestion was said by
Blumenthal and Wolff to distinguish tumor from normal tissues. Yet
their results were not uniform and were probably determined by the increased
amount of nucleoproteid in some of the tumors.

Excess of potassium and deficiency in calcium in rapidly growing tumors
free from necrosis, and the opposite relations in slowly growing or old and
necrotic tumors have been demonstrated by Beebe and by Clowes.

Pentose was greatly increased in a fibrocarcinoma of the breast in com-
parison with the amount in the normal breast in cases studied by Beebe
and Shaffer. These authors also found that the pentose content in different
tumors varied and bore no relation to the nucleoprotein, or to the presence
of degeneration. In hepatic carcinoma and in hepatic metastases of gastric
carcinoma Neuberg found 70-80 per cent, more pentose than in normal liver.

Lactic acid appears in tumors, according to Fulci, in considerable
quantities. It is more abundant in epithelial than in connective tissue
growths and increases in the more malignant actively growing tumors. Its
formation is dependent on metabolic activity of the tumor-cells, its source
the blood carbohydrates and possibly the proteins. It appears to have no
relation to cachexia.

Of the total phosphorus of the normal liver B. Wolter found 24.68 per

For a fuller discussion of this subject with literature consult Wells, "Chemical
Pathology."

90 NEOPLASTIC DISEASES

cent, as phosphatid phosphorus, in the tumor-free portions of a liver with
primary carcinoma 22.04 Per cent., and in the tumor nodules 16.28 per cent.,
while the protein phosphorus in the same materials ran 20 per cent., 25.5
per cent, and 26.70 per cent. In 0.0634 gm. of dried tumor substance he
found 1.40 per cent, of cholesterin.

Tryptophan was markedly increased in an epidermoid carcinoma of skin,
and in an hepatic carcinoma, over the proportions found in normal skin and
liver in cases studied by Fasal, but this substance was absent in a mammary
fibrocarcinoma.

Fats. — The chemistry of tumor fats has been studied extensively in renal
and adrenal tumors (q.v.). In general it appears from Bossart's work that
actively growing tumors free from degeneration contain little fat and much
lecithin, while with degeneration and necrosis free fats replace lecithin.

Purin bodies were found by Wells and Long in about the same form
and amount as in normal tissue and less abundantly than the nuclear
content would suggest. The purin enzymes were also identical with those of
normal tissues, guanase being constantly present and adenase absent.

The delicate methods of immunological studies indicate that there
are biological differences between certain tumor-tissues which are probably
based on chemical distinctions but the results obtained in this field are not
decisive. Following Michaelis' failure to produce specific immune bodies
against mouse tumor cells, Beebe working with purified nucleoproteids of a
leukemic spleen produced a serum which agglutinated the emulsified cells of
this spleen and those of a lymphosarcoma, but acted feebly and only in strong
concentration on cells and nucleoproteids of normal spleen and other tissues,
as well as of cancer and spindle-cell sarcoma.

Other data bearing on this question are considered in the discussion of
experimental immunization.

Tumor Ferments. — The study of special ferments in tumors by Buxton
and Shaffer demonstrated no distinct differences in quantity or quality from
equivalent normal tissues. Weil using the viscosimeter found more proteo-
lytic activity in certain cellular tumors than in certain normal tissues but was
not prepared to say that the difference did not depend on leukocytes. Abder-
halden, however, concluded that extracts of tumor-tissue and those of normal
tissue split certain polypeptids in a different manner. Extracts of normal
mouse liver cleave certain polypeptids slowly while those of mouse tumor act
much more quickly. In comparing the extracts of mouse and human
tumors with those of normal tissues he found differences in the split products
of the proteins after the action of these ferments. Comparing the pepto-
lytic action of normal and tumor-tissue from lower animals on peptone,
Abderhalden and Medigreceanu found' occasional but no constant or striking
differences.

Autolysis is often observed to proceed more rapidly in certain tumor
tissues than in normal tissues, but it is probable that all such differences
depend on the more cellular character, and presence of degenerating tissue,
edema, leukocytes, and bacteria. It is extremely difficult to obtain normal
tissue which may safely be compared with tumor-tissue in this respect.

The increased activity of autolysis is well illustrated in Yoshimoto's
experiments in which an hepatic carcinoma yielded 7.2 gms. N in the split
products as compared to 4.8 gr. in equivalent units of normal liver. With
a mammary carcinoma the difference was even greater. In the tumor auto-
lysate purin N was reduced, while that of diaminoacids, peptone,; and
ammonia was increased in proportion.

It is commonly believed, on the basis of Jacoby's experiments, that

CHEMISTRY OF TUMORS; SEROLOGY 91

autolytic ferments have a high degree of specificity for the proteins of the
organs in which the ferments are found. Blumenthal and Wolff have reported
that when measured amounts of tumor-tissue and of normal tissue are auto-
lyzed separately in one series, and conjointly in another the autolysis is
always greater in the conjoined series. They conclude that the tumor ferments
attack the normal tissues and exhibit a heterolytic property. On this basis
rests the claim that infiltrative growth and cachexia depend on the heterolytic
activities of the tumor ferments. Baer and Ettinger demonstrated a pro-
teolytic activity in cancerous ascitic fluid which failed to appear with
ascitic fluid from other sources, but Kepinow and Hess and Saxl were unable
to verify any of these observations. The possible presence of bacteria,
necrosis, or postmortem decomposition has not apparently been considered,
although Neuberg has subsequently denied that bacteria or leukocytes have
any influence on the results.

Ascitic fluid of carcinomatous origin yielded little euglobulin (12.44
per cent.), increased albumin (64.92 per cent.), and the usual proportion of
total globulin 35.07 per cent. (Joachim, Wolff). Similar proportions of
proteins were determined in edema fluid and expressed cancer juice by Wolff.

The milky character of carcinomatous ascitic fluid is ascribed by Wolff
to the presence of cholesterin-acid-ester combined with euglobulin. In
a series of cancerous and other ascitic fluids Weil demonstrated occasional
but inconstant hemolytic and hemagglutinative properties, abundance of
complement in two cancer cases, and some antitryptic action, but no constant
distinction between the cancerous and non-cancerous fluids. Signs of active
autolysis in a peritoneal exudate accompanying ovarian carcinoma are
reported by Umber, who found increase in non-coagulable N, albumose,
leucin and tyrosin. Eppinger reports similar findings. In a bloody cancer-
ous exudate K. Wiener demonstrated an ereptic ferment, but any tryptic
ferment present was masked by the blood. In this fluid were traces of
histidin and arginin.

J. W. Vaughan has observed a striking relation between anaphylactic
sensibility of guinea-pigs inoculated with tumor residue and the lymphocy tosis
excited by the inoculation. Animals receiving the water-soluble residue of
cancer-cells after their extraction with alkalized alcohol, or a vaccine of
tumor-cell emulsion after extraction with alcohol, showed in many cases very
high lymphocytosis, and in such sensitized animals anaphylactic death was
readily produced. The sensitization was quite transitory, lasting only during
the 4 to jo-hour period of lymphocytosis, and the author interprets the
result as depending on the action of lymphocytic ferments on the tumor-cells.

Wassermann Reaction in Cancer. — The results obtained with the Wasser-
mann reaction in cancer patients have varied very widely. Caan secured
positive reactions in 41 per cent, of 85 cases; in 6 of 7 lip carcinomas; in
9 per cent, of breast tumors; and in 17 per cent, of gastro-enteric tumors.
All of these cases were free from clinical signs of lues. A. Foerster secured
36 negative reactions in 37 cases, and Noguchi 38 in 39, while F. J. Fox
reports 5 positive reactions in 210 cases of cancer. Positive reactions in
patients with cerebral tumors free from syphilis appear to be not uncommon
(Cohn).

Complement Deviation with Autogenous Tumor Antigen. — In over 100
cases of carcinoma and 16 cases of sarcoma the complement deviation test
of the blood serum has been made, using tumor antigens of the same or
similar tumors. In the majority of cases the test has been positive, but in a
large number the results have been negative. Recently, W. Barratt, using
the patient's own tumor as antigen, got negative results in six cases. De

92 N EOF LA STIC DISEASES

Marchis often obtained negative results in both early and advanced cases.
A positive result he regarded as of considerable diagnostic value although it
occasionally occurred in syphilis and other diseases. With an antigen pre-
pared from human carcinoma v. Dungern claims to have obtained comple-
ment deviation with the serum of both carcinoma and many other tumors
such as lymphosarcoma, glioma, and even myoma. These paradoxical
results failed of verification in the hands of Edzard, Schenk, and Coca.

It is evident that the subject of complement deviation in tumors is without
substantial foundation.

Complement deviation by antigen of Micrococcus neoformans tested
with serum of cancer patients, in all but 7 of 144 cases, was secured by Yama-
nouchi and Ly tchkowsky. The reaction was also positive in 44 cases of lues,
but not in benign tumors. F. Green obtained positive reactions in cancer
with the antigen of Micrococcus neoformans and also with those of staphy-
lococci and streptococci.

Antitryptic Power of the Blood. — Blood serum has long been known to
inhibit the action of certain ferments. Brieger and Trebing first found that
the serum of cancer patients inhibits very markedly the action of trypsin.
Using various technical methods, these authors, followed by Bergman and
Meyer, Herzfeld, Roche and others, showed that in about 90 per cent, of
cancers there was marked increase in the antitryptic power of the blood serum
but that considerable increase occurred also in many other diseases, especially
in those attended with leukocytosis (Wiens, Schlecht). Weil by an exact
quantitative method determined that the "antitrypsin" is increased in some
cancer cases beyond that observed in any other diseases, while in other cases
it failed to fall as low as the ratio observed in other diseases. All authors
agree that the failure of any increase is rather strong evidence against the
existence of established malignant disease. Brieger regarded the phenome-
non as a sign of cachexia and an immunity reaction against excessive amounts
of proteolytic ferments derived from tumor-cells. Wiens and Schlecht
trace a close relation with leukocytosis. Weil points out that the exact
nature of the inhibiting substance is undetermined and that no specific relation
to trypsin need necessarily exist, since blood serum also inhibits saponin.
Among 57 cases of cancer and three of sarcoma S. M. Lewin found much in-
creased antitryptic power in 57. He could not refer the antiferment action
to leukocytes but attributed it to a reaction to proteolytic ferments discharged
into the blood from degenerating tumor-tissue.

Meiostagmin Reaction.— This reaction is based upon a change in the
surface tension of blood serum. When to a dilute solution of an alcohol-
ether extract of cancer tissue is added a small portion of blood serum from a
carcinoma patient, a change in the surface tension is produced which may
be estimated by the reduced number of drops of the fluid passing in a
given time through a specially designed pipet or stalagmometer. This
physiochemical alteration was employed by Ascoli in the study of cancer
serum and was considered by him to result from a somewhat specific inter-
action of cancer antigen and cancer antibody developed in the serum. The
specific character and immunological nature of the reaction was soon set
aside when it was discovered that extracts from many organs and even syn-
thetic substances, as linoleic and ricinic acids, were equally effective as antigens
(Ascoli, Izar). It was also shown that the sera of a great variety of diseases
and of pregnancy reacted in the same manner with a variety of antigens,
thus establishing that the production of the reacting factors was the result
of a constitutional process of widespread occurrence.

To carry out the test one may best employ a solution of 0.2 gm. ricinic

CHEMISTRY OF TUMORS; SEROLOGY 93

acid plus 0.5 gm. of linoleic acid in 10 c.c. absolute alcohol. To i c.c. of serum
is added, by dropping carefully from a pipet, o.oi to 0.02 c.c. of the antigen
solution and then 9 c.c. of 0.85 per cent. NaCl with thorough mixing. As
a control i c.c. of serum is added to 9 c.c. of salt solution. Both tubes
are kept i hour on a water bath at 5o°C. and after 2 to 6 hours the drops
are counted by the stalagmometer. The count increases in the sera receiving
antigen, an increase of 1.3 or less being regarded as negative, 1.7 + posi-
tive, intermediates uncertain.

Various other antigens may be employed according to the choice of the
investigator. Burmeister prepared several antigens by different methods
all with practically identical results. The results obtained vary considerably.
Ascoli and Izar secured nearly constant figures with tumor sera. N. Blu-
menthal (1915) finds that 78 per cent, of gastro-intestinal carcinomas react
positively, while in other forms the positive results are much less, and in
cutaneous and hepatic carcinoma and sarcomas very few. He concludes
that the test is of diagnostic value only in gastro-intestinal carcinoma, and
in pregnancy, while it is always necessary to exclude diabetes, uremia, in-
fectious fever, tuberculosis, lues, chronic joint diseases, and cirrhosis. The
diagnostic importance is therefore practically nil.

Various hypotheses have been suggested in explanation of the reaction.

1. The presence in the serum of abnormal lipoids resulting from fermen-
tative processes in the cancer-cells. This view is favored by the heat-resist-
ance of the serum; by the ready removal of the active factors by extracting
the serum with alcohol, ether or chloroform (Izar, Michaeli, Cottoretti) ;
by the discovery of synthetic antigens as linoleic acid (Kohler, Luger);
and by the demonstrated increase of lipoids in reacting sera (Michaeli,
Cottoretti). The reaction may also depend on a diminution in blood
cholesterin (Izar).

2. A diminution in blood albumens, and presence of peptone. This
condition is observed in most diseases giving the reaction.

3. Changes in the alkalescence of the blood. Heating the serum in-
creases the reaction and drives off CO% from the bicarbonates.

The epiphanin reaction of Weichardt depends upon a change in the alka-
lescence of the serum. This reaction has been found positive in 81 per cent,
of a series of cases studied by Jozca and Tokioka. By this means E. Rosen-
thai finds it possible to demonstrate antibodies in the blood of guinea-pigs
immunized by human or mouse tumor and in the serum of tumor-bearing
mice.

Stammler's Reaction. — Most tumor extracts exhibit a slight or distinct
opalescence. Stammler observed that the addition of cancer serum clears
up this opalescence with the formation of a slight precipitate, wThile most
normal sera fail to act in this manner.

Ransohoff's Test.— Ransohoff observed that the injection of 3-5 c.c. of
blood serum from cancer patients in guinea-pigs which had previously been
sensitized by i c.c. of such sera, caused none or very weak anaphylactic
reaction, while normal human serum produced the usual violent reaction.
Since the same immunity followed sensitization by tumor extract, he con-
cluded that the immunizing substance of the serum was derived from the
tumor. In a series of 30 cancer cases 92 per cent, gave a positive reaction
while the test was always negative in other conditions. F. Green was
unable to verify these results.

CHAPTER VI
THEORIES OF THE NATURE OF CANCER

The Embryonal Theory. — For many years before the appearance of
Cohnheim's work, observations had been accumulating to show that tumors
were in some way related to the embryonal growth of tissue. Lobstein,
1829, likened the growth of a tumor to that of embryonal tissues and con-
ceived that neoplastic growth had lost the control of the organism. Recamier,
1829, noted that cancer developed from irritated moles and pointed out that
supernumerary organs, "tons les tissues extraordinaires accidentels," readily
degenerated into cancer. Rokitansky regarded certain myxomas, in his
class of collonema, as derived from embryonal connective tissue. Houel,
1864, designated certain sarcomas as embryonal, because they seemed to
represent an abnormal growth of the same elements which in the embryo
formed normal organs and tissues. In the subsequent decade there were
several observations of tumors arising in connection with abnormalities of
development, and the embryonal theory was believed to apply to the group
of complex teratomas (Lucke). A further basis of the embryonal theory
existed in the belief maintained by Remak, 1854, that cancer arose from
misplaced islands of epithelial cells in tissue not normally containing epithe-
lium. Paget in 1853 remarked that invisible defects in the formation of
organs might render them or portions of them peculiarly apt for the seats of
malignant disease.

In 1874 Durante clearly stated the doctrine that all tumors arise from
embryonal groups of cells. He observed sarcoma twice developing from
pigmented moles, examined many nevi, and described the embryonal character
of the cells composing them. Hence he concluded that similar circumstances
must surround the origin of all tumors, especially the malignant growths.

The modern embryonal theory was placed on a comprehensive basis by
Cohnheim whose original conceptions were ably supported by his own ob-
servations and have been steadily strengthened by very numerous contribu-
tions from many sources during the past forty years. While not a theory
of universal application, that embryonal cells possess more than any others
the essential factors of tumor growth is, perhaps, the most important single
fact in our knowledge of tumor genesis.

Cohnheim believed that tumors develop from masses of simple or complex
tissue misplaced during embryonal development. Or, they arise from small
groups of superfluous cells which have retained their embryonal characters
but are not necessarily misplaced. The idea of the embryonal character
of the cells appeared to him essential. Most of the embryonal cells result
from overproduction after the formation of the germ layers and before the
appearance of definite rudiments of the organs, and he held that these super-
fluous cells were either distributed throughout the viscera or were gathered
at certain points, as the mucocutaneous junctions. The sudden develop-
ment of the cells he referred chiefly to changes in the blood-supply.

The entire group of mixed tumors and the simple heterologous growths
were at once included in the scope of the embryonal theory. Indeed when
one explores the group of teratomas there seem to be all intermediate forms

THEORIES OF THE NATURE OF CANCER 95

from the complex sacral tumors up to parasitic implantations containing
parts of organs or limbs and even up to such phenomena as identical twins.
Likewise when one passes downward through the complex heterologous
tumors of the parotid to the simple heterologous growths which arise from
small groups of cells misplaced or remaining embryonal it would seem that
tumor genesis were chiefly a question of the mechanics of development.
The present support of Cohnheim's theory is extensive. Congenital tumors
of many varieties, chiefly mesoblastic but also epithelial, exist at birth or
develop shortly after, and the evidence is clear that embryological disturb-
ances are concerned in their origin. Such tumors include fibroma, myxoma,
lipoma, chondroma, angioma, glioma, myoma, mixed tumors of kidney,
dermoids, and teratomas.

Congenital cancers affect the kidneys (Leibert), adrenal (Reiman),
testis (Phillip), vagina, ovary (Ahlfeld), pylorus (Cullingworth), pancreas
(Bohn),skin (Braun), shoulder (Selberg),neck (Kronlein), pleura (Muus), etc.

The embryonal tumors of adults which yield a type of tissue closely
simulating the embryonal counterparts and resemble the congenital tumors
of the same regions form a well-recognized group for which an identical
etiology seems highly probable (Wilms). Among such tumors are myxomas,
rhabdomyoma of heart, amyelinic neuroma, tubular neuro-epithelioma, and
a great variety of very cellular malignant tumors whose histogenesis has not
been fully traced. Rudimentary organs are specially susceptible to tumor
growth, as undescended testes, Luschka's gland (Defosses), the paro-ophoron
(Ricker), the neurenteric canal (Kraske).

Supernumerary organs are frequent seats of tumors. The misplaced
adrenal rests have a wide distribution and give origin to many heterotopic
growths, in and about the kidney, along the genito-urinary tract, in testis
and ovary, throughout the pelvis, and elsewhere (Chiari, Askanazy,
Lubarsch). Supernumerary breasts are occasional sources of mammary
cancer. Aberrant portions of thyroid, thymus, pancreas, uterus, and ovary,
give rise to many tumors in the regions of these organs. Some authors
assume the presence of straggling sex cells all the way from the cephalic
to the caudal extremities of the embryo to account for complex teratomas in
neck, thorax, and abdomen.

The association of tumors with local abnormalities of development
strongly supports the embryonal theory. Prominent in this category are
the melanomas arising from pigmented moles and pigment spots in sclera
and choroid; the gliomas associated with spinal hydromyelia and various
abnormalities of cord and brain; sarcoma in cystic kidneys; adenomyoma of
uterus; gliomas, dermoids, and mixed tumors, with spina bifida; adenoma
with cysts of liver.

Persistent remnants of embryonal structures clearly originate the bran-
chiogenic cysts, epitheliomas and chondromas. The thyroglossal duct
gives cystic or solid tumors sometimes lined by ciliated epithelium at base of
tongue, in floor of mouth, or deep in the neck. Similar cystic tumors with
ciliated epithelium occur also in esophagus, peritoneum, and liver. Certain
embryonal tumors of uterus and adnexa and bladder are probably derived
from remnants of Wolfnan body or Gartner's duct. The pars postanalis
intestini yields epithelial tumors of the lumbar region, and the omphalo-
mesenteric duct and urachus give rise to abdominal tumors.

The extensive lists of heterologous tumors are most readily explained as
growths from aberrant cell groups. These include chondromas of tonsil,
breast, parotid, bladder, uterus, thyroid; epithelial tumors in connective
tissues and organs not normally containing such cells; the mixed tumors of

96 NEOPLASTIC DISEASES

uterus, bladder, breast; lipoma of pia and brain, and myo-lipoma of sper-
matic cord (Sazarin). While the heterologous tumors and teratomas of the
sex glands are probably derived from sex cells, the origin of teratoid tumors
in abdomen, thorax, pharynx, and other organs may still be referred in part
to aberrant cell groups of another type.

The predilection of tumors for mucocutaneous junctions, ostia at the
points of fusion of embryonal structures, and fissures formed by incomplete
union of such structures, impressed Cohnheim and all later observers as
strongly favoring the theory of origin from superfluous cells.

Here must be mentioned the frequent cancers of lip, nares, anus, rectum,
cardia, pylorus, portio vaginalis uteri, rete testis, and those at the tracheal
and esophageal junction where squamous and ciliated epithelial tumors have
been found transposed across normal boundaries. Misplacements at em-
bryonal fissures must be connected with the cholesteatomas and epidermoids
of skin, breast, abdominal and cranial cavities, spinal canal, and middle ear.
Many chondromas of the skeleton, as multiple chondroma of spine and spinal
canal, trachea, etc., are referred to irregularities in formation and separation
of islands of cartilage. The chordomas of spine, base of skull, and nares
reproduce the embryonal chorda dorsalis. Dentigerous cysts, odontomas,
and the frequent adamantinoma of alveolar borders arise from superfluous
or isolated remnants of the teeth. Symmetrical tumors sometimes strongly
suggest embryonal irregularities, examples of which are symmetrical nevi,
xanthomas (Rayer, Ehrmann), lipomas (Grosch, Kottnitz), angiomas,
myomas (Brigidi, Marcacci), sarcoma of epiphyses.

There are recorded many notable examples of symmetrical tumors in
paired organs, as fibrolipoma of kidneys, adenoma and carcinoma of kidneys,
ovaries, tubes, breast, adrenals, and lymphosarcoma of testis. Multiple
systemic tumors of the nerve-trunks, neurofibroma, suggest an imperfect
differentiation of endoneurium. From this point one is led into the exten-
sive field of multiple primary tumors of the same or different organs. Studies
in this field have usually led to the conclusion that developmental eccentrici-
ties were involved.

Later followers of Cohnheim's suggestions, especially Ribbert and Wilms,
have urged that in extra-uterine life cell groups may become isolated and
superfluous by various mechanisms, and form the basis of tumors. The
history of phylogenetic and ontogenetic development suggests that certain
tumors signify spasmodic reversions to the anatomic conditions of prehis-
toric man or of other closely related animal species. Thus the fusion of
multiple renculi, the coalescence of multiple uteri and breasts, the reduction
in length of stomach, intestine, appendix and colon, loss of lymphoid tissue
in the relatively narrow human cecum, and the elimination of hair and
sebaceous follicles in the face, suggest a source of superfluous cells and lay a
significant foundation for the atavistic growth of tumors in many organs.
Such influences, however, probably form only the feeblest of the predisposing
causes of tumors.

The studies of R. Williams, Lubarsch, Ribbert, Borrmann, Meyer, and
many others, have shown that embryonal rests are far more frequent than was
at first imagined. Wiesel for example, finds that adrenal rests are almost
constantly present along the spermatic cord and in the pelvic tissues of both
sexes. It is possible to argue with fair success, as R. Williams has done, that
all known tumors of the uterus arise from aberrant, or superfluous, or embryo-
nal cell groups. From a study of the various tumors of the testis I have
been led to the conclusion that practically all of them are derived from sex
cells. For tumors of the ovary Ribbert reached a similar conclusion. Thus

THEORIES OF THE NATURE OF CANCER 97

the more careful analysis of the origin of tumors has extended rather than
restricted the number of tumors that are known to arise from cells that have
lagged behind in development.

Limitations of Cohnheim's Theory. — The pursuit of the embryonal theory
has added extensively to our knowledge of aberrant cell groups and at the
same time revealed many new difficulties in the way of the embryonal theory.

It has been shown that neither the isolation nor misplacement, nor
abnormal persistence of cell groups, are necessarily followed by tumor growth.
The fate of tissue rests varies: (i) they may remain stationary; (2) they
may pass through normal stages of development and eventually atrophy;
(3) they may experience only a limited growth; (4) cysts may form from
them, or (5) tumor growth may appear.

Various hypotheses have been suggested to account for neoplastic growth
from rests. The period of isolation of the cells is an important factor. The
earlier its occurrence the less is the differentiation and the greater the capacity
for growth. Early embryonal rests when starting to grow meet conditions
which do not favor normal development.

Since only certain rests produce tumors it may be that the embryo-
genie disturbance which produces the rest stamps the cells with abnormal
qualities (Aschoff). This disturbance may perhaps be associated with
failure of the cells to experience their proper idioplastic development and
thus leave them in a condition unusually favorable to growth when such
potencies are in excess. Or the relation to the surrounding tissue may in-
fluence the growth of the rest. Separation from the normal nervous control
of the tissue is here to be considered. Organized cell groups such as those
composed of epithelium with supporting connective tissue, according to
Ribbert, tend to develop in an orderly manner, while epithelium alone
tends to develop a malignant tumor. Considering the great number of
organized adrenal and thyroid rests, tumors from these sources are rare.
The attempts to produce malignant tumors experimentally by transplanta-
tion of tissues, adult and embryonal, have not succeeded. On the contrary
the very numerous studies in this field have served to show that something
more than the separation of cell groups from their natural environment
is necessary for progressive growth (cf. Section on Experimental Research).

Thus it becomes evident that Cohnheim's theory while it explains the
structure and occurrence of many tumors wholly fails to reveal why the
embryonal cells begin to grow and when growing produce malignant tumors
instead of normal structures.

The limited growth of many benign tumors has been approached by
the structures produced by transplanted tissues, but the complete eman-
cipation of malignant neoplasms from the normal laws of growth remains
the obscure and essential element. In the attempt to solve this difficulty
the theory of cell autonomy has grown up.

Theory of Cell Autonomy. — The defects of Cohnheim's theory were
brought to light by studies undertaken in its defense. They showed that the
mere presence of embryonal cells was not sufficient to account for their growth
in tumors, and that tumors grow where probably no embryonal cells exist. It
is necessary to consider how tumors arise from cells which are neither origi-
nally misplaced nor essentially embryonal. In this field the theory of cell
autonomy has developed.

The germ of the theory of cell autonomy appeared in the studies of
Remak and Thiersch who traced the antagonistic relation of epithelium and
connective tisue throughout embryonal development. Epithelium seemed
everywhere to be the dominating embryonal tissue and to cease growing when

98 NEOPLASTIC DISEASES

it met sufficient resistance from the connective tissues. Thiersch found
in the weakening of the stroma of the involuting breast a relief of tension
capable of releasing the formative tendencies of gland-cells with their
longer span of vital activity . The decay of connective tissues he regarded as
senile atrophy and the growth of cells as degenerative proliferation. The
idea of cell autonomy appears also in Cohnheim's theory but here it was over-
shadowed by the embryonal element in the originating cells.

To account for the limitless growth of cells, embryonal or adult, the
theory of cell autonomy introduces the conception of tissue tension.

Ribbert endeavored to explain the growth of tumors solely through
the removal of certain cells from the influence of a tissue tension by which
their growth is normally restrained. He abandoned the theory that the dis-
turbed cells must be embryonal, claiming that the regenerative capacities of
adult cells are quite sufficient to account for all the characters of malignant
tumors.

Conception of Tissue Tension. — The theory of tissue tension assumes that
cells are capable of growing indefinitely unless restrained by a complex
group of forces. This assumption is perhaps not yet proven but there are
many facts in its favor. The astonishing regenerative powers of injured
tissues in plants, lower animals, and of many. organs and tissues of ver-
tebrates, the remarkable rate of growth of the vertebrate embryo, the hy-
pertrophy of the gravid uterus, the indefinite reparative capacity of injured
or transplanted epidermis, all suggest that normal cells, although eventually
restrained by organized forces, yet in proper environment are capable of
growing without limit. Ribbert insists that no unusual power of prolifera-
tion exists in cancer-cells, that these cells freed from the restraints of tissue
tension are merely exhibiting the powers of growth with which they are en-
dowed from the ovum. Weigert and Roux have also asserted that the re-
generative capacities of cells are determined from the moment of their de-
rivation from the ovum and can never be increased by any external stimulus.

Many observers have not accepted the Weigert-Roux hypothesis.
Lubarsch finds it incompatible with the extensive growth of metastatic tumors
and claims that external stimuli may induce an enormous increase in the re-
generative capacities of cells. I believe it is here necessary to distinguish
between the organized regenerative properties of tissue cells, which are truly
determined in the ovum, and the mere power of multiplication without or-
ganization which is subject to immense variations from the influence of the
environment. Tumor-cells seem to have more than their ancestral power of
growth as when without pressure they erode bone. In any case the facts
of normal and tumor growth seem to place the doctrine of growth restraints
and tissue tension in an unassailable position.

What, then, are the restraints to growth which control the multiplication
of cells and maintain the tissue in a physiological condition while permitting
normal repair? At least four such factors are known:

1. Mechanical pressure of cells on each other.

2. The distribution of nutriment.

3. The influence of specialized functions.

4. Organization.

Under each of these heads belong important contributions to the
theory of cell autonomy.

i. The influence of mechanical pressure may be traced both in the incep-
tion and in the course of tumor growth. In the former case it is somewhat
difficult to visualize the action of pressure. Thiersch thought that relief of
mechanical pressure followed the decay of the stroma about epithelial cell

THEORIES OF THE NATURE OF CANCER 99

groups and permitted the expansion of the cell mass, but this element is
inadequate to explain the inception of any tumor. The rapid lateral growth
of regenerative epithelium in skin grafts may be referred in part to the ab-
sence of lateral pressure. Loeb has made an effort to analyze this element
experimentally. Given a certain grade of epithelial overgrowth, as in the
tense ducts of chronic mastitis, trauma would relieve tension and facilitate
expansion of the cell mass. Acting upon blood-vessels pressure is a promi-
nent factor in controlling the progress of tumors. Fibrous encapsulation
causes some tumors to regress, and relief of pressure by incision of capsule
releases active growth. These events are frequently seen in both early and
late stages of tumor growth.

2. Distribution of Nutriment.— Many clinical and experimental data have
established the importance of blood- supply both for the physiological pro-
liferation of cells and the inception and progress of tumor growth. The
normal development of organs is regulated partly through the plan of the
arterial system, and partial agenesia follows arterial defects. Cohnheim
believed that cell rests begin to grow chiefly because of increased blood-
supply. The minute study of many early tumors indicates that increased
vascularity precedes the hypertrophy and multiplication of cells. Yet rela-
tive anemia is perhaps equally common.

While the blood-supply is often increased the abnormal capacity of tumor-
cells to absorb nutriment is a more obscure and significant feature of the
disturbed nutrition of neoplastic cells. Its explanation would throw much
light on the nature of the tumor process. The increased demands for func-
tion determine increased vascularity in certain tumors (thyroid cancer).
In the case of chorioma an increased supply of lutein secretion, according
to Pick and others, is associated with abnormal growth of the chorion over
whose normal growth this secretion presides. It is possible that other hor-
mones may by unusual activity favor the growth of tissues with which they
are concerned, especially in the field of multiple tumors of paired or func-
tionally related organs. Thus there is extreme fibrosis of the ovaries in
many cases of mammary cancer. The theory that a specific nutritive sub-
stance, not itself the nutrient molecule, presides over the growth of tumors
has been applied by Ehrlich to explain the results of his zig-zag transplanta-
tion of mouse tumors, from mouse to rat and back. While this theory
seems out of accord with certain observations concerning these transplant-
able tumors and seems to have little bearing upon the problem of tumor
growth in man yet it presents a new point of view for the study of the origin
of tumors in general.

3. The Influence of Specialized Functions. — The energies of cells are nor-
mally divided between proliferation and specialized function, between
work and growth. Normal function diverting the energies of the cells must
be a constant restraint or regulator of growth. In most organs certain
groups of cells are set apart for growth and from these are derived the more
specialized functionating cells. The germ center cells of lymph-nodes, the
cells at the bases of intestinal villi, and the basal cells of the epidermis, are
the ones that respond to demands for growth and from them tumors arise.
Overresponse to demands for growth and loss of functional requirements
both seem to precede the development of cancer, as in the adenomas of cir-
rhotic livers, and in the atrophying breast. Adami has presented the general
importance of this principle designating the tumor process as " the cumula-
tive habit of growth, replacing the habit of work."

Thiersch and Beneke have interpreted the tumor process as a degenera-
tive overgrowth of cells. That there is overfunction in some degenerating

100 N EOF LA STIC DISEASES

cells, as in the paralytic hypersecretion of glands, has been pointed out by
Oertel who urges that overgrowth may also characterize degenerative proc-
esses. In protozoa the germinative and vegetative functions reside in
separate nuclear structures, the macro- and micronucleus, and it seems
possible that the overgrowth of tumor-cells may be accompanied by excess
of germinative nuclear material. This conception of idioplastic variations
in the cells has been pursued by Rulf.

Active growth is usually associated with active function. In thyroid
cancer of fish there is apparently an example of a certain type of malignant
tumor developing as a result of overresponse to functional stimulus. There
are many examples of adenomatoid hyperplasia from excessive functional
stimuli and it seems probable that this element may be concerned in the
inception of certain tumors. Proliferating chromatophores ' and mucous
goblet cells exhibit excessive function. Thus both overfunction and loss of
function seem to be related to tumor growth.

4. Organization. — The limitless growth of tumors early suggested that
the cancerous tissue had lost the control of the organism. Recamier in 1829
definitely formulated this idea and the conception has steadily enlarged with
the progress of biology.

The fertilized ovum reproduces its kind because of very complex factors
which are best interpreted as the influence of environment on hereditary
characters. Yet after the last analysis there is always an unexplained resid-
uum about regeneration which justifies the teleological concept. The forms
of regeneration among the lower animals show many processes that seem to
be purposeful. The regeneration of limbs at the breaking joints of crusta-
ceans; the variable regeneration of one or two heads in flat worms according
to line of incision; the regeneration of the lens in Triton indifferently from
capsule, iris, choroid, or retina; the polarity of the hydroid Antennularia,
which transforms twigs into roots according to its accidental needs; illustrate
the extreme adaptability of regeneration to the uses of the organism. The
mechanism by which these results are brought about, whether purposeful or
not, is called organization. Some biologists, notably Morgan, claim that this
influence can be defined only in terms of purpose, and cannot be wholly
resolved into any known physical forces. However that may be, it is a fact
that a tumor can be defined only in terms of purpose. All the known features
of a malignant neoplasm are exhibited by the normal chorion, even the de-
structive invasion and cachexia, but the process is not a tumor because of
its purpose which shows that it is under the control of the organization.

Embryology and cellular biology have thrown much light on the nature of the forces
concerned in organization.

First, it has been shown that at all stages the organization has an equilibrium which is
maintained by the altruism of the tissues. The dividing embryo in some animals up to
the sixteen-cell stage yields cells any one of which if separated from the others is capable of
producing an entire embryo (Wilson, Zoja). Beyond this stage and usually before, the
cells become differentiated, different cell groups going to produce different specific tissues.
According to \Yeigert and Roux the differentiation results from an unequal division among
the cells of the properties of the ovum (the mosaic theory). According to others (Spencer,
Hertwig), the differentiation is accompanied not by loss but by suppression of certain
properties of the ovum. Owing to the unequal distribution or activity of qualities or
potencies, some cells come to possess more of one type and others come to possess more
of another, while the sum total of all the potencies is necessary to maintain the equilibrium
of the organization. Hence the cells, tissues, and organs stand in a relation of antagonism
or correlation which maintains an equilibrium, any change in one affecting more or less all
the others. This interdependence has been called by Hansemann, the altruism of the cells.
Removal of one kidney is followed by compensatory hypertrophy of the other, through the
physical factors of increased urea in the blood, increased blood-supply and nervous stimulus,
all acting harmoniously under the influence of the organization. There is altruistic hyper-

THEORIES OF THE NATURE OF CANCER

101

trophy of bones with tumors of the hypophysis, and altruistic atrophy of the adrenals in
anencephalic monsters. A definite chemical substance conveys this altruistic influence in
corpus luteum secretion which controls the growth of the chorion.

Many recent observations and experiments have emphasized the importance of the
current of nutrition in determining the growth of normal and neoplastic tissues. Murphy
finds that the presence of a small fragment of growing splenic tissue prevents the growth of
tumor-tissue implanted in the chicken egg, a result probably signifying that the growing
splenic tissue diverts and absorbs the available nutriment. This principle has received
experimental confirmation in an interesting way by J. Loeb in observations on plants.
Stockard shows how the rate of regeneration of the amputated arms of the starfish depends
on the number amputated. There are many clinical observations indicating that the
growth and even the inception of tumors may depend chiefly on the stream of nutrition to
the part, and also upon the character of the nutrition.

Second, the study of cell division reveals a mechanism by which the altruism of the
cells and the control of the organization may be disturbed. As long as the cells multiply

FIG. 10. — J. Loeb's experiment with leaf of Bryophyllum calicynum, illustrating growth
restraints. The leaf, notched as above, fails to develop shoots while attached to stem, but
does so when severed from stem. The influence is thought to depend on the flow of nutri-
ment, which ceases to pass from leaf when it is severed.

by normal mitosis and each stage of differentiation in one group is accompanied by equiva-
lent antagonistic qualities in others, equilibrium is maintained. But if inflammation or
chemical or mechanical factors derange the mitotic process single chromosomes may be
destroyed and the resulting cells will not have the proper antagonists to balance it. By
repetition of this process a new type of cell may arise which is more and more removed
from the normal and fails to receive any restraining influence from the organization.

The study of tumor-cells shows that irregular, asymmetric and multipolar mitoses
and destruction of chromosomes are frequent in malignant tumors. Hansemann applies
the term anaplasia to the condition of such cells, which signifies loss of normal differentia-
tion, specific function, and organization. These physiological properties which charac-
terize malignant tumor-cells are usually but not always associated with pronounced changes
in morphology. Anaplastic cells are not embryonal cells but a new type which have lost
their place in the organization. More or less anaplastic cells occur in inflammation, but

102 NEOPLASTIC DISEASES

there are many degrees of anaplasia, and its occurrence in inflammation accords with the
fact that inflammatory hyperplasia may pass into neoplastic.

The abnormal capacity for growth has long suggested that tumor-cells
have some relation to sex cells. In some animals the entire series of sex cells
from the fertilized ovum up to the new egg cell has been traced as a distinct
series apart from the somatic cells. In this series the mitotic nucleus exhibits
only one-half the usual number of chromosomes, and these instead of assum-
ing a V shape and radial arrangement are ring or loop shaped or composed of
coarse granules. This gametogenous mitosis has also been observed in the
growing edges of tumors (Farmer, Moore, Walker) and it may be produced
by chemical irritants. Its occurrence does not signify that tumor-cells are
equivalent to sex cells, and yet in connection with the invasive properties and
striking altruistic relations of both classes it shows that tumor-cells and sex
cells have some interesting points of resemblance. Spencer, Hertwig and
others claim that the sex potencies of somatic cells are not lost but only
suppressed. On this basis Williams has built an elaborate and ingenious
argument to show that tumor growth signifies the reawakening of the re-
productive functions in the somatic cells. According to this theory tumor
growth is a form of agarnogenesis comparable to the budding of plants.

Many have supposed that tumor-cells are fertilized cells, through conju-
gation with leukocytes (Klebs), by parthenogenesis (Waldeyer), by conju-
gation of endothelium and fibroblasts (Recklinghausen), by nuclear conjuga-
tion (Auerbach, Bashford), or by endogenous cell infection.

None of these hypotheses has survived criticism and the theory of cell
autonomy remains content in the position that tumor-cells emancipated from
growth restraints are merely exhibiting their natural capacity for growth.

The theory of cell autonomy appropriates all the observations regarding
the mechanisms of the isolation of cell groups. It also accepts the principle
that adult cells which have not lagged behind in development and are not
embryonal or superfluous may be isolated and freed from growth restraints.

Ribbert lays great stress on the mechanical separation of epithelial cells
by new connective tissue. In early carcinoma of stomach, epithelioma of lip,
and psoriasis linguae he finds strands of new connective tissue growing
between the epithelium and snaring off cell groups. Or, round-cell infil-
tration of inflammatory origin beneath the epithelium creates an abnormal
environment, and nullifies the restraints to grow. Central enchondromas
and many exostoses he refers to groups of cells isolated by irregular ossifica-
tion as in rickets. Malignant tumors he thinks may develop from groups of
cells snared off in the course of benign tumors or from implantations during
removal, as of ovarian cystomas. So carcinoma develops from isolated cell
groups in cirrhosis of liver, or contracted kidneys.

Further it must be assumed that trauma isolates predisposed cell groups
as in many bone-sarcomas. The evidence that malignant chorioma may
develop from emboli of normal chorionic cells is practically conclusive (Mar-
chand, Pick).

In £-ray carcinoma there is chronic edema, round-cell infiltration, and
fibrosis altering the relation of the epithelium long before the -downward
growth of these cells. In chronic mastitis multiple cancer nodules appear
at minute points where the fibrosis is unusually dense and the disturbance
of normal relations most marked.

There is little doubt that the minute study of the conditions surrounding
the early stages of cancer, as instituted by Ribbert, forms a strong support to
the theory of cell autonomy, while its bearing on the early diagnosis and pre-
vention of cancer is obvious. Yet these observations fail to show whv the

THEORIES OF TEE NATURE OF CANCER 103

isolated cells so often regress and only rarely succeed in producing tumors, and
it is clear that the mechanical isolation of cells is, like the embryonal charac-
ter, only a predisposing factor in tumor genesis. To cover this defect various
hypotheses have been maintained.

i. The isolated cells have been altered and their growth tendencies
increased by previous irritation. 2. There is a local predisposition to tumor
growth. 3. There is a general predisposition to tumor growth.

1. Billroth;s dictum "Without previous chronic inflammation cancer
does not exist," while subject to exceptions, is yet so generally true as to
establish the great significance of chronic irritation as a factor in tumor gene-
sis. Interpreted according to the principles of the theory of cell autonomy it
is clear that successive generations of cells subjected to chronic irritation will
suffer increasing loss of growth restraints with disturbance of their normal
rate of growth, the size of their nuclei and cytoplasm, their blood-supply, and
their relations to neighboring cells. All of these changes are observable in
the preliminary stages of lingual and other cancers. In this condition it
seems but a short step to downward growth of such cells when the cumulative
process reaches a sufficient stage or when more abrupt mechanical isolation
of cells occurs. Whether these cells in their continued progress are merely
exhibiting normal powers of growth or have acquired new powers constituting
them an entirely new biological series it is difficult to decide. Here it must
be urged that the continued growth of cancer is an entirely different problem
from its inception. Many new factors intervene to facilitate extension and
metastases. It is by no means clear that malignant tumor-cells are more
viable than normal cells. They are more readily autolyzed and in early cases
tumor emboli enjoy less resistance to destructive forces than normal cells.

For the inception of many tumor processes, chronic irritation acting upon
normal cells seems to adequately explain the observed phenomena. Thus
the cumulative effects of chronic irritation alter the nutrition and growth
activities of cells so that when they become isolated they are not normal cells
but are in a state of disturbed equilibrium with a tendency toward exag-
gerated growth. Such conditions are commonly observed in the precancerous
lesion.

2. A local predisposition to tumor growth must be assumed to exist to
account for the capricious development of many neoplasms. The factors
which lead to the inception of tumors in one locality or individual often seem
incapable of bringing this result under other circumstances. Many of the
factors constituting this local predisposition form the basis of Cohnheim's
theory, including (i) Isolation without misplacement of embryonal cell
groups. (2) Persistence of cell groups and organs which normally regress
after embryonal life. (3) Formation of superfluous cell groups. (4) Gross
abnormalities in development of regions, organs, and systems. (5) Disturb-
ance in the idioplastic development of cell groups without visible changes in
morphology.

In addition, Rindfleisch assumed that imperfect nervous control is one of
the factors predisposing to exaggerated growth of tissues and tumor forma-
tion. While the effectiveness of such a factor may readily be granted, there
seem to be no observations in favor of its existence except the absence of
intrinsic nerves in tumor-tissue. Likewise imperfect idioplastic development
may be conceded as certainly favoring tumor growth but in the absence of
definite criteria of such a condition this factor remains largely in the field
of speculation and as a problem for future studies. A reasonable speculation
also is that of Israel who supposes that tissue cells, like bacteria, in the course
of repeated or abnormal generations tend to vary and in some tissues they

104 N EOF LA STIC DISEASES

vary in the direction of overgrowth. Yet as normal cells do not vary in this
way Israel is assuming an original local predisposition to overgrowth. Thus
the well established elements in the doctrine of local tissue predisposition
belong under the embryonal theory, while the others still remain seductive
hypotheses.

3. A constitutional predisposition toward tumor growth has long been a
favorite field of discussion. There is a vast amount of literature concerning
the relation or antagonism between cancer and tuberculosis, syphilis, malaria,
diabetes, insanity, arthritism, obesity, gall-stones, dermatoses, heart disease,
mental disturbance, etc. The many interesting observations in this field
seem to have wholly failed to throw any light on the etiology of malignant
tumors, nor have they established any definite connection between cancer and
the diseases mentioned.

It has long been recognized that cancer is prone to develop in plethoric
individuals. Williams sums up an elaborate argument with the conclusion
that cancer occurs chiefly in the well nourished, the well-to-do, and the well-
protected against infectious disease, that it is especially prevalent in peoples
with whom the consumption of meat is high, and that it is a tax on civiliza-
tion. Yet all of these factors may exhaust themselves in increased longevity,
by which more individuals of weaker type reach the cancer age, and none of
them seems to establish any definite predisposition to the disease. It is
conceivable that overnutrition should facilitate overgrowth but it is not so
clear why overnourished tissues should tend toward neoplastic instead of
normal growth.

The immense variation in the nervous and physical conformation of
individuals suggests to Borst that there may be equal divergences for or
against neoplastic growth of tissue cells. The quality of the body proteins,
the general organization of the body, the relation of tissues and organs to the
vascular and nervous systems may give rise to individual peculiarities which
are of importance in the origin or failure of tumor growth, but there are few
facts to support this speculation. At best it can only mean that the capacity
for tumor growth is far more general than the occurrence of tumors. The
existence of multiple tumors is more properly referred to definite multiple
disturbances of development or to the existence of several recognizable ade-
quate factors than to any general predisposition.

The individual of cancerous type is described by Benecke as revealing a
large heart and arteries, small lungs and pulmonary arteries, long and
capacious intestine, and well developed osseous, muscular, and adipose tis-
sues. Yet these are just the subjects most likely to reach the cancer zone,
where the age factor becomes far more prominent than anything we know
about predisposition.

Imperfect balance between the sexual and other organs, the status o/ the
thyroid gland, and the chromafiine system, have been suggested as forming
the basis of a cancerous predisposition, but the observations in these fields are
as yet quite inadequate to form the ground of an effective argument. Many
of the above considerations may be adduced in favor of the hereditary
theory of cancer.

According to Williams the growth of malignant tumors is favored by
an altered metabolism of the body consequent on the decline of the sexual func-
tions. He refers to the increased frequency of cancer after removal or
destruction of the ovaries (Wells, Kratzenstein), and in cases of congenital
absence or defect of the sexual organs (Neugebauer). Sticker also found that
50 per cent, of a series of cattle and horses with malignant tumors were
castrates.

THEORIES OF THE NATURE OF CANCER 105

The thyroid gland exhibits in most adult cancer patients that tendency
toward involution which belongs to advancing years, but that this involution
is more marked in cancer patients has not been shown; nor has any relation
been established between cancer and the various members of the chromaffine
system. A small proportion of adrenal tumors is associated with malignant
tumors in other organs (Williams, Adams, Guthrie). The usual integrity of
the pancreas does not favor the theory of Beard that cancer depends on defect-
ive pancreatic secretion.

Thus although the facts of tumor growth seem to demand the assumption
of a constitutional predisposition, the basis of this doctrine is as yet imper-
fectly laid. Clinical observations, studies in histogenesis, and gross anatomy,
and chemical researches fail to reveal why the same factors succeed in one but
fail in another subject to produce tumors. The most suggestive hypotheses
seem to be those concerned with overnutrition, the decline of the sexual func-
tions, and congenital disturbance in the idioplastic development of the cells.
The constitutional element seems to be too subtle for ordinary methods of
study, and to show itself most clearly in the relation of heredity to tumor
growth, where, however, with certain exceptions, its practical importance
diminishes almost to the vanishing point.

Heredity. — Nothing about cancer is more generally accepted than its
hereditary nature, and nothing is less satisfactorily proven. The evidence
favoring this doctrine consists chiefly in records, some very notable, of cancer
families, and in statistical studies of the incidence of the disease in the rela-
tives of numerous cancer patients. Recently experimental evidence has
been adduced in its favor.

Cancer Families. — In 1837 Warren reported a family history in which the
grandfather had cancer of the lip, while the son, his daughter, two sisters,
and the daughter of one of them, all died of cancer of the breast. The most
famous cancer family is that reported by Broca, 1866, of Madame Z, the
details of which were furnished by a medical member of the family. Of
twenty-six members, mother, children, and grandchildren, reaching the age
of thirty, sixteen died of cancer of breast, liver, or uterus. Napoleon I, his
father, one brother and two sisters, are said to have died of cancer of the
stomach. Sibley observed cancer of the left breast in a mother and her five
daughters. Korteweg saw cancer of the breast, and Paget cancer of the
uterus in mother, daughter and granddaughter.

Retinal glioma occurred in 10 of 16 children of healthy parents in a family
encountered by Newton, and in eight children of a family seen by Wilson.
These, however, are instances of congenital, not hereditary origin. Williams
has collected many other references to cancer families.

Levin analyzes the conditions under which the clinical study of heredity
in cancer may be conducted and points out that the occurrence of cancer in a
family member may not necessarily mean an hereditary influence. An
extended investigation of the families of five cancer patients failed to show
any unusual incidence of the disease. In fact he seems to have encountered
unusually resistant families in which cancer was of occasional but rare
occurrence. Warthin on the other hand records several very striking
histories of families in which cancer was unusually frequent. Thus in one
family, 17 of 48 descendants of a cancerous grandfather developed cancer,
chiefly of uterus or stomach. In another, eight descendants of a cancerous
great-grandfather all died of the disease. Warthin adds that these families
became extinct; but clearly not from cancer. These observations emphasize
the occasional occurrence of cancer families, and suggest that members of
such families may properly take definite precautions against the disease.

106 NEOPLASTIC DISEASES

Statistical studies began with Paget who traced cancer or other tumors in
the relatives of 23.6 per cent, of 254 cancer patients, but in only 18.3 per cent,
of 147 non-cancerous tumor cases. Baker found cancer in the relatives of
24.2 per cent, of 322 cancer cases. Velpeau thought that at least one-third of
his cancer patients had a family history of cancer. Leichtenstein collected
histories of 1137 cancer cases in which heredity appeared in 17 per cent.

The proportion of women with cancer of breast in whose relatives there
was a history of cancer has been estimated by Butlin at 37 per cent., by Nunn
at 29.3 per cent., by Williams at 24.2 per cent., and by Leaf at 23 per cent.
Yet Campiche and Lazarus-Barlow place the proportion in 100 recent records
of the Middlesex Hospital at 15.6 per cent., Williams found a history of he-
redity in cancer of uterus in 19.7 per cent., of breast 24.2 per cent., of other
female cases 23.9 per cent., and in men suffering from cancer (209 cases) n
per cent.

On the other hand Lebert placed the percentage of inheritance at 8.5 per
cent.; Sibley in 305 cases at 8.5; Winniwarter in Billroth's clinic at 8.8 per
cent. Billroth found one parent affected in 5.8 per cent, of 170 cases. Till-
mann quotes reports showing 8.5 per cent, and 10 per cent, of hereditary
cases of cancer of stomach. Ziel collected 200 cases with n per cent, heredi-
tary. H. Cripps excluded distant relatives, as cousins and aunts, and in 169
cases only 6.4 per cent, had a cancerous parent. He found that in England
and Wales (1861-70) i in 29.1 deaths occurring after 20 years of age was
from cancer. Comparing this ratio with that of cancerous parents of cancer
cases he concluded that cancer in one parent does not increase the liability to
the disease. Recently Hillier and Tritsch made an elaborate study of family
history in 3000 cancer cases in the Middlesex hospital. Of these 13.1 per
cent, had a history of cancer in relatives, while of 417 non-cancerous cases
14 per cent, gave cancerous antecedents. Pearson who interpreted these
data hesitated to accept the necessary conclusion that a family history of
cancer confers a very slight immunity to the disease, yet unless the collection
of the data was very much biased it is clear that statistics do not support the
doctrine of the general hereditary nature of cancer.

Bashford points out that in England of those living at 35 years of age one
man in eleven, and one woman in eight, die of cancer. This ratio signifies
that a history of cancer will occur in one out of every two families of the
general population. In the families of 669 cancer patients he obtained a
history of cancer in 31 1 or 50 per cent. In Stuttgart, Weinberg examining the
cancer records from 1872 to 1902 found no evidence that heredity plays a
dominant part in the etiology of cancer. His data show that the deaths from
cancer in each 100 relatives of cancer patients were, of the patients' parents,
6.6, brothers and sisters, 3.9; of their husbands and wives' parents, 5.9;
brothers and sisters, 3.1.

There are numerous sources of error in the conclusions drawn from
statistical studies. It is quite unlikely that any hospital population can give
reliable information regarding the existence of cancer in their parents, much
less in their other relatives. There are numerous errors both of omission and
commission in the diagnosis of cancer. The nature of any hereditary element
in cancer is wholly obscure so that it is impossible to decide whether cancer
in cousins and aunts, or only in parents should be considered, whether the pre-
disposition may skip generations, whether the influence affects the same
organ or all the organs, or whether the influence of a similar environment,
climate, food, and habits, may not submerge any form of heredity. Con-
sideration of the age factor completely altered the conclusions suggested by
Guillot's statistics. In 352 patients he found a cancer history in 10 per cent.

THEORIES OF THE NATURE OF CANCER 107

of the non-cancerous and in 17.4 per cent, of the cancerous. But the average
age of the living relatives of the non-cancerous was 37 years, that of the
others 52 years. So that the expectation that cancer would later develop in
the relatives of the non-cancerous before their average age reached 52
changed the true percentage of cancerous relatives of the non-cancerous to
1 6, or 1.4 per cent, less than for the cancerous group. In view of all these
considerations it must be confessed that the statistics of cancer heredity in the
present state of our knowledge are inconclusive or even worthless. .

The evidence presented by the many notable cancer families seems to have
a different value. It seems impossible to attribute to coincidence, or envir-
onment, or erroneous observation the remarkable prevalence of cancer in the
families mentioned by Warren, Broca, Manichon, Le Tulle, and others.
These cases seem to show that in rare instances a pronounced hereditary pre-
disposition to the disease exists. It is, however, important to emphasize that
the history of these families indicates that when an hereditary predisposition
exists it displays itself in unmistakable form and it in no way justifies the
assumption that hereditary influences prevail for cancer in general, on which
point the evidence is wholly negative. These family histories show how very
uncommon an effective hereditary influence really is. From the clinical and
statistical evidence therefore one must, I think, subscribe to the conclusions
of Le Doux-Le Bard, (i) Nothing authorizes us to affirm that cancer is
hereditary. (2) In the interests of the public this doctrine ought to be
combatted.

The influence of heredity upon tumor incidence has been submitted to
experimental test. Bashford bred mice of cancerous stock and ones that
had actually suffered from the disease, attempting by inbreeding to inten-
sify the hereditary influence. His results followed the laws of age and sex
distribution.

Tyzzer has conducted breeding experiments with the offspring of a female
mouse, suffering from a cystadenoma of the lung. Of 100 offspring of this
one cancerous parent 65 survived six months and 3 more than two and a
half years. Of these, 20 (32 per cent.) developed one or more tumors, 17
being pulmonary tumors. Among 68 of these mice born of cancer-free par-
ents 9 (13 per cent.) developed tumors, while among 29 with one cancerous
parent n (39 per cent.) developed tumors. The increasing frequency of tu-
mors in the old mice (2 years) of this family indicated that cancer was almost
inevitable for animals which survived infectious diseases. While no satis-
factory controls were secured these interesting results strongly support the
hereditary theory, at least for this family of mice.

Maud Slye has conducted elaborate experimental studies on the influence
of heredity on the incidence of mouse tumors and has proven that inbreeding
of tumor-bearing animals greatly increases the incidence of tumors. This
work has continued over several years and includes over 10,000 autopsies
revealing 722 tumors. It should be noted, however, that this list of tumors
includes and attributes equal significance to processes which are very distantly
if at all related, such as lymphosarcoma, peculiar tumors of the lung, and
cancer of the stomach or breast. Until the experimental studies have been
confined to identical or closely related neoplastic diseases, their results for
mice must be regarded as of uncertain significance while the application of
the results to man seems premature.1

A general survey of the work in this field suggests several considerations
which seem to deserve attention before definite conclusions can be reached.

There are many indications that the conception of all tumors as a single
1 Similar results were later obtained with hepatic cancer alone.

108 N EOF LA STIC DISEASES

disease and the merging of all varieties in the search for signs of heredity
are unwarranted, and that the studies should be confined to single closely
related types of malignant tumors in which common exciting and similar
predisposihg factors exist. Cancer of the breast in three generations of
women is much more suggestive of heredity than a series in which mammary
cancer is followed by hypernephroma, and this by teratoma ovarii.

The Mendelian characters noted in the heredity of some pathological
conditions have not been traced with tumors. It has often been urged that
the cancerous predisposition may result from factors acting in each case in
utero, i.e., that the predisposition is congenital without being hereditary,
but this possibility has received little attention from the advocates of the
heredity doctrine.

It would be interesting to know if cancer in markedly hereditary sub-
jects pursues an unusual course. In the absence of data on these and other
matters and owing to our lack of knowledge of the nature of any transmissible
influence, the problem of heredity in cancer seems for the present unsolvable.

CHAPTER VII
THE SPECIAL ETIOLOGY OF TUMORS; TRAUMA

While one general and essential principle, best portrayed in the theory
of cell autonomy, seems to underlie the inception of all tumors yet it is be-
coming more and more apparent that the etiological factors are variously
combined for nearly all neoplasms. In this sense it may almost be said that
the etiology of each form of tumor is specific and that a practical knowledge
of tumor etiology requires a minute analysis of all the factors concerned in
each case.

Thus the conditions surrounding the inception of cancer of the breast are in
many respects quite different from those concerned with cancer of the tongue.
This distinctive quality is even more obvious in the clinical course and
termination of different malignant tumors, so that there is theoretical basis
for and practical value in considering each tumor as a distinct clinical entity.
Well-known examples of specific etiology are seen in various tumors connected
with occupations, as #-ray cancer, multiple epithelioma of the skin of
workers in paraffin, and anilin dyes, scrotal cancer of chimney-sweeps, and
the rare cancer of the lung in metal workers, weavers and cigar makers.

The cumulative effects of the habits of the individual are seen in smokers'
cancer of the lip, pharynx, and larynx, Kangri and Betel-nut cancer of African
natives, and cancer of the skin in arsenic eaters.

Particular forms of chronic irritation and inflammation precede many
well-known clinical forms of cancer, as epithelioma of tongue from jagged
teeth, cancer of skin from chronic eczema, indolent ulcers, burns, or along
chronic sinuses from necrosing bone, and with Paget's disease of the nipple.

Specific chronic granulomas occasionally lead to cancer, as syphilitic
psoriasis linguae, and lupus of the skin. Sarcoma also develops after lupus
and syphilis of bones. Chronic inflammation of mucous membranes pre-
cedes cancer as in uterus, stomach, urinary passages, nares, and with chole-
lithiasis. Chronic inflammation of glandular organs frequently forms the
essential basis of cancer, as in the cirrhotic liver, contracted kidney, and hy-
pertrophic prostate. Chronic hyperplastic and benign neoplastic processes
rather rarely become transformed into malignant tumors, as warts, polyps,
myoma uteri, and simple epithelial cysts of many organs. Abnormal in-
volution designates the conditions leading to many cancers of the breast,
appendix, prostate, and thyroid. Trauma seems to be the sole tangible
factor in originating many tumors of bone, glia tissue, testicle, and many
other organs.

The wide differences in the nature of the embryogenic disturbances which
lead to isolation of embryonal cell groups and tissues set apart a very large
class of tumors whose etiological factor is distinctive for each member as
well as for the entire class. Thus branchiogenic cancer, Wilms' renal em-
bryoma, and the teratoid testicular tumors which are probably derived from
sex cells, deserve to be considered as enjoying quite a different etiology.

If, as seems probable, Hodgkin's granuloma becomes transformed into
a nearly autonomous lymphosarcoma, there is very little resemblance be-
tween its etiology and that of bilateral lymphosarcoma of the testis of a

109 •

110 NEOPLASTIC DISEASES

child. If abnormalities of the lutein secretion enable emboli of normal
chorionic cells to develop malignant tumors there is little wisdom in discuss-
ing its etiology with that of smokers' cancer of the larynx. The two dis-
eases are as different in etiology as gout and erysipelas, both of which pro-
duce exudative inflammations of the skin.

Thus the special etiology of tumors presents extremely numerous and
complex problems which have immediate practical bearing on diagnosis,
treatment, and prevention, and which are probably much nearer solution
than is that of the nature of the neoplastic process. It seems important to
emphasize the separate nature of these departments of the subject of eti-
ology and to point out that in many respects our knowledge of the etiology
of tumors is very clear and precise. Yet the action of all these special etio-
logical factors, as irritation, trauma, and inflammation is only secondary
and indirect, and without combination with other predisposing conditions
they are incapable of inducing tumor growth. In a great many cases the
above special factors exist but no tumor develops.

Therefore the special etiology of tumors can deal only with the conditions
under which tumors arise, but not with the intrinsic properties of cells which
find their expression in the tumor process.

Trauma. — Mechanical trauma is an important factor in the causation
of tumors. From the scope of trauma in this relation should be excluded the
various forms of chronic irritation, inflammation, surgical wounds, cicatriza-
tion and chemical escharotics. By trauma is here understood a single or
repeated more or less contusing, crushing, or lacerating mechanical injury.
This much discussed subject would be greatly simplified if the statistical
tendency were replaced by clearer ideas of the results of trauma in different
tissues and of the mechanism by which such lesions lead to tumor growth.
Studies in this field are as meager as the statistical contributions are
superabundant.

The important effects of trauma here are: (i) Solution of continuity,
minute and gross; (2) separation of cell groups and tissue masses, as of skin,
glands, bone; (3) necrosis of tissue; (4) confined hemorrhage requiring ab-
sorption or encapsulation; (5) accelerated regenerative processes with hy-
peremia, and newgrowth of specific cells, blood-vessels, and supporting
tissue; (6) cicatrization.

All of these conditions are well-proven elements entering into the causation
of tumors, and the failure of attempts to produce tumors by experimental
trauma in given cases does not reduce their importance when associated
with other necessary predisposing factors. When one or several of them
meet with the relatively rare predisposing conditions, we have a somewhat
satisfactory explanation of the facts observed regarding the relation of
trauma to tumors.

The predisposing factors take many forms: (i) There may be a benign
or a minute malignant tumor in the tissue before the injury. Many patients
with cancer of the breast attribute their disease to some form of injury. Prob-
ably very few of these tumors are the direct sequel of the trauma, but a slowly
growing cancerous nodule in chronic mastitis may be accelerated by a blow
where the injury alone seems to be the immediate cause of the tumor. In
any organ a preexisting lesion renders the effects of ordinary injury more
severe and more noticeable.

2. The precancerous condition may be precipitated into a malignant
process by injury. Examples are wounds of a psoriatic tongue by the teeth,
injuries of the breast altered by chronic mastitis, and incomplete surgical
removal of indolent ulcers, mucous polyps, fistulous tracts, and benign

THE SPECIAL ETIOLOGY OF TUMORS; TRAUMA 111

tumors. Leukoplakia of the tongue is said never to develop cancer until it
becomes complicated by cracks and fissures.

3. Misplaced and undeveloped organs are predisposed not only to tumor
growth but also to trauma. The results of this unusual combination are
seen in cancers of undescended testes and supernumerary breasts.

4. Aberrant quiescent cell groups may be included in the damaged tissue.
The best known example is the malignant melanoma arising from an injured
mole. Definite injury frequently precedes the appearance of the various
forms of teratoma testis, and since trauma is an effective method of producing
artificial parthenogenesis, there is good reason to believe that the relation
of the injury to the tumor is in this case direct, for these tumors develop
from immature aberrant sex cells. Throughout the entire series of embryonal
tumors there is a sound basis for ascribing more than ordinary significance
to a history of severe or mild and repeated injury. Ribbert thinks that many
adrenal rests are incited to growth by trauma.

5. Normal cells under the conditions established by trauma develop
benign or malignant tumors. There seems to be no sufficient reason for
denying the relation between trauma and many chondromas, osteomas,
lipomas, fibromas, and fibromyxomas, with which the history of a blow is
rather common, and there is little ground for assuming that the trauma acts
on any but normal cells. Also with the two most striking forms of traumatic
tumors, gliosarcoma and osteosarcoma, where a definite history of injury
is frequent, there is no evidence that any but normal cells are involved.

The character of the injury followed by tumor growth varies widely.
Traumatic cancer usually appears after repeated mild injuries often amount-
ing to chronic irritation, while sarcoma commonly develops after a single
blow. Yet many cancers have appeared after single injuries (Ziegler,
Lowenthal, Jordan, Segond). Only the severer injuries are capable of reach-
ing the deeper tissues from which sarcoma develops. Cancer has been clearly
traced to lacerations by rough instruments, rusty nails and pins, thorn pricks,
insect bites, surgical wounds, and to blows without visible destruction of
tissue.

Fractures, lacerations of deep tissues, contusions and concussion, all of
which are apt to cause hemorrhage, represent the usual type of injury pre-
ceding sarcoma and benign mesoblastic tumors.

The mechanism by which injury induces tumor growth is generally
obscure. The traumatic dermoid clearly originates from implanted epider-
mis and fair success has attended its experimental production. Yet it has
been abundantly proven that simple misplacement of other normal tissue
cells is quite inadequate to explain tumor growth. Hyperemia may be the
remaining factor necessary to excite the proliferation of aberrant rests, and
precancerous foci. Blood extravasation requiring absorption or organization
creates conditions especially favorable to mesoblastic overgrowth. Certain
tissues are predisposed to excessive overgrowth in the presence of hemorrhage.
The periosteum, the tissues of the scrotum and cord, the omentum, and the
pia-mater frequently exhibit very active overgrowth of tissue following
hemorrhage, yielding bulky products, which have the gross and many of the
microscopical appearances of tumors. Such pseudosarcomas are especially
frequent in the scrotum. Cornil and Berard have noted the very active
proliferation about traumatic hematomas, and locate the early sarcomatous
process in the cells about new blood-vessels. Some early sarcomas of the
brain present appearances implicating the new vessels in the sarcomatous
process.

The common superfluous callus about fractures reveals the great pro-

112 N EOF LA STIC DISEASES

liferative capacity of periosteum, and Benecke believes that the regenerative
process in periosteum may run directly into sarcoma. In traumatic myositis
the new tissue is often suggestive of sarcoma. Yet the full explanation of
traumatic sarcoma seems to require the assumption of special local or general
predisposing factors which have never been traced in microscopical structure.
The chemical composition, blood-supply, and lymph supply of brain tissue
are peculiar but give no clue to the frequency of traumatic gliosarcoma. The
presence of necrotic tissue should receive attention as a possible specific
factor in the development of traumatic tumors. It is possible that products
of autolysis or decomposition of protein tissue may exert peculiar influence
on regenerative processes, as in the brain. Kottnitz cites many cases of
lipoma in which a traumatic factor appears acting directly or through the
nervous system.

Ribbert admits that we have not the slightest knowledge why trauma,
which affects many cell types in large areas, excites tumors of one cell type
in one focus. He thinks that the results of experimental separation of cell
groups have often approached the condition of benign tumors some of which
may regress. The most extensive proliferation is obtained by partial separa-
tion of tissues, as along three sides of a square, of the rabbit's ear. Epithelium
completely separated dies, but regenerating connective tissue is much more
resistant.

The frequency of the traumatic origin of tumors varies with different
statisticians, according to their conception of trauma and their critical
standards. Composite statistics vary from 2.5 per cent, by Kempf to
44.7 per cent, by Lowenthal. Of 6780 tumors of all varieties reported in the
literature with reference to trauma 494 or 7 per cent, were regarded as of
traumatic origin. Of 2641 cancers, 107, 5 per cent., and of 938 sarcomas 186,
or about 19 per cent., were classed as traumatic. In a large proportion of
these cases the relation of the trauma was extremely uncertain. The figures
represent the present attitude of most clinical writers which, as Lubarsch
and Schimmelbusch have said, is often extremely uncritical. Only the
statistics relating to single tumors are of practical value. Of 55 melanomas
Werner-Rowe found 19 with a history of injury of a mole.

Of glioma of the brain Adler collected 1086 cases of which 8.8 per cent,
were preceded by rather definite traumatic history. In this class of cases
the relation between the trauma is often clear, the symptoms of trauma
merging into those of tumor and occasionally a scar has been found in bone
or dura directly connected with the tumor.

There are important medicolegal aspects of the relation of trauma to
tumors. To establish the relation of trauma several classes of evidence are
necessary, as is recognized especially by the French statutes.

i. The authenticity and sufficient importance of the trauma. (2)
Previous integrity of the wounded part. (3) A reasonable time relation,
three weeks to three years or more in certain cases. (4) Continuity of patho-
logical changes or symptoms in the wounded part and the appearance of
the tumor. (5) Microscopical proof of the existence of a tumor.

It is necessary to distinguish also between, complete and partial liability.
When a healthy adult receives a blow on the head, remains unconscious for
days, never recovers full mentality, shortly develops signs of brain tumor,
and dies in a few months of gliosarcoma of suitable size and location, the
liability is generally accepted as complete. When a patient with symptoms
of abdominal disease receives a blow in the epigastrium and rapidly succumbs
to carcinoma of an abdominal organ it is reasonable to assume that the
trauma hastened the progress of an existing tumor. As Segond states,

THE SPECIAL ETIOLOGY OF TUMORS; TRAUMA 113

trauma reveals, aggravates, or serves as a pretext for the origin of tumors;
so that in each case very careful consideration of all circumstances are
required to establish the relation of the injury.

In the German courts definite liability has been assumed for cases in
which the connection between trauma and tumor is very uncertain and in-
capable of proof, as with carcinoma of colon or stomach appearing several
years after a blow on the abdomen.

CHAPTER VIII
THE PARASITIC THEORY

The parasitic theory is the oldest hypothesis of the origin of cancer.
It appealed to the ancients, was tacitly accepted throughout the Middle
Ages, was definitely argued by modern observers, and reached the height
of its popularity as a scientific theory about 1895, but during the last fifteen
years it has rapidly lost ground, and today few competent observers consider
it as a possible explanation of the unknown element in blastomatosis.

The data concerning the parasitic theory fall into four main classes:
(i) Studies of the incidence of cancer; (2) the search for specific parasites
in tumors; (3) the experimental production of tumors; (4) theoretical
consideration of the nature of cancer.

The Incidence of Cancer. — In 1809 Arnaudet reported that in certain
rural districts in Normandy during a period of eight years, the cancer mor-
tality reached 14.88 per cent. He noted the occurrence of cancer in several
members of the same household, and he concluded that the neighborhood
of a cancer patient was contaminated through the water.

Many similar reports of cancer districts and cancer houses soon appeared
from Guelliot, Webb, Fiessinger, D'Arcy Power, Bosc, and others. Behla
found the cancer mortality of the low-lying portions of Luckau to be four
times that of the central portion. He noted the frequency of cancer in the
dogs of the town, the large quantities of home-grown vegetables consumed
by the cancer families, and concluded that cancer is an infectious disease
carried to its victims through contamination of the soil.

In 1892 Haviland from an elaborate analysis of the English census
concluded that cancer is a disease of low-lying districts and of seasonably
flooded riparial lands where subsoil is constantly moist, while in high dry
localities it is rare.

Very minute studies of cancer localities have been made in England and
other countries by numerous observers all tending to show a relation between
cancer and all manner of local peculiarities; as living in "old and cancer
houses" (Park), "infected streets" (Mason), houses with defective plumbing,
leaky sewers (Nason), proximity to trees, especially large ones (Lloyd-
Jones), collections of decaying vegetable matter, stagnant water (Poppel-
man), abundance of certain insects (Bosc), etc. The uncritical character
of these observations hardly needs comment. Many of the fallacies involved
in them have been pointed out by Sticker and by Prinzing.

At the height of their popularity, Symons showed that there were no
cancer houses in Bath where cancer mortality was the highest in England.
Out of this fanciful discussion Williams draws the sane conclusion that cancer
is a disease of civilization, choosing its victims from the well-to-do, the well-
nourished and the well-protected against infectious diseases, and that it
flourishes in just the opposite conditions from those which favor the spread
of tuberculosis. At one time there was a tendency to report small epidemics
of cancer among men (Webb, Fiessinger), and to point out its epidemic char-
acter. Later, epidemics of cancer among cattle were described (Loeb),
or among rats and mice used for breeding purposes (Gaylord, Borrel, Loeb),

114

THE PARASITIC THEORY 115

for which old age and inbreeding are sufficient explanations. Bashford, in a
very wide experience with captive rats and mice found no evidence of any
"cage infection."

Epidemics of thyroid cancer among artificially bred trout have menaced
the fish industry in several countries. Pick and Plehne concluded that it
arises from overcrowding, overfeeding, and inbreeding. Gaylord demon-
strated the true cancerous nature of a certain proportion of these cases, but
Gudernatsch pointed out the remarkably wide distribution of the thyroid
lobules in many species of fish and rendered doubtful the neoplastic character
of the great majority of the "tumors." Marine and Lenhardt have shown
that many of the hyperplastic thyroids regress under proper hygiene.

Statistics elaborately presented by Williams and by Hoffman show a
remarkable increase in the recorded deaths from cancer during the last
fifty years. In England in 1840 the cancer deaths were one in 129 of the
total; in 1905 one in 17. Very similar indications are found in the records
of most civilized countries (Hoffman, Lit.). Williams calculates that in
England, 1900, i in 15 of all men, and i in 9 of all women, living at 35 years
of age are destined to die of cancer. The increase seems to be affecting
men more than women, although in England cancer is now a more fatal
disease for women than is tuberculosis. The increase of cancer is con-
comitant with a decrease of tuberculosis.

Of the apparent increase in cancer deaths a considerable proportion must
be referred to improved diagnosis. Riechelman shows for the Berlin hospitals
that there was still, 1902, room for a 20 per cent, increase in the recorded
deaths from cancer through improved diagnosis alone. The remaining por-
tion must be largely referred to the longer tenure of life through immunity to
infectious diseases and improved hygiene, which permit a larger proportion
of persons to reach the cancer age. In Prussia, vital statistics show that the
average person lives twenty-five years longer than in 1860. Willcox in a
critical analysis of this subject shows that the sources of the recorded increase
are quite complex, including improved diagnosis, changes in age composition
of population, elimination of old age as a cause of death, improved regis-
tration, and widening of the definition of cancer.

He shows that the increase is chiefly of inaccessible cancers, among the
lower classes of society, in males rather than in females, in negroes and the
foreign born, and in the country more than in the cities.

The impression that cancer is actually increasing to a slight extent which
cannot wholly be explained by the above factors and is more often appearing
at earlier ages, is probably correct, but such a fact cannot stand as an argu-
ment for the parasitic theory.

The contagiousness of cancer was at one time supposed to be proven by
clinical observation. Lusitanus (1557) claimed to have observed infection
of three children by a cancerous mother. Tulpius reported the direct
transfer of the disease between human beings. In the i7th and i8th cen-
turies cancer was regarded as quite as infectious as phthisis with which it
was often confounded. Lebert and Friedreich believed they had observed
cancer infection of the fetuses of cancerous mothers.

The numerous observations on contact infection were supposed to point
to a parasitic factor but relatively few of these cases seem to have been genuine
and in these it must be held that the infecting agent is the cancer-cell. Of
the many cases of cancer a deux reported by Budd and Guelliot none appears
to be properly attested, while Demarquay found that in only one of 134
cases of cancer of the penis did the wife have cancer of the uterus, and Bossi
reported that of 180 husbands of women with uterine cancer, none contracted

116 N EOF LA STIC DISEASES

the disease. The attempts of Alibert, Wickham and Senn to inoculate them-
selves with cancer, failed. Finally, it is the universal experience of surgeons
that the disease is not contracted by the treatment and care of cancer patients.

The conclusion may thus be drawn, that nothing in the incidence of
cancer points to its infectious nature.

Microorganisms in Cancer. — With the advent of microbiology each new
class of microorganisms in turn was isolated from cancer tissue, many were
grown in pure culture, and some were claimed to reproduce the disease upon
inoculation.

(a) Bacteria. — Rappin, Schill, Francke, Lampiasi, and others made
unwarranted claims for the data regarding the bacteria isolated by them and
they were soon forgotten. In 1887, Scheurlen obtained pure cultures of a
bacillus from mammary cancer and with it claimed to have produced tumors
of the breast in dogs. Baumgarten showed this bacterium to be the potato
bacillus. In 1890 Koubassoff offered a complete claim of evidence for a thick
motile bacillus from gastric cancer. In 1910 Doyen announced his Micro-
coccus neoformans as the cause and cure of cancer. It was soon shown that
this microorganism had nothing to do with cancer, and the Societe de Chirur-
gie (1905) reported it to be valueless in the amelioration of the disease.
These studies led to certain results of positive value . Shattuck and Ballance
showed that non-ulcerated tumor-tissue could easily be kept sterile. Verneuil
in necrotic foci and Zahn in some metastatic growths at autopsy found many
bacteria. Richet found pyogenic bacteria common in cataneous cancers.
Maragliano often found staphylococci in the blood of patients with ulcerating
tumors, even without fever, but never with non-ulcerating growths.

(b) Coccidia, differing in many details, were described by several observers.

Dariers psorosperm of Paget's disease secured much support from Wick-
ham and the histological evidence alone sufficed to impress many with the
belief that this structure was the true cause of this and other cancers. It
was repudiated by its discoverer in 1904.

Thoma (1888) and Sjobring (1890) described much the same intracellular
and intranuclear structure as a parasitic coccidium.

Metchnikoff supported Sudakiewitsch's intracellular coccidium.

Adamkiewicz asserted that all cancer-cells are parasitic coccidia (Coc.
sarcolytum) giving origin to a specific toxin (cancroin) and much this same
view was held by L. Pfeiffer and J. Clarke.

(c) Miscellaneous Protozoa. — Other observers could not regard all the
cancer-cells as alien parasites, but certain of the tumor-cells they identified
as parasitic amebae because of their bizarre forms and long pseudopodia
which stretched between adjacent cells. These were the Rhopalocephalus
carcinomatosus of Korotneff, and Cancriameba macroglossia of Eisen. L.
Pfeiffer described and depicted intracellular structures which resembled
the microsporidia of muscle-tissue.

Podwyssoski and Sawtchenko described as sporozoa a variety of free and
encapsulated intracellular structures many of which resembled Sudakie-
witsch's parasites. Ruffer and Walker improved the technical methods of
demonstrating the cancer bodies and endeavored to distinguish between
true and spurious parasites. Kahane thought he detected a minute proto-
zoan in the circulating blood of cancer patients. In cancerous ascitic fluid
Schaudinn observed a large ameboid cell which he named Leydenia gemmi-
para. Schliller traced the complete cycle of a minute intranuclear protozoon
in cancer-cells which differed from nearly all other cancer parasites.

Bird's-eye Inclusion.— From the beginning of the search for the cancer
parasite special interest always centered in a certain intracellular body called
the " bird's-eye inclusion."

THE PARASITIC THEORY 117

This body appeared in the cycle of many of the parasites described by
various authors. It was first cautiously suggested by Foa as the probable
cancer parasite. In 1902 Feinberg made a final effort to establish specific
features in this body, double contour, metachromatism and nucleus sur-
rounded by a clear zone, but these features were promptly and authorita-
tively discarded by Hertwig.

(d) Mycetozoa. — L. Pfeiffer early pointed out the resemblance of many
cancer bodies to forms of mycetozoa, especially Plasmodiophora brassicae.
This organism was first described by Woronin as the cause of club root, a
common disease of plants, and its complex cycle was worked out by Nawas-
chin. Some of its forms closely resemble the bird's-eye inclusion of cancer,
while others are extremely minute and difficult of detection in the infected
cells. Behla found the disease common in the gardens of his cancer houses
in Luckau. Elaborate attempts to demonstrate that this or a similar organ-
ism is the cause of cancer have been made by Behla, Podwyssoski, Feinberg,
Gaylord, and Robertson and Wade.

Several observers claimed to have secured cultures of these protozoa
and to have reproduced tumors by inoculation of the cultures in animals.
Sjobring used a medium containing ascitic fluid, peptone, glucose and soap
made from human fat, and claimed to have isolated his rhizopod from human
tumors. Cultures produced tumor-like growths in mice. Yet the German
pathologists denied that the growths were neoplasms and Israel asserted
that the rhizopods were fat droplets. By the inoculation of material from
club root Podwyssoski and Gaylord produced granulomatous swellings in
animal tissues, the cells of which contained the englobed parasites, which
closely resembled some of the intranuclear bodies seen in cancer. Yet v.
Tubeuf and others have inoculated many animals with club root and failed
to produce any lesions resembling neoplasms. According to v. Tubeuf the
histology of club root is not that of a neoplasm, the tumor resulting from
distension and degeneration of cells surrounded by an area of inflammatory
overgrowth. The picture of infected cells in club root distended with
enormous numbers of very definite parasites is wholly different from anything
seen in cancer.

Smith has shown on an elaborate scale that Bacillus tumefaciens, isolated
from crown gall, is capable of producing a variety of tissue overgrowths in
plants which he regards as true tumors, both simple and teratomatous. Yet
this observer fails to distinguish between chronic productive inflammation
in plants and neoplasia, he does not consider that even in animals inflamma-
tory hyperplasia may pass into neoplastic, while his infectious "embryomas"
in plants cannot have any relation to the embryogenic disturbances known
to give rise to teratomas in the animal body.

Schiiller claims to have cultivated his protozoon and to have produced
by it both carcinoma and sarcoma. Yet no one else has been able to find
this organism in cancer and Schuller's technic fell under suspicion when
Volcker pointed out that the very characteristic large forms of this protozoon
exactly resemble cork cells.

(e) Spirocheta. — In 1905 Borrel reported the occurrence of spirochetae
in two mouse tumors without attributing to them etiological significance.
Wenyon has shown that mice are susceptible to blood infection by these
organisms. Gaylord and Calkins, finding a single type of spirochetae
in ten mouse cancers and in 16 transplants therefrom suggested that the spiro-
chetae were the cause of the tumors. Yet Gaylord and Clowes succeeded
in freeing their tumors from spirochetae by treatment with KCN, and
Tyzzer found many tumors in mice not infected with spirochetae. In

118 NEOPLASTIC DISEASES

thirty-five human tumors and twenty-five in the dog I found spiral organisms
only on ulcerated surfaces or in necrotic areas. Similar results were obtained
by Mulzer and by Lowenthal.

(/) Blastomycetes. — In 1890 Russell fully described certain small and
large round bodies in cancer-cells which stained intensely with fuchsin and
which he recognized as parasitic budding fungi or yeasts. Although these
bodies had long before been noted by Fox, and Klein and Lubarsch soon
showed that they were found in many normal and diseased tissues, the yeast
theory of cancer was taken up systematically by San Felice and the Italian
school. From 1895 up to the present time San Felice has devoted much
labor to the support of this theory. He experimented first with a culture
obtained from fruits, Saccharomyces neoformans, and one from the lymph-
nodes of an ox dying with carcinoma of the liver; Saccharomyces litogenes.
Later he obtained cultures from human tumors. With these cultures he
produced infection of many animals, chiefly dogs.

With Saccharomyces neoformans he thought he produced a sarcoma in the
breast of a bitch and in many other animals, but most of the lesions were
clearly inflammatory. Saccharomyces litogenes produced very similar lesions.

Repeated passages increased the virulence of the strains and their neo-
plastic properties. Cultures from human tumors were non-pathogenic for
animals. It was not possible to recover the organism from the tumors, a
result which San Felice attributed to the death of the yeasts which then
assumed the form of fuchsin bodies. In his latest studies San Felice com-
bines the soluble toxines of yeasts with the living cultures, finding that the
toxines rather than the bodies of the organism cause proliferation of cells.
Nevertheless the lesions which he pictures seem to have the features of infec-
tious granulomas and not those of tumors.

Many other observers claim to have isolated blastomyces from tumors
and produced other tumors by inoculation, as Plimmer, Roncali, Corselli
and Frisco, Curtis, Monsarrat, Leopold, Wlaeff, Klein, etc. Against their
conclusions stand an equal number of very competent studies which show
that blastomyces are rarely present in tumors and that they are incapable
of producing neoplastic lesions. Foulerton and Richardson examined several
hundred human tumors without securing a single yeast. Their rare presence
in tumors is attributed by most bacteriologists to secondary infection, and
the high proportion of successful cultures secured by many observers is
clearly the result of air contamination. Meser found lycopodium seeds
from the dressings deep within the tissue of carcinoma. The pathogenic
action of a number of yeasts have been elaborately studied by many com-
petent observers including Mafucci and Sirleo, Foulerton, Rabinowitsch,
Petersen and Exner, and Nichols, none of whom found any indication that
these organisms can produce tumors.

The various blastomycetes known to be pathogenic for man produce
characteristic granulomas but not tumors. It is true that in certain chronic
blastomycotic lesions, especially of the skin, considerable hyperplasia of
epithelium resembling cancer has occasionally been seen, but there is no
indication that this hyperplasia exceeds that observed with syphilis and
tuberculosis. Genuine cancer sometimes follows such lesions and yet no one
supposes that the tubercle bacillus is the cancer parasite. The identity
of yeasts, dead or alive, with Russell's bodies has been subjected to careful
criticism by many observers, especially by Sternberg and Nichols, who
conclude that there is no adequate proof that blastomyces produce any con-
siderable proportion of the fuchsin bodies.

Otto Schmidt claims to have isolated from human carcinoma and sarcoma

THE PARASITIC THEORY 119

an organism which he calls Mucor racemosus and which he believes falls
in the class of mycetozoa. With this organism he has produced ten sarcomas
in rats and mice, some of which he has transplanted through several genera-
tions, the tumor strain finally reaching 100 per cent, of successful implan-
tations. He is able to immunize rats against the organism and against
its tumor-producing properties, and rats with tumors he is able to cure by
inoculation with killed cultures of the mucor. Six out of 19 cancer cases at
the Heidelberg Institute gave what he regards as anaphylactic reactions
against the mucor. Baisch has succeeded in verifying some of Schmidt's
results. On investigation it does not appear how often Schmidt secures
cultures from human tumors nor with what precautions the successful cul-
tures were obtained. The mucor cannot be identified in sections of the
tumors. Some of the growing forms of the parasite Schuberg regards as fat
droplets. From the experimental tumors the parasite is not recoverable.
Ten tumors were produced, but hundreds of animals were used and it does
not appear that the proportion of successful results greatly exceeds that of
spontaneous tumors in rats subjected to other traumatic influences. The
cure of the rat tumors is accomplished after very severe intoxication by the
injected cultures and the death of many animals. Schmidt claims to have
cured human cancer by his toxins but others have not succeeded. There
seem to be no grounds for accepting the conclusion that human patients show
anaphylaxis to the cultures of mucor. In fact Schmidt has not adduced
satisfactory evidence that Mucor racemosus has anything to do with human
cancer. What he seems to have accomplished is to add to the list of toxic
agents that are known to excite hyperplastic inflammation which, especially
in rats, may exhibit metaplastic changes and possibly pass over into tumors.
He has not apparently controlled his work by equally energetic efforts to
produce similar changes by other agents. Yet his observations seem to fall
in line with those of other observers who by various means succeeded in
causing notable hyperplasia and metaplasia of animal tissues, as Fischer
with Sudan III, Jores with Scharlach R in paraffin, Stohr and Stoeber
with naphthalamin, paratoluidin, and amidoazotoluol, and Stoeber and
Wacker, with indol and skatol. With the expressed juice or the nucleo-
proteids of yeasts Galeotti and Pentimalli have also produced a considerable
variety of tumor-like hyperplasia in dogs and rats, but they hesitate to assume
that these processes are identical with progressive neoplasms. It is even more
doubtful if the agents they used actually occur in spontaneous tumors.

The Experimental Study of Tumors. — The inoculability of carcinoma
was once supposed to demonstrate its parasitic nature. Long after Peyrilhe's
failure several experimenters claimed to have succeeded in transferring cancer
to lower animals by intravenous inoculations of fresh emulsions (Langen-
beck, Follin, Velpeau). These results were later met with many more nega-
tive reports by Virchow, Weigert and Billroth. The more recent claims of
successful implantations of human cancer into lower animals by Boinet
(1894) (epithelioma into dogs), Juergens, 1896 (melanoma into rabbits);
Dagonet, 1904 (epithelioma into a rat); and Werner, 1907 (carcinoma into a
dog) leave open the question how far human cancer may survive in these
animals. Extensive melanosis of the organs as well as local tumors followed
the inoculations of human melanoma by Goujon, Lang and Bosc, and Vedel,
while Pfeiffer thought he was able to carry his melanoma into one of a second
series of mice. Yet Fischer repeatedly failed to transfer melanoma to rats
and Roux and Metchnikoff were unsuccessful with the chimpanzee. In
none of the successful cases does it appear that the resulting process was
anything more than a local or general reaction to the cells and pigment intro-

120 NEOPLASTIC DISEASES

duced. While it is possible that the reactions observed in some of these
animals must be classed with the tumor-like processes produced by chemical
agents acting upon tissue cells there is no proof that the injected human cells
multiplied during the considerable periods over which the animals were
observed.

Firket, Boinet, Gaylord, Lewin, Bosc and Vedel, and others, claim to have
produced cancerous nodules by inoculation into animals of various human
cancers. While it is impossible to detect definite fallacies in all of these cases,
especially in that of Dagonet, there are many difficulties in the way of their
acceptance. A much greater number of negative results are recorded by
many observers, as Shattuck and Ballance, Fischel, Sticker, Hemmeter,
and many others. Herzog found that the nodules first forming invariably
disappeared if the animal survived long enough and this has been the common
experience of many pathologists working in this field. The experience of the
last decade with transplantable tumors, showing how narrowly balanced is
the nutrition of tumor-cells, renders it extremely unlikely that human tumor-
cells can proliferate extensively in distantly related animals. The frequency
with which spontaneous tumors occur in laboratory animals has been greatly
underestimated by most observers, but has been clearly pointed out by Tyzzer.

The apparent impossibility of inoculating tumors from one lower animal
to another of the same species long stood as evidence against their parasitic
nature. Since the transfer of tumors among lower animals has become
extensively practised it has become evident that this inoculability does not
favor the parasitic theory but rather stands strongly against it, since it has been
shown that the tumor-cells are transplanted and no evidence of a parasitic
agent has been obtained. It is, of course, conceivable that a parasite is trans-
ferred with the cells and maintains their tendency to growth, but no evidence of
such a parasite has thus far been secured, and there is no indication of the
existence of any such form of parasitism anywhere in the animal or vegetable
kingdom (Lubarsch).

Therefore the results of the study of transplantable tumors are every-
where regarded as a new and serious obstacle in the way of the parasitic
theory.

The development of epithelioma following #-ray burns is a phenomenon
which upon analysis seems to prove that this tumor develops entirely apart
from any parasite and arises through slow disturbance of the nutrition and
mechanical relations of the epithelial cells.

Clunet has succeeded in producing a malignant sarcoma in a rat by
repeated exposures to x-ray and, in a case reported by Senger, round-cell
sarcoma seems to have developed after a lupus cancer treated with arrays.

Chemical agents of great variety have been employed by many observers
to produce tumors and not without a certain success.

Emanating from a different point of view, but falling in the same general
class, are the results of San Felice, Schmidt and Galeotti and Pentemalli,
previously mentioned, who by means of extracts of yeasts seem to have suc-
ceeded in rare instances in producing genuine malignant tumors in lower
animals. Since the great majority of such attempts are failures, the occa-
sional success may be accepted without in any way involving the conclusion
that such agents are commonly at work in producing spontaneous tumors in
man or animals. They seem merely to illustrate the indirect action of
irritants on predisposed tissues, which is a principle of tumor genesis long
since established by clinical and pathological studies in man.

Likewise the striking observations of Rous that filtered extracts of a
transplanted and very virulent sarcoma of chickens causes the growth of the

THE PARASITIC THEORY 121

tumor in a considerable proportion of cases, is probably to be classed as an
instance of chemical stimulation of cells.

This observation has the additional interest that the chemical deriva-
tives of this tumor possess an unusual capacity to excite the neoplastic
hyperplasia and recalls the well-known observations frequently made in
man, that normal cells are drawn into the tumor process by the gradual
diffusion of some influence from the tumor-cells. As an alternate hypothesis
one may assume that an invisible microorganism passed through the filter,
but here again the evidence of the existence of such a parasite is defective.

There are several other observations that chemical agents arising in the
course of tumor growth possess a notable capacity to excite tumor-like
growths of tissue cells and it seems probable that in some instances genuine
neoplasms have been produced by such agents.

By repeated subcutaneous injections of extracts of human cancer filtered
through porcelain Mayet claims to have produced cancerous lesions in
white rats, and Franco tte and DeRechter report similar results with cancer
juice in white mice. Hemmeter by local injections of filtered extract of
cancer of the stomach from the dog has produced cancerous-like prolifera-
tion in the walls of experimental gastric ulcers in the dog.

Theoretical Objections to the Parasitic Theory. — It is often assumed that
the establishment of a parasitic cause of cancer is surrounded by no more
difficulties than those which beset the search for the causes of syphilis or
other infectious diseases. It should be pointed out, however, that there are
many theoretical objections which would render unusually difficult the
establishment of any cancer parasite even though supported by strong
objective data.

The known infectious diseases display features of incidence, course,
and anatomical character which sharply separate them from malignant
tumors. The study of the age and sex incidence of cancer presents a body
of data which reveals a fundamental difference in the etiology of cancer and
all known infectious diseases. The distribution of cancer is as widespread
as inflammation in general, indicating that blastomatosis is not a subdepart-
ment of the reaction of tissues to injury, but a distinct and separate phenome-
non in the life of the cell. Over against degeneration and inflammation
stand regeneration and neoplasia. The anatomical and physiological
characters of malignant tumors differ essentially from those of known infec-
tious processes. The isolation of the cells of origin of tumors is wholly differ-
ent from anything recognized in parasitic diseases. The abnormal size of
nucleus and cell body revealing overnutrition is contrary to the rule in infec-
tious processes. The types and degrees of metaplasia observed in tumors
find no parallels in inflammation. The progressive growth of malignant
tumors reaches a degree which constitutes it a different pathological entity
from the regenerative process in the healing of wounds and the reaction
to irritants. Parasitic diseases cause regressive processes in the infected
tissues and general deterioration of the system by toxic agents, but tumors
exert no deleterious action on the system or on the organ involved or even on
the cells affected except through secondary agencies. The metastases of
tumors reveal conditions wholly different from any phenomena observed
with infectious diseases. There is no more impressive illustration of the
difference between tumors and infectious granulomas, which they most
nearly resemble, than the comparison of the fate of tumor-cell emboli and of
emboli from a tuberculous focus. In the former case the tumor-cells grow
where they lodge, receiving only nutriment from the blood of the part;
in the latter case the embolic cells die and the transported bacilli excite an

122 NEOPLASTIC DISEASES

inflammatory process in the adjacent tissues. Similarly, transplantable
tumors survive in the progeny of the transferred cells.

It is conceivable that an invisible parasite lives with the tumor-cell
stimulating its growth and nutrition but there is no evidence of any such form
of parasitism anywhere in the animal kingdom. Parasites occur in mitotic
cells, especially in club root, but this process is not a tumor (Tubeuf). Where
parasitism is known it is at the expense, usually, of the life of the cells, while
degenerative processes in tumors are secondary.

Weigert and Roux assume that the growth capacities of the cells are
determined in the ovum and can never be increased except by fertilization,
and Ribbert concludes that a tumor-producing parasite is therefore incon-
ceivable. Yet it must be admitted that the growth of cells is greatly influ-
enced by the environment and that peculiar external irritants of parasitic
origin may greatly stimulate the nutrition and growth of cells. It has also
been assumed that tumors result from release of the restraints of growth,
but our knowledge of the nature of growth restraints seems hardly sufficient
to warrant the conclusion that parasites may not be concerned in abolishing
these restraints. Biology cannot argue the cancer parasite out of existence
but it can demand objective data in its support.

The general facts of the genesis of tumors are strongly against the possi-
bility of a parasitic origin.

Tumors arise in some instances from a single cell (teratoma testis),
in most cases from a narrowly circumscribed group of cells, and grow chiefly
or exclusively from their own resources. The gradual inclusion of neigh-
boring cells in the process is as well explained by the diffusion of chemical or
other influences as by the transfer of a parasite, while there is much evidence
directly in favor of the former hypothesis. The embryonic nature and
isolation of the cells of origin of a large proportion of tumors, as embodied in
Cohnheim's theory, are incompatible with a parasitic origin of such tumors,
and yet they possess all the qualities of malignant neoplasms which are not
known to be derived from embryonic cells. The occurrence of highly malig-
nant congenital tumors in several members of the same family, as glioma
of retina, reveals an embryogenic and hereditary disturbance as the essential
factor. Clinical experience strongly impresses the importance of chemical
and mechanical irritants and various disturbances of nutrition as the exciting
causes of tumors. Here stand the numerous list of occupational cancers,
from paraffin, anilin, chimney-soot, the predisposing influence of arsenic
(Dubreuilh, Hutchinson) and tobacco, #-ray cancers, the influence of chronic
mechanical irritation, and severe trauma. Likewise clinical observation and
anatomical study reveal the fact that cancers which are not of embryogenic
origin do not arise except after long continuous previous change in the tissue.
These changes do not favor the establishment of any known form of parasit-
ism but rather suggest disturbances in the nutrition and function of the
cells. Thus Billroth expressed the conviction that without previous changes
in the originating tissue cancer does not exist, and his report of an epithelioma
arising after many years over most of the area of an extensive scar from a
burn, well illustrates the basis for his belief.

Few writers have ventured to suggest that benign tumors can be of
parasitic origin, and yet occasionally tumors which are otherwise indistinguish-
able from benign growths, as adenoma of the thyroid and leiomyoma, may
exhibit all the characters of malignancy.

The developmental history of many tumors exhibits the natural unfolding
of embryonic potencies. However extensive may be the scope of metaplasia
in tumors, it cannot cover the facts observed in the field of malignant tera-

THE PARASITIC THEORY 123

tomas. The teratomas arising from sex cells yield many pure forms of
benign and malignant tumors on the one hand and highly complex structures
approaching a parasitic fetus. The metastatic cells from such tumors again
go on to develop specific structures in lymph-nodes and distant organs.
Thus in a metastasis of an ovarian teratoma Lubarsch observed brain tissue
and ependyma in orderly arrangement. Metastases of many tumors are
distinctly organoid in character maintaining polarity in arrangement and
functionating as organs. If the above phenomena are of parasitic origin
then, as Wilms points out, the whole history of embryonic development
must be conceived as within the scope of parasitism. Hopeless dilemmas
arise when one attempts to conceive of the necessary properties of the cancer
parasite. It must pick out minute aberrant groups of embryonic cells in
protected situations even in the fetus of a healthy mother. Misplaced and
embryonal tissue invaded by metastases escapes infection by the parasite.
Shaffer and Lubarsch have described misplaced islands of gastric mucosa
in the esophagus invaded by epithelioma of the esophagus but showing no
hyperplasia. Berent observed a misplaced adrenal rest in the kidney
unaffected by a metastatic nodule from epithelioma of the jaw. With the
most actively growing metastases adult normal tissues are not infected but
as a rule behave passively. In chorioma the parasite invades the fetal but
spares maternal tissues. In the metastases of melanoma the parasite produces
extremely rapid proliferation of cells in one case, or it remains dormant for
many years.

Contrary to all known forms of parasitism the cancer parasite stimulates
growth and nutrition of cells and renders them viable after transplantation
in the same or other animals. It stimulates the absorption of nitrogen by
the host (Cramer) and fails, except through secondary influences, to exert
any toxic or deleterious action on the body.

In view of the considerations thus briefly reviewed it is impossible to
regard as a valid hypothesis the conception of a specific group of parasites
living in symbiosis with the cancer-cell and stimulating its growth and
nutrition. All the facts are reasonably explained by regarding the cancer
parasite as the cancer-cell. The temporary popularity of the search for a
specific parasite must be attributed to the undue influence of the germ theory
of disease which can be effectually combated only by further knowledge
of the biology of the cell.

The Scope of the Relation of Parasites to Cancer. — Although the concep-
tion of a specific cancer parasite living in symbiosis with the cell and stimu-
lating its growth is without definite foundation and is incompatible with the
nature of many tumors, there remains a certain field for parasites as etiolog-
ical factors in tumors.

In the familiar coccidiosis of the rabbit's liver parasitic ova excite a
tumor-like proliferation of the bile ducts. The process is strictly dependent
upon the presence of the ova and regresses when these are removed and
hence it is not a true tumor, but it has some of the qualities of a neoplasm and
these are dependent on a parasitic irritant.

In Bilharzia infection cancer of the bladder follows in a certain pro-
portion of cases. Here the disease is true cancer, it is less intimately con-
nected with the presence of the parasite, but it is nevertheless rather obviously
a sequel of the infection and reveals a peculiar capacity of this form of
irritation to produce cancer.

Lowenstein has described papilloma of the bladder in rats infested with
Trichodes. Primary carcinoma of the liver in cows suffering from Distomia-
sis has been referred to the irritation of this parasite (Haaland). In a pap-

124 NEOPLASTIC DISEASES

illomatous gastric tumor of pigeons Wasielewski has found a species of
Dispharagus. Brumpt describes an adenoma of the stomach in monkeys as
referable to infection by Physaloptera. Febiger has fully demonstrated
the relation of Spiroptera to a gastric carcinoma in rats. Askanazy attributes
to a trematode, Apistorchis felineus, an etiological relation to certain* hepatic
carcinomas in man, and similar relations have been claimed for Distomum
spatulatum and Japonicum by Katsurada and others.

Many observers have considered the possible relation of trichinosis
to carcinoma and several have stated that carcinoma is peculiarly frequent
in chronic trichinosis (Langenbeck, Babes). I rather frequently find trichina?
in cancerous tongues.

Borrel has observed several cases of sarcoma and adenocarcinoma of the
rat in which a nematode worm was found in the center of the tumor. Regaud
and Saul have reported similar cases and Bridre found several sarcomas in rats
growing about cysticerci. Borrel finds acari in the early spontaneous lesions
of the lymphosarcoma of dogs. In 12 early epitheliomas of the face in man
he found numerous acari inclosed in the tumor-cell nests. In the nipple
of certain cases of Paget's disease and cancer of the breast he finds acari
or another animal parasite, Demodex folliculorum. Borrel admits that these
same parasites occur not infrequently in the healthy skin or nipple where
they usually produce hypertrophy of the sebaceous glands. These ecto-
parasites he regards merely as the carriers of the true cancer virus.

Saul has also drawn attention to the occurrence of worms in mouse
tumors, and in two human ovarian tumors he found a parasitic mite, Tarsone-
mus. It has been suggested that the Tarsonemus gained access to the
material after its removal from the body.

All of these observations indicate that animal parasites or their deriva-
tives have a peculiar capacity to excite hyperplasia in the tissues they infect.
Yet it has not been proven that they are present in any bat superficial tumors,
or that their presence signifies anything more than a secondary invasion.
Nor is it known that the tumor-like processes in which they are usually found
have any other significance than the hyperplasia excited by Sudan III which
regresses upon the removal of the irritant. In lower animals especially,
animal parasites of the skin are very common while cutaneous tumors are
rare.

Certain manifestations of syphilis have a close though indirect relation
to tumors. The lingual cancer following leukoplakia may be regarded as
the result of the disturbed nutrition and relations of the epithelial cells long
established in the disease and yet the frequency of this form of cancer
reveals a certain unusual capacity of syphilis to excite neoplastic growth.
Likewise the syphilitic sarcoma described by Hansemann shows this same
peculiar influence exerted on mesoblastic cells, the full scope of which is
possibly not yet recognized.

Tuberculosis in several of its phases has an indirect relation to certain
tumors. In a small proportion of cases of lupus, epithelioma develops
through long disturbance of the nutrition and relation of the epithelial cells
of the affected area. That there is something specific in the tuberculous
process is suggested by the greater frequency of epithelioma after lupus
than with simple chronic eczema.

In some forms of tuberculous lymphadenitis, tumors of endothelial
cells develop under conditions strongly suggesting that the neoplasm is a
sequel of the tuberculous infection. Tuberculosis may cause a widespread
hyperplasia of the lymphatic tissues of the body with miliary lymphomas
in many organs. The frequent association of lymphatic leukemia with

THE PARASITIC THEORY 125

tuberculosis has suggested to many that this disease, which has several
characters of a neoplasm, may be dependent on tuberculous infection or
intoxication. Hodgkin's granuloma which is either tuberculous or caused
by a related organism, has been shown in several cases to pass over into a
sarcomatous process.

Hence the sequels of both syphilis and tuberculosis have a definite
relation to tumors, which reveals the microorganisms as indirect cancer
parasites. In both cases the resulting tumor process seems not to be depend-
ent on the presence of the parasite but to arise from the natural momentum
of the disturbance originally excited by the parasite.

FIG. II. — Growth resulting in 31 days from inoculation in sugar beet of Bacillus tumefaciens
obtained from poplar gall. (After Smith.)

In the lower animals, especially in rats, the momentum of inflammatory
processes which may lead to tumor growth seems distinctly less dependent
on the presence of the parasites than in man.

In plants the observations on crown gall, especially those of Smith,
point to the conclusion that in the vegetable kingdom progressive hyper-
plasias originally excited by parasites may be still less dependent upon their
continued presence than in animals.

All these considerations encourage the search for new microorganisms
which may have a special capacity to excite inflammatory processes which
tend to go on to tumor growth, but they offer no support to the theory of a
specific cancer parasite living in symbiosis with the cancer-cell and constantly
stimulating its growth.

The results in this field show that parasites may be concerned only with

126

NEOPLASTIC DISEASES

the inception of certain tumors but that their influence cannot explain the
continued autonomous growth of malignant neoplasms, wherein lies the real
mystery of the cancer process.

The study of the parasitic relations of cancer suggests the following
classification of tumors with regard to their possible connection with a para-
sitic origin:

i. Tumors of embryonal origin and their derivatives to which Conheim's
theory applies, and to which parasites have no relation whatever.

FIG. 12. — Centers of cell proliferation in daisy stem inoculated with Bacillus tumefadens.

(After Smith.)

2. Malignant tumors of exposed surfaces or internal organs with which
parasites may figure as occasional indirect or direct exciting causes.

3. Sarcomas, especially those of lymphoid type, which are known to
be the sequel of infectious diseases or on account of their imperfect neo-
plastic qualities may probably be regarded as more or less dependent upon
the presence of parasites.

4. Tumors of lower animals in which the momentum of a parasitic process
tends, more than in man, to assume autonomous qualities.

CHAPTER IX

EXPERIMENTAL CANCER RESEARCH

EXPERIMENTAL PRODUCTION OF TUMORS

Among the various fields of the experimental study of cancer the oldest
and probably the least fruitful is the attempted experimental production
of tumors. Today it may be said that no one has succeeded in producing
cancer under conditions that are strictly experimental, although cancer and
sarcoma have been observed to follow #-ray inflammation in man and ani-
mals, and Febiger has observed the development of cancer on chronic
gastritis produced by feeding rats with cockroaches infested by a nematode
worm. Febiger's work may probably be accepted as presenting the con-
trollable conditions of an experiment, but the proportion of cancers pro-
duced was small.

Efforts to produce tumors have passed through several phases suggested
by theoretical views of the nature of tumors.

i. Transplantation of adult tissues or cells was early found by Zahn and
Leopold to result in eventual and usually prompt absorption. Squamous
epithelium from the combs of fowls Kaufmann found to persist for an un-
usual period, producing small cysts, and thus duplicating the observed mode
of origin of traumatic epidermoids.

Lengemann followed the fate of misplaced cells of liver, kidney, and car-
tilage. He failed to observe any features of tumor growth, and concluded
that misplacement alone, hyperemia, or partial degeneration of the cell
mass, were insufficient to excite tumor growth, while the weakened state
of the animal had no influence on the fate of the cells. In his hands salivary
gland and thyroid tissue exhibited the greatest proliferation.

Stilling chose the spleen as the most suitable soil and after transplanting
fragments of uterine muscle and mucosa in rabbits found in some cases a
growth of muscle-cells far exceeding their normal limits and resembling
fibromyoma, and in other cases he observed the development of large cysts
lined by proliferating epithelium.

Nichols in an extensive series of tests found definite proliferative powers
of adult transplanted cells only in epidermis, uterine epithelium, cartilage,
and placenta. I. Levin used cells from healing wounds without result. Pass-
ing interest was excited by Lack's report that multiple carcinoma developed
in a rabbit's abdomen 14 months after scraping and leaving loose germinal
epithelium from the ovary. Yet spontaneous carcinomas arise in this
region in the rabbit (Boycott), and Fraenkel failed in several attempts to
duplicate Lack's results.

Lubarsch appears to have encountered a similar coincidence in finding
a large renal adenocarcinoma in the kidney of a rabbit into whose kidney
he had some months previously transplanted a fragment of salivary gland.

Ribbert implanted portions of many organs in the peritoneum, skin,
anterior chamber of eye, and lymph-nodes, always with eventual atrophy.
He concluded that fully organized tissue masses might become implanted in
these new positions and go on to functionate. The transplantation of whole
organs, or large portions of ovary, thyroid, testis, mamma, has been accom-

127

128 NEOPLASTIC DISEASES

plished by many observers. The transplanted thyroid may relieve myxe-
dema (Eiselsberg) ; the transplanted ovary is said to have led to pregnancy
(Krauer); the testis atrophies without necrosis; and transplanted mammary
tissue has secreted milk in gestation (Ribbert).

2. Transplantation of embryonal tissues has been pursued to a formidable
extent with the general result of showing that embryonal tissues exhibit much
greater proliferative capacity than adult but still lack an essential factor
in tumor growth. Loeb, however, found certain adult tissues to grow b'etter
than the embryonal.

Leopold concluded that the younger the embryo the better was the growth,
while Tiesenhausen specified five days as the optimum age of chick embryos.
Zahn correlated the growth with the extent of vascularization of the trans-
plant. Cartilage is said to have increased twenty times in bulk in Nichols'
animals, and Leopold thought he obtained true chondromas. Intermittent
heating of the organ seemed to increase the growth in the rabbit's liver of
fragments of periosteum injected by Birch-Hirschfeld and Garten. Preg-
nancy was found to create a more favorable soil in the work of Askanazy
and Jentzer in rats, but Shattock found it less favorable for cartilage growing
in rabbits, while Rous found the most favorable period in mice to be after
delivery.

Successive transfers of transplanted tissues at eight day intervals seemed
to increase the growth in Wilms' experiments with chicks, but an opposite
result is recorded by Fichera. In most circumstances transplanted embryo-
nal cells exhibit a certain amount of differentiation as well as of growth but
in the direction of normal tendencies rather than toward tumor growth.

Transplantation of complex tissues or portions of embryos, intact or
comminuted, usually results in abortive teratoid growths. Freund secured
such growths in 74 per cent, of rats inoculated intraperitoneally with emul-
sified rat embryos. Such emulsified cells grew for six weeks in rabbits (v.
Hippel), or eight weeks in chicks (v. Tiesenhausen), but gradually regressed
after 6-12 months. Fichera estimated the growth in rats at twenty times
the original bulk but saw no resemblance to true tumors. Cartilage and
epiblastic tissues are usually the most active.

Rous mixed embryo with tumor-tissue, finding that both components
grew in association but the tumor-cells soon outgrew the normal cells, or
both failed together, but growing tumor-cells did not stimulate growth in
the others.

Traina implanted whole limbs arid complex masses of embryonal tissue
in the ovaries of guinea-pigs and secured striking degrees of proliferation,
but no tumors.

The negative results of this extensive department of experimental re-
search become easily explicable when one compares the obvious crudity of
the experiments with the minute analysis of pathological data bearing on the
conditions under which misplaced cells are observed to give origin to tumors.
Thus among essential conditions for the neoplastic growth of misplaced
cells are the following: (i) The cell group must not possess the intrinsic growth
restraints of an organ. Otherwise it will grow or functionate as an organ.
Evidently there is a nice adjustment between the demands for function and
the capacity for growth in misplaced cell groups that develop tumors. (2)
The misplaced tissue should not be completely divorced from its normal
environment but only partially so. Otherwise it will fail to receive
sufficient blood-supply for active growth. (3) A considerable period is
usually necessary for the misplaced cells to adjust themselves to the abnor-
mal environment. Exceptions to this condition appear probably in some

EXPERIMENTAL CANCER RESEARCH 129

traumatic sarcomas. (4) An unusual source of hyperemia is usually neces-
sary for tumor growth, for this factor facilitates nutrition, and lessens re-
straints to growth. (5) The misplaced cells must possess some special
capacity for growth either by virtue of an embryonal character or from the
retention of proliferative tendencies of more than ordinary degree. Thus
tumors do not arise indifferently from all portions of an organ but from
the cells of ducts or from the germ centers of lymph-nodes. (6) The experi-
mental studies ignore the importance of the preliminary changes which are
observed to precede the development of tumors from normal or misplaced
cells. These precancerous stages, the "indifferent vorstadium" of Ribbert,
are not provided in the experimental transplantation of tissue cells.

Some of these objections have been met in the efforts to alter the char-
acter and accelerate the growth of cells before transplantation. G. Lewin
injected emulsion of a human ovarian carcinoma into the peritoneum of a
dog. After several weeks the omentum was found studded with miliary
nodules which seemed to be of inflammatory character. Those were again
emulsified and injected and the process repeated through five series of dogs,
the resulting nodules presenting eventually a structure which Lewin regarded
as sarcomatous. These observations have not yet been verified.

In somewhat the same manner Stieve produced granulomatous inflam-
mation about injections of infusorial earth, transplanted this granulomatous
tissue, and saw more and more atypical proliferation approaching that of
sarcoma.

Influence of Lipoid Solvents on Epithelial Proliferation.— A series of
experimental studies undertaken from various view-points have indicated
that cells treated or influenced by lipoid solvents tend to exhibit increased
and atypical proliferation.

Reinke, noting atypical epithelial growth after the injection of 4 per cent,
ether into the eye of a salamander, transplanted the proliferating epithe-
lium into the peritoneum of other salamanders where it continued to grow
more atypically so as to resemble carcinoma. Askanazy mixed emulsion
of rat embryos with ether before inoculation and secured larger teratoid
tumors than by means of untreated embryos, but Freund could not duplicate
these results.

B. Fischer introduced an interesting field of study by inoculating under
pressure a saturated solution of Scharlach R in olive oil under the skin of
rabbits' ears. The basal epithelium of skin and hair follicles after a few days
began to proliferate and continued to grow downward inclosing oil globules
and producing a picture resembling epidermoid carcinoma, but the growth
ceased when the oil had been absorbed. In the mammary gland of rabbits
a saturated ethereal solution of the dye produced a squamous epithelial
growth replacing gland lobules. Since no such effect followed injection of
simple oils and fats Fischer assumed that the dye contained a specific chemo-
tactic substance (attraxin) stimulating epithelial growth. Many experi-
menters verified these observations, offering various explanations of the
result. The wide variety of materials used in this connection and the general
results obtained have been conveniently tabulated by Haga.

Meyer found that when the arteries of the ear were ligated olive oil alone
produced the results, which he was inclined to refer to chronic inflammation.
Stoeber and Wacker found certain components of Scharlach R. and Sudan
III equally effective, and by using 5 per cent, solutions of indol or skatol in rab-
bit fat they produced very active growth more closely resembling epidermoid
carcinoma. White produced the usual changes with oleic acid, and Benthin
used a great variety of materials, finding that the best were Sudan III and

180

NEOPLASTIC DISEASES

Scharlach R. These dyes have shown a variable influence upon trans-
plantable tumors of animals.

In the mammary glands of rats (I. Levin, White), in the kidneys of
rabbits (Meyer), and in the prostate, seminal vesicles, liver, and lung of
rats (Bullock and Rohdenburg), injections of Scharlach R. have produced
considerable atypical proliferation of inflammatory character, but much

FIG. 13. — Atypical epithelial proliferation of epithelium caused by injection of scharlach R.

(Bullock, Rhodenburg.)

less marked than in the skin of the ear. Yet Haga succeeded in producing
markedly atypical but self -limiting proliferation in the tongue, stomach,
breast, and liver of rabbits, which in some cases was difficult to distinguish
from malignant growth.

Reviewing these results, in general it appears that the property of certain
lipoid solvents to excite epithelial proliferation has been established but
no true tumors have been produced (Wacker, Schmincke, Lit.).

FIG. 14. — Adenomatous growth of the rabbit's stomach, produced by feeding lanolin.

(After Haga.)

That the lipoid solvent property is an essential factor in the Result,
although suggested by much collateral evidence, appears uncertain. J.
Loeb concluded that it was the lipoid solvent properties of the sub-
stance employed that produced artificial parthenogenesis. The theory of
solution of a lipoid cell membrane has been pursued by Clowes as the key
to atypical cell proliferation. Bullock and Rohdenburg reject this theory

EXPERIMENTAL CANCER RESEARCH

131

on the ground that all lipoid solvents do not act as does Scharlach R. They
secured considerable effect from injections of pine tar, indigo, and calomel,
in oil, and they refer all the effects to cell death and regeneration. Never-
theless it is clear that certain fat stains exceed all other irritants so far
tested in their ability to excite epithelial proliferation. That they possess
somewhat specific properties in this respect is also indicated by their effect-
ive use to stimulate epithelial growth of ulcerating surfaces.

After exciting proliferation by means of Sudan III, Lamezan, and Haga,
have each attempted to transplant the growing cells to other tissues of
the 'same animal or to other animals of the same species but without success.

FIG. 15. — Epithelial proliferation of lining cells in ligated duct of salivary gland. (After

Ribbert.)

Chronic Inflammation in the Experimental Production of Tumors.—

Many experimenters have employed various forms of chronic inflammation
in the endeavor to produce tumors.

Ribbert produced small but typical fibre-epithelial papillomatous
tumors of the rabbit's lip by repeatedly scraping the regenerating epithelium.
In many organs he saw atypical growth of mechanically displaced epithelium,
but in no instance was a true tumor observed. One of his most notable results
was obtained by ligating the ducts of salivary glands in rabbits which was
followed by extensive atypical overgrowth of duct epithelium approaching
the appearance of duct carcinoma.

Brosch assumes that preexisting chronic productive inflammation is an
essential condition in the experimental production of tumors by means of
chronic irritants. After cauterizing and crushing a portion of the skin

132

N EOF LA STIC DISEASES

of the back in white rats he rubbed melted paraffin into the inflamed area
over a period of 8-12 weeks and secured atypical epithelial proliferation
closely resembling beginning carcinoma.

Cazin employed a variety of traumatic influences in the unsuccessful
effort to produce cancer from normal epithelium. Over a period of 5
months he rubbed soot into the inflamed skin of a dog without producing
any atypical proliferation.

The particular chemical agents believed to be responsible for many of
the forms of cancer observed in the trades, as in workers in paraffin, coal
tar, soot, tobacco, etc., have been rather extensively employed in the study
of experimental atypical epithelial proliferation, but in no case has a pro-
gressive tumor resulted (Haga, Lit.). Special interest attaches to the rather
notable influence of tobacco extract in exciting epithelial proliferation.

FIG. 1 6. — Gastric carcinoma in the rat, caused by infection with Spiroptera.

(After Febiger.)

Effect of Extract of Human Tumors. — Wacker and Schminke injected
into the rabbit's ear fat extracts from mammary carcinoma, chondroma, and
gastric carcinoma, and secured moderate epithelial proliferation. I have
employed the alcoholic extract of a comedo-carcinoma of the breast hi
intramammary injections in the rabbit, securing only an inflammatory reac-
tion. These experiments were suggested by the impression that the ex-
tension of comedo-carcinoma in the breast keeps pace with the diffusion of
fatty material in the obstructed ducts.

By mixing the expressed juice of carcinoma tissue with Sudan III and
injecting into the stomach wall of rabbits Haga secured well-marked tume-
factions of the mucosa with considerable ingrowth of glandular epithelium
presenting several histological characters of carcinoma.

Experimental Production of Tumors by the X-ray. — While the frequency
of development of carcinoma from x-ray dermatitis places these observa-

EXPERIMENTAL CANCER RESEARCH

133

tions virtually in the experimental class, deliberate employment of the .r-ray
for the production of tumors has been reported by Marie, Clunet, and Raulot-
La Pointe. These authors describe the exact dosage and the intervals of

FIG. 17. — Position of spiroptera in center of carcinoma of stomach in rat. (After Febige r.)

treatment followed in a successful effort to produce a malignant tumor in
the rat. The growth was a spindle-cell sarcoma and proved transplantable
in other rats.

Febiger's Experimental Gastric Carci-
noma in the Rat. — Having discovered the
remains of a nematode worm in a spontaneous
gastric carcinoma in a rat, Febiger identified
this parasite as one occurring in cockroaches
(Periplaneta Americana, and P. orientalis).
He designates this parasite as Spiroptera neo-
plastica. It was later found to infect other
hosts. He next discovered a source of in-
fested cockroaches in a Danish sugar factory
and by feeding a series of rats with the bodies
of these insects observed the development of
chronic inflammation, papillomatosis and car-
cinoma of the stomach. Of 62 rats which
survived the feeding more than 60 days 12
developed carcinoma. The interval required
was as brief as 64 days, and in one case metas-
tases were observed after 104 days.

The inflammation and papillomatosis affected a large portion of the
gastric mucosa and reached such an extensive grade as to fill or even occlude
the stomach. Structurally the process showed extensive papillary' over-
growth of epithelium with marked keratosis, while the supporting tissue

FIG. 1 8. — Spiroptera neoplas-
tica. (After Febiger.}

134

NEOPLASTIC DISEASES

was richly infiltrated with eosinophile leukocytes. From this lesion there
was progressive invasion of the mucosa and stomach wall by proliferating
epithelial masses producing the structure of carcinoma. In two animals
pulmonary metastases were observed in which tumor-cells but no worms
or ova were found. In the gastric tumor numerous spiropteras with ova
were commonly present within the proliferating masses.

This brilliant study presents an experimental production of a well-recog-
nized form of gastric carcinoma in the rat, demonstrates the dependence
of the malignant tumor upon the presence of a nematode worm, and reveals
the gradual assumption by the epithelium of the power of independent
growth apart from the irritant originally exciting its proliferation.

FIG. 19. — Structure of experimental carcinoma of stomach of rat, caused by Spiroptera.

(After Febiger.)

There appears to be no reason for introducing the idea of a constitu-
tional dyscrasia in the particular animals yielding the carcinomas, nor for
assuming the existence of a microorganism carried along with the nematode.

TRANSPLANTATION OF TUMORS

Between Animals of Different Species. — The early period of attempts
to transfer cancer from human beings to lower animals, from the time when
Peyrilhe's servant mercifully terminated the sufferings of the dog into which
^he had injected cancer emulsion, down to the present date, has practically
'demonstrated the impossibility of this mode of transfer. The numerous
failures recorded in the literature are doubtless far exceeded by the number
of unreported experiments. Even using anthropoid apes Metchnikoff and
Roux and Jobling had negative results, but it is perhaps not to be assumed
that in these animals whose blood relationship to man is comparatively
close, a successful transfer may not prove possible. The significance of

EXPERIMENTAL CANCER RESEARCH 135

the few alleged but paradoxical successes has already been considered.

Between Man and Man. — Cornil reported that an unnamed surgeon
grafted a fragment of spindle-cell sarcoma of the breast into the other breast.
At the end of two months the tumor reached the size of an almond and
proved on section to resemble the original growth. With an adenocarcinoma
a similar result was obtained but the resulting nodule was not sectioned.
Fortunately no other clinical record of successful deliberate transplantation
seems available (cf. Milner). Hahn successfully transplanted a portion of
skin containing a carcinomatous nodule.

From the period when vaccine treatment was very widely employed
I have learned of four cases in which tumors grew from injected unkilled
cells in the vaccine, some of which were mentioned by Coca. The study of
spontaneous tumor metastases removes the necessity of experimental
evidence in this field.

Between Related Species of Lower Animals.— The early observations
on transplantable tumors of lower animals indicated that successful grafts
could be made only on animals of the same species and even then only
under favorable conditions, but later studies have shown that the suitability
of the soil is of somewhat wider scope and extends with some tumors to closely
connected or even distantly related species. Thus Sticker transferred the
lymphosarcoma of dogs to foxes: v. Dungern carried his hare sarcoma into
rabbits: Funk claims to have secured successive transplants of rat sarcoma
in rabbits long fed on emulsified rat sarcoma. Murphy was able to culti-
vate mouse sarcoma in rats subjected to repeated T-raying of the spleen
but as soon as the lymphocytic function of the animals was restored the
tumors regressed.

Strauch reports an anomalous result of transplanting Ehrlich's mouse
carcinoma in rabbit. Three weeks after inoculation he secured in the rabbit
a well defined tumor which recurred after extirpation. The extirpated tumor
then failed to grow in the mouse but produced an increasingly malignant
tumor in other rabbits even giving metastases. Happe succeeded in trans-
planting rat sarcoma into the lens of a rabbit where it grew out into choroid
and retina.

Thus it appears that the viability of the cells of certain tumors of lower
animals is somewhat greater than once seemed likely but is nevertheless
sharply restricted to species enjoying a definite blood relationship. There
seems to be no theoretical difficulty in the way of still further adaptation
of the cells of one animal to growth in related species.

Between Lower Animals of the Same Species. — It is highly suggestive
of the factors determining the results of transplantation of tumors that the
first success was with the most easily transferable growth, the lymphosarcoma
of dogs. Yet Novinsky in 1876 had only two positive results in 42 attempts.
Hanau's transplantation (1889) of epidermoid carcinoma of the vulva in a
rat was rather more impressive since he dealt with a better known malignant
tumor and secured extensive metastases. Yet Wehr at the same time inter-
preted the lymphosarcoma of dogs as a carcinoma, obtained metastases in
lymph-nodes and spleen in inoculated dogs and noted spontaneous regres-
sions. In 1890 v. Eiselsberg succeeded in transferring to the mesenteric
tissues a spindle-cell periosteal sarcoma from a rat.

The first systematic study of a transplanted tumor and one which revealed
the possibilities of this method of study was that of Moreau (1891). A
cylindrical cell carcinoma of a mouse he carried through several generations,
the tumor gradually losing viability. In the offspring of tumor mice as we 11
as in pregnant animals it grew more rapidly. Traumatism produced metas-

136 N EOF LA STIC DISEASES

tases which were otherwise usually missing. Other animals were insus-
ceptible. The tumor-tissue when not ulcerated was free from microorgan-
isms. Firket carried a spindle-cell sarcoma through three generations of
rats, and Velich lost his periosteal spindle-cell sarcoma only after it had
passed eight generations, when it failed to survive in a new breed of rats.

In 1901 and 1902 the general revival of interest in the cancer problem
gave to the studies of Loeb in America and Jensen in Denmark a special
interest. Loeb (1900) carried a cystic sarcoma of the rat's thyroid through
40 generations without observing change of structure or metastases, and
reported observations on other transplantable rat tumors. Jensen (1902-
1903) reported the transmission of a mouse carcinoma through 19 generations
again without metastases. Both these authors convinced themselves that
the tumor grew from the transplanted cells, but their data on this point were
not decisive and Loeb assumed the existence of an agent apart from the cells.
Jensen found the tumor-cells very susceptible to heat, light, drying and
antiseptics, but was able to preserve their viability for 18 days at — i°C.
He further announced that he had seen the regression of large tumors in mice
receiving injections of antiserum prepared in the rabbit. Borrel strengthened
the evidence in favor of the carcinomatous nature of the mouse tumors by
observing numerous metastases in lungs and lymph-nodes. With these and
other studies shortly following, the modern field of experimental cancer
research definitely opened.

Of the permanent results of this new era of experimental research it is
too early to speak with certainty. In many respects the recent work has
deepened our insight into the conditions of growth of tumors, especially the
narrow range of their viability and at the same time their apparently un-
limited capacity for growth in suitable environment. Particularly fortunate
are the conditions provided for the detection of any immunity factors that
may be concerned and yet progress in this field has perhaps been more
limited than in others. It is apparent that many phenomena encountered
in the study of transplanted tumors and hastily interpreted as new observa-
tions had long before been fully recognized in spontaneous human tumors
by those familiar with this field. Many observations on change of structure,
the apparent discrepancy between histological appearance and biological
behavior, the mechanism of tumor regression, the conditions governing
metastasis, the elements contributing to cachexia, have proven little more
than welcome reappearance, under experimental conditions, of facts and
principles previously established in the human subject. The study of
transplantable tumors has shed no light on the histogenesis or mode of
origin of neoplasms. In the field of practical therapeutics it has opened
up many new trails which unfortunately have led mostly astray. Chief
among the less important results is the further evidence supplied by the
extension of the work to various lower animals that different tumors are
often quite different clinical and pathological entities, and that observations
on one may not safely be applied to another.

The problems arising in the study of transplanted tumors may now be
considered in brief detail. For a full discussion of this subject cf. Woglom.

Problems of Transplantable Tumors. — Nature and Origin of the Tumors.—
Many doubts were first expressed regarding the malignancy and even of
the neoplastic nature of the transplantable tumors. Yet it has been abun-
dantly shown that the chief tumors in mice often exhibit infiltrative growth
and metastases. Bashford, Murray, and Cramer described in detail local
infiltration and metastases in the Jensen tumor, and Apolant showed that
this type of growth developed when the tumor met dense resisting tissues-

EXPERIMENTAL CANCER RESEARCH 137

Murray found pulmonary metastases in about 50 per cent, of his spon-
taneous tumors but they were often microscopic. The significance of the
morphology of these tumors must also be regarded as unequivocal. When
the whole list of mouse tumors now described is considered, it appears that
this animal is subject to a considerable variety of tumors comparable to those
of man and a standard of tumor morphology for this animal has been
established.

The origin of the chief mouse tumor has been shown by Bashford and
Murray and Apolant to be from widely scattered mammary tissue. Many
other mouse tumors have been described and traced to their probable origin,
as epidermoid carcinoma of the mouth (Borrel, Haaland), adenocarcinoma
of intestine, carcinoma of stomach, adenoma of liver, spindle-cell sarcoma of
renal region ( Bashford, Murray, and Cramer), chondroma (Ehrlich), adeno-
carcinoma of kidney, adenocarcinoma of ovary, melanoma, myoma uteri,
adenocarcinoma of sebaceous glands, and many others (Haaland, Tyzzer).
Apolant thought that 95 per cent, of mouse tumors arise in the mamma,
but in Tyzzer's series of 70 tumors of mice 74 per cent, arose in the lung.

In the rat the series of observed tumors is almost equally extensive.
Loeb's tumor was a spindle-cell growth apparently sarcomatous arising in the
thyroid. Other sarcomas are described by Herzog and by Jensen. Stohr
reports a fibro-epithelioma of the tongue, Flexner and Jobling an adeno-
carcinoma of the seminal vesicle; and Lewin and Michaelis a mammary
carcinoma; Gaylord, a spindle-cell sarcoma. Many of these tumors have
been extensively transplanted.

In the dog, mammary carcinoma is a common tumor which presents
many peculiarities but all the essential features of malignancy. It has been
transplanted in the Loomis Laboratory by Teague into animals weakened by
distemper. The infectious lymphosarcoma of dogs has been variously inter-
preted. It is a large round or rather polyhedral cell-growth probably arising
from the reticulum cells of the lymph-node. Beebe and the writer have
shown in bacteria-free transplants that it arises fron; the transplanted cells.
Whatever may be the conditions surrounding the inception of this tumor,
when fully developed it presents all essential features of a malignant neo-
plasm. Many efforts to cultivate bacteria have failed, and spirochetae
occur only on ulcerating surfaces. The conditions permitting transplan-
tation are similar to those observed with other tumors.

In the fowl lymphocytomas with and without leukemia are comparatively
common. In Wernicke's summary of the recorded tumors of fowl it is
seen that a considerable variety of newgrowths has been observed. Ehren-
reich found seven tumors of carcinomatous or sarcomatous type among 1000
old chickens. An attempt to transplant one of the carcinomas failed. Pick
observed an epidermoid carcinoma of the mouth; Tyzzer reports myxosar-
coma of the thigh and leiomyoma of the mesentery. Fujinami and Inamoto
have described a myxosarcoma which was readily transplantable and pro-
duced numerous metastases in the inoculated fowl.

Rous has described three chicken sarcomas, spindle-cell, and osteochon-
dromatous, all of which are transplantable. The juice from the spindle-cell
sarcoma strained through a Berkefeld filter (No. 5, medium) as well as the
dried and powdered tumor-tissue reproduced the growth. The effective
agent remained in the dried tissue for seven months but was destroyed by a
temperature of 55°C., and would not pass a Chamberland bougie (F. i).
It was very susceptible to antiseptics. Quite remarkable was the increase
in viability of this tumor, for while it was at first transferred with great diffi-

138

NEOPLASTIC DISEASES

culty it eventually gave 100 per cent, of successes in Plymouth Rocks. It
could not be transplanted to other fowl.

FIG. 20. — Structure of nodule of lymphosarcoma of dog three days after transplantation.
Note line of separation between tumor-cells and host's tissues.

FIG. 21. — Section of a pulmonary metastasis of Rous' chicken sarcoma.

In animals inoculated with the juice secondary tumors very often devel-
oped at points of trauma, but always much more slowly than in animals
inoculated with cells. Filtrates from the spindle-cell tumor and from the

EXPERIMENTAL CANCER RESEARCH 139

chondroma reproduced only the original tumor. It thus appears that in
Rous' sarcoma a tumor-producing agent can be separated from the tumor-
cells by coarse filtration. The nature of this agent has not been determined.

It seems probable that the action of this agent may be compared to
that of substances diffusing from certain human tumors into surrounding
tissues and causing peculiar collateral hyperplasia and even the gradual
transformation of normal into tumor-cells. It may also be pointed out
that various chemical agents have been shown to be specially adapted to the
excitation of atypical overgrowth of cells. Another factor of undetermined
value may be a peculiar quality in the reaction of chicken tissues to irritants.
The principles of avian pathology are not as yet fully expounded. It is of
little moment to inquire whether or not the Rous sarcoma is a true tumor.
It is obviously not a simple inflammation but enjoys several essential features
of a neoplasm. At present it must be regarded as a disease sui generis
without exact parallel in other animal species.

In rabbits a considerable number of tumors have been described but
none appears to have been extensively transplanted. In the hare v. Dungern
and Coca discovered a slowly growing spindle-cell sarcoma in the skin of the
ear. It contained spindle-cells mingled with large polyhedral eosinophile
cells and somewhat resembled a granuloma. It proved readily transplantable
in rabbits, and from the serum reactions of the inoculated animals the
authors concluded that the tumor-cells even in late generations retained the
properties of hare protein. The significance of these serum reactions is,
however, open to doubt.

Fate of the Transplanted Tumor. — The demonstration of the survival of
the tumor-cells in the transplanted tumor has been a highly important
result of experimental studies, since it establishes an essential distinction
between neoplasms and infectious processes. This principle had, of course,
been previously demonstrated by observations on metastatic processes in
human subjects but the experimental evidence has been more decisive.
Observations at intervals upon the implanted tumor grafts have shown for
the tumors of Jensen, Loeb, Ehrlich, the lymphosarcoma of dogs, and Rous'
chicken sarcoma, that while the central portions of the mass suffer simple
necrosis, the peripheral cells stimulate the formation of new blood-vessels
and the multiplication of fibroblasts, and with this support they multiply
and produce the new tumor. This reaction has been attributed to somewhat
specific formative powers acting on fibroblasts or angioblasts and producing
chiefly connective tissue or granulation tissue about the tumor graft (Ehrlich,
Gierke). A leukocytic or a lymphocytic reaction is also observed, especially
when there is much necrosis in the graft, or when it is infected. Much
exudative inflammation often interferes with implantation. V. Dungern
and Coca describe a phagocytic absorption of tumor-cells in the hare by
means of large mononuclear leukocytes, which interfere with implantation.
The stroma of the transplanted tissue usually undergoes hyaline transfor-
mation and absorption but in some cases it may be preserved for a certain
period. Thus Beebe and the writer, in the lymphosarcoma of dogs, found
on the third day arterioles in the graft filled with circulating blood. Pro-
gressive proliferation of the transplanted stroma has not been satisfactorily
traced.

The time required for the appearance of proliferation varies greatly
with different tumors. It may be visible in 24-48 hours. A palpable tumor
seldom appears before 10 days, usually it may be detected in two or three
weeks, but occasionally is delayed for months (Bridre, Stohr).

140 NEOPLASTIC DISEASES

Adaptation. — Great variation in the proportions of successful transplants
has nearly constantly appeared. Nearly all observers found difficulty in
securing the first graft, while subsequent generations have usually followed
much more readily, so that some tumors, as the Buffalo rat sarcoma, have
eventually yielded 100 per cent, of "takes." Careful analysis of the conditions
of successful transplantation has been necessary in order to determine whether
the differences were due to an increase in the growth capacity of the cells
or to some peculiar adaptation to the experience of transplantation. The
former possibility led to the employment by Ehrlich of the conception of
increased virulence.

It was soon shown -that the chief factors resided in the transplanted
cells, since within the range of animals commonly employed the increase in
number of successful grafts and in their rate of growth was invariable. Pre-
liminary heating to 39-41 °C. or exposure to mercuric chloride or iodide,
yielded a larger percentage of takes in the experience of Clowes and Baeslack.
Heat beyond 45°C. or a few minutes exposure to 2o°C. kills most tumor-cells
(Jensen, Loeb). Yet Ehrlich transplanted a carcinoma kept for two years
at — io°C. although the tumor soon ceased to grow. Liquid air at a tempera-
ture of — ig5°C. failed to kill all cells in the experiments of Moore and Walker,
while Gaylord and Haaland eliminated the carcinomatous elements from a
mixed carcinosarcoma by heating to 44°C. for 30 minutes. With the excep-
tion of Rous' chicken tumors it has always been found necessary to transplant
intact cells, while extensive comminution or drying abolished growth. Most
tumor-cells are comparatively resistant to ordinary antiseptics.

Spontaneous fluctuation in growth energy of the implanted tumor has
been assumed in order to account for variations in the results of implan-
tation. As stated by Bashford, Murray and Cramer, " considerable varia-
tions in success attend the inoculations of one and the same tumor at different
times. Thus one series of inoculations may give a small percentage of slow-
growing tumors which at a subsequent period may begin to grow rapidly
or, on transplantation, while still growing slowly, give a high percentage
of quickly growing tumors." From a large series of inoculation experiments
taking into account the percentage of "takes" and the rate of growth, these
authors constructed curves showing rhythmic variations in growth energy.

It is thus interesting to note that in this experimental field conclusions
may be drawn which support clinical observations frequently made in the
human subject, that the rate of growth of many tumors varies at different
periods of their course. Whether the two sets of observations are exactly
parallel may be doubted. It may further be concluded from clinical and
pathological study that the rate of growth of different portions of the same
tumor varies enormously, the active portions being usually peripheral, that
one tumor may be active while another neighboring mass is quiescent, that
superficial tumors may regress when internal metastases are active, and that
in general the rate of growth of tumors is subject to fluctuations from a great
variety of factors which are chiefly dependent on the uncertain nutrition
of both tumor and host. Under these complex conditions it is extremely
difficult to determine whether anything properly designated as increased
virulence or adaptation of tumor-cells has so far been demonstrated in the
experimental field. On the contrary it would appear that successive trans-
plantation involves a process of sifting out the more viable cells and providing
for them a highly favorable soil.

Uniformity in technic of transplantation is an obvious essential in a
comparison of results. Emulsions of cells in salt solution, or thin slices of
tissue, are chiefly employed and in either case is has been found that an

EXPERIMENTAL CANCER RESEARCH 141

optimum quantity exists, viz., i to 2 cm. of emulsion and i or 2 cubic
millimeters of tissue. Larger amounts may yield initially larger tumors but
in many cases subsequent standstill or regression are observed.

With large doses it has been assumed that partial immunity resulted from
absorption of much of the tumor-tissue.

The site chosen for inoculation is ordinarily the subcutaneous tissue,
into which the tumor material is injected or implanted. The internal
organs, especially the spleen, have proven less suitable (Goldmann). Uhlen-
huth secured grafts by rubbing an incised wound with the Jensen rat sarcoma,
and Beebe and the writer transferred the dog sarcoma in this same manner
which is apparently the natural mode of transfer of this disease during
coitus.

Influence of Variations in the Soil. — That slight variations in the tissues
of the host greatly influenced the results of transplantation was very early
noted. Not only was the same species of animal required but the results
were more successful in animals of exactly the same color and antecedents.
Brown and wild strains differed in susceptibility from white and domesticated
families. Rous found it impossible to transfer his chicken sarcoma at first
to any but Plymouth rocks, preferably of the same brood. Haaland found
it impossible to propagate on Danish mice fed on grain a Berlin tumor coming
from mice fed on milk. Many others have had difficulty in transferring
propagable tumors from the animals of one country to those of another.

The influence of diet has since been shown to be highly important. Beebe
and Van Alstyne were able to render rats highly refractory to the Buffalo
sarcoma by a previous course of carbohydrate-free diet. They have also
shown that, the course of this tumor is distinctly retarded by carbohydrate-
free diet, and accelerated by butyrates among the fats. Sweet also has
observed increased resistance to implantation in animals on a carbohydrate-
free diet. That these rules may not hold for all tumors is highly probable
and specifically shown by Woglom's negative results in carcinoma. Benedict
brought about the complete regression of large sarcomas in rats rendered
diabetic by phloridzin.

Simple restriction of food has been shown by Moreschi to retard the
growth of implanted tumors. With the Flexner-Jobling rat carcinoma Rous,
however, failed to influence the growth by restricted diet.

By substituting lime substances for the usual diet Sweet, Corson and
Saxon rendered rats markedly insusceptible to implanted sarcoma, and
when a graft succeeded in such animals its growth was accelerated by return
to normal diet. Castration also favored growth. Centanni reports that a
diet of wheat bread and corn but without green food renders mice highly
insusceptible to tumor implantation. Oser and others find that tumors
grow better in splenectomized animals.

Spontaneous absorption of implanted tumors was first recorded by Loeb
and its comparative frequency and the increased resistance to reinoculation
were emphasized especially by Clowes and Baeslack. About 23 per cent, of
tumors derived by Gaylord and Clowes from the Jensen tumor were found
to regress, and Bashford reported as high as 50 per cent. Most of the regress-
ing tumors have never reached a large size but some very large growths appear
to reach a critical point beyond which nutrition fails and complete absorption
follows. It is a notable fact that during absorption the animals do not
suffer from intoxication and that recovery may be complete. The histolog-
ical changes in regressing tumors vary widely. A simple necrosis is often
the primary event, followed by absorption and fibrosis, or a progressive
fibrosis may overtake the tissue and lead to gradual atrophy of tumor-cells.

142 N EOF LA STIC DISEASES

Phagocytic processes by mononuclear cells are frequently observed (Gaylord,
Clowes, Bashford).

Structural Changes in Propagated Tumors. — While many tumors maintain a
uniform structure through many generations, some carcinomas have exhibited
notable changes in structure which are difficult to interpret. As a rule
these changes duplicate those observed in the human subject, and on the whole
they appear to be less violent than are frequently observed in human material.
Thus Bashford's study of 85 propagable tumors, 35 of which had been in
cultivation for 3 years, revealed the usual series of minor changes in the
size and structure of alveoli, appearance and disappearance of various forms
of epithelial metaplasia, formation of bone and cartilage in sarcomas and
variations in vascularity. Metastases were not always more atypical than
the original growth. Apolant was disposed to attribute the reversion of a
solid carcinoma to an adenoma to increased resistance in partly immunized
animals, a conclusion from which Murray dissents.

Considering the variation observed in propagable tumors in comparison
with the structural changes in recurrent human tumors the entire scope
appears very much more restricted in the lower animals than in man.

The most important change credited to the propagable tumors is the
sudden assumption of malignant neoplastic properties by the previously
normal stroma. This change was first observed by Ehrlich and Apolant
in the tenth generation of an adenocarcinoma of the mouse. A reverse trans-
formation, viz., the disappearance of spindle-cells from an adenocarcinoma
is also recorded by Apolant, but in this instance it was concluded that the
spindle-cells were merely altered epithelium.

Many later observations of the development of sarcoma in carcinoma have
been recorded in both rats and mice (Loeb, Lewin, Bashford, Russell).

The change appears- to occur rather suddenly after the 8-ioth or later
generations. Russell fixed the period at which the change usually appears
at the 55th to 6oth day of propagation and states that it is independent of
the number of transfers. When once established it is usually progressive
and in certain cases the spindle-cell tissue has eliminated the other element,
or both structures persist together, or separate strains of sarcoma and carci-
noma are obtained. The rate of growth of the mixed tumors appears in-
creased rather than diminished. In metastases either sarcoma or carcinoma
were encountered, but the sarcomatous element when present was more
prominent in metastases (Haaland, Clunet).

Several theories have been advanced in explanation of the sarcomatous
transformation of mouse carcinoma.

It was at first considered possible that the growths were originally mixed,
but this theory was abandoned for lack of evidence.

Most observers have concluded that the sarcoma represents a neoplastic
transformation of the stroma of the host caused by a stimulation of stroma-
cells by the epithelium. The exact nature of this stimulus is not clearly
defined but it has been conceived as a sort of growth stimulus possibly
carried by chemical derivatives of the epithelium.

Repeated transplantations are not necessary. Both Haaland and Russell
describe in detail the appearance of foci of overcellular stroma located in the
center of carcinoma nodules, the increase of mitotic figures in the stroma-
cells, the survival of these altered stroma-cells in grafts and their rapid in-
crease until they overgrow the epithelial elements. Haaland describes
peculiar halos of large cells surrounding epithelial groups, and intermediate
between epithelium and stroma-cells. Others have failed to trace the
spindle-cells to either stroma or epithelium.

EXPERIMENTAL CANCER RESEARCH 143

The third possibility, which seems to the writer to have been too hastily
dismissed, is that the spindle-cells are altered epithelium. Such transfor-
mations are relatively common in the early or advanced stages of many
human tumors and especially in recurrences after operation, and this fact
establishes a probability that a similar change in mouse tumors has a similar
significance. On the other hand there is no parallel in human pathology
for the development of sarcoma in stroma supporting carcinoma, so that
observations in mice would introduce a new principle into oncology. In
man spindle-cell transformation usually goes with increased growth and
malignancy and such is the case in mice. It is difficult to conceive how an
original carcinoma can be made to yield all its growth energy to normal
stroma-cells and completely retire from the field, yet this anomalous result
appears to be reached in the pure sarcomas developing from mouse carcinoma.
The crucial evidence is that presented by Haaland and Russell of gradual
transformation of stroma into sarcoma. Yet the interpretation of transi-
tional pictures is notoriously hazardous, and few observers have been able to
convince themselves that it actually occurs. Orth thought that Lewin's sar-

, V*.^*"5- o ? Xs" • <* •'• « ~~ ••-•-.?,.'• U? '> ^*S* '»<!&•'& e£t*SL-f.

FIG. 22. — Halos of pale cells surrounding epithelial cell groups, in the sarcomatous trans-
formation of carcinoma in the rat. (After Haaland.)

coma-cells represented granulation tissue. I have examined, through the
kindness of Woglom, several cases purporting to show the sarcomatous trans-
formation of stroma-cells, but have been forced to draw from these sections
the opposite conclusion, viz., that the spindle-cells were derivatives of epi-
thelium. Since such an interpretation is at least admissible, it may be
urged that further evidence is required before the sarcomatous transformation
of mouse carcinoma can be accepted as proven.

Resistance. — In the elucidation of the factors concerned in natural and
acquired resistance to tumor implantation the experimental studies have
opened up a new and highly fruitful field. The results apply strictly to the
artificial conditions in normal animals receiving tumor grafts, but not them-
selves developing spontaneous tumors. It has repeatedly been shown that
animals resisting implantation may often develop spontaneous tumors
(Bashford, Thorel, Clunet). Likewise very young animals which do not
develop cancer may prove very favorable soil for implantation. This prin-
ciple reappears in the rapid growth of many carcinomas occurring in human

144 NEOPLASTIC DISEASES

subjects of youthful age. The problem of the continued growth of a tumor is
therefore quite different from that of its inception. It follows also that
an animal may be susceptible to one tumor while insusceptible to another,
and it is equally clear that the body tissues of animals in general are very
favorable soil for the growth of lawless cells which must therefore be re-
strained by purely local factors.

Natural Resistance. — Age has been shown to have no definite influence
on the susceptibility to certain tumor grafts since both young and old animals
have proven suitable for experimental studies. Most observers have pre-
ferred stock from 4 to 8 weeks of age (Haaland, Albrecht, Hecht).

Racial differences were believed to account for the capricious behavior
of many tumors when transferred from animals of one country to those of
another. Yet it has appeared that many indications of resistance seemingly
referable to racial differences were the result of altered diet, and Gierke
strongly supported this view. In many instances strange animals at first
resistant soon became susceptible when housed under the same conditions as
the animals furnishing the graft (Stohr, Cuenot, Mercier). For absolutely
comparable results the use of animals of one litter or parentage is probably
advisable.

Good health appears to favor the growth of tumor grafts and poor con-
dition to retard it. Yet Teague succeeded in transplanting mammary carci-
noma of dogs only in animals weakened by distemper. Observations on the
effect of pregnancy are conflicting, Moreau and Herzog finding acceleration,
while Haaland, Bridre and Cuenot saw retardation of growth in gestation.

Acquired Resistance. — The first observations concerning acquired resist-
ance were made by Gaylord, Clowes, and Baeslack who noted frequent
spontaneous regression of the Jensen rat tumor and also the insusceptibility
of these recovered animals to reinoculation. Similar results were soon re-
ported by many observers with various tumors and the question arose
whether the diminishing proportion of successful takes in reinoculated
animals was due to a gradual sifting of naturally immune animals or to active
immunity caused by repeated absorption of the tumor grafts. The latter
theory was strongly supported by Bridre who found that by inoculating very
large doses his resisting animals rapidly became quite immune. Michaelis,
Borrel and Ehrlich verified these results. It next became apparent that
the resistance thus established while most pronounced against the tumor
employed extended also but to a lesser degree to other tumors. Ehrlich
was inclined to believe that the resistance was practically universal (pan-
immunity).

That the actual temporary growth of tumor-cells was necessary to
excite the resistance was strongly suggested by its failure to appear in ani-
mals treated by tumor-cells killed by heat or mercuric chloride (Clowes);
or killed by chloroform (Michaelis); or treated with the filtrate of tumor
emulsion (Bridre); or by cells injured by grinding and freezing (Haaland).
Whether the principle has been fully established is perhaps doubtful.

Normal tissue cells are almost equally effective in exciting resistance,
as first shown by Bashford using red corpuscles, and later by Schone, using
liver, testis, or emulsion of mouse embryo; by Borrel and Bridre, with spleen,
liver, or testis; by Higuchi with blood-free placenta. With lactating mouse
breast Moreschi secured variable results. Both Russell and Woglom
produced the resistant state by emulsions of embryo skin and Woglom
ascertained that the immunity reached a maximum 10 days after inoculation,
remained high until the twenty-fourth day, and vanished about the seventy-
fifth day.

EXPERIMENTAL CANCER RESEARCH 145

Devitalization of the normal tissue cells generally robbed them of their
immunizing power, while Woglom showed that injection of the animal's
own tissues were ineffective.

When these experiments were transferred to tumor-bearing animals the
results became less definite, although Russell considerably reduced the
proportion of successful secondary inoculations when the reimplantation
was preceded by an injection of tumor or embryo-emulsion. The practical
test of these methods in animals with spontaneous tumors proved entirely
fruitless in the hands of Haaland who failed by this form of vaccination to
influence the growth, prevent post-operative recurrence, or diminsh metas-
tases from spontaneous tumors. Likewise in the human subject, vaccination
therapy employed on a vast scale, while attended by some paradoxical
successes, has failed to establish its usefulness (Coca).

Passive Resistance. — Attempts to convey actively acquired resistance
to other animals has not been distinctly successful. The use of the serum
of resistant animals has usually failed to render new animals passively
resistant to inoculation (Michaelis, Ehrlich, Haaland). Repeated reinocula-
tions of immune rats by Uhlenhuth failed to render their serum effective in
preventing successful inoculation in fresh animals receiving first serum and
then tumor, or serum and tumor together. Bridre prepared in sheep and fowl
an antiserum against mouse cancer which did not retard and even appeared
to accelerate tumor growth. This method has been extensively employed in
human therapy using as antigen either the whole tumor or various protein
fractions, with uncertain results (Vidal, Beebe, Berkeley).

Nature of the Factors in Resistance. • — The blood serum having failed to
yield proof of possession of the immunity factors it became evident that
resistance to tumor implantation must be of more complex nature than that
excited by bacteria. In this emergency Ehrlich pronounced his theory of
athrepsia to account for the failure of tumor grafts to grow in resistant
animals. Having found that mouse carcinoma after surviving in rat tissues
for a week may then be successfully restored to active growth by returning
the graft to the mouse, he succeeded in conducting a series of zig-zag transfers
from mouse to rat to mouse, etc.. without permanent injury to the tumor.
From this data he argued (i) that there were no cytolytic agents in the rat,
otherwise the tumor-cells would have been injured, and (2) that the mouse
graft failed to grow in the rat after a few days sojourn because it soon ex-
hausted a specific nutritive substance, which was not the nutritive molecule
itself but acted as a stimulus to nutrition. Replacements in the mouse
provided new supplies of the .T-substance. This theory abandoned the idea
of antagonistic substances in the resistant animal and substituted the con-
ception of an inert lack of nutriment as the factor in resistance. The theory
was possibly a correct interpretation of the experiments cited but failed to
meet the conditions in animals of the same species. Here two valid objec-
tions were soon raised by many authors (Uhlenhuth, Borrel, Hertwig and
Poll, Bashford). It has been shown (i) that a tumor-bearing animal may
usually be reinoculated, both tumors advancing or regressing together, the
one not interfering with the nutrition of the other; and (2) that when a
second inoculation fails it is usually due to an immunity excited by the partial
absorption of the original graft.

While thus failing to account for actively produced resistance Ehrlich's
athreptic theory has served to emphasize the probable importance of the
nutritive qualities of the soil as opposed to antagonistic substances in the
blood of resistant animals.

A further illustration of this principle may be found in the experiment of
10

146 NEOPLASTIC DISEASES

Beebe and Crile who regularly caused the disappearance of the lymphosar-
coma of dogs by exsanguinating the animals and immediately transfusing them
with the blood of resistant dogs. Here it may be assumed that an antagon-
istic substance was carried over in the blood, but it is simpler and equally

FIG. 23. — Cultivation of mouse carcinoma-cells in blood-plasma. (Lambert and Hanes.)

reasonable to suppose that the transfused blood was better adapted to the
normal than to the tumor-tissue, and that its presence turned the balance of
nutrition in favor of the normal tissues and against the tumor which then

FIG. 24.— Rat sarcoma, growing in pigeon plasma. (Lambert, Hanes, Crocker Reports,

Vol. 2.)

suffered slow atrophy and absorption. Rather, specific evidence against the
purely athreptic nature of tumor immunity has appeared in the successful
cultivation of rat and mouse tumor-cells in various alien plasmas (Lambert,
Hanes).

EXPERIMENTAL CANCER RESEARCH 147

Cultivation of tumor-cells in vitro. The conditions requisite for the prolonged survival
or actual multiplication of tissue and tumor-cells in vitro seem to be a fluid medium per-
mitting of nutrition and diffusion, fixed points of attachment for the cells, and a suitable
temperature. Nutrient fluids exactly homogeneous with those to which the cell has been
adapted are not necessary. These conditions were partially provided by Loeb who saw
slight spreading of epithelial cells over the surface and into clefts of an agar medium.

The fixed points of support were missing in the circulating whole blood used by Beebe
and the writer, and we secured only prolonged survival of dog tumor-cells. An adap-
tation of Harrison's technic by Burrowres proved successful in his hands and Carrel's in
permitting definite multiplication of tissue cells in the fibrin meshes of coagulated plasma,
and this method had been extensively used. Epithelial cells grow out in coherent sheets
from the parent mass, while mesoblastic cells tend to grow out in long sprouts or become
widely scattered. The importance of the results of experimental cultivation of tissue
and tumor-cells in vitro has not been as great as might have been anticipated, but it has
been shown that these cells are capable of living in much more varied media than once
seemed likely, and that the natural immune substances supposed to exist in the serum of
refractory animals has little influence on the growth. Tumor-cells as a rule seem to be less
capable of survival or growth than corresponding normal tissue cells, and only after some
difficulty has Burrowes succeeded in cultivating certain human tumor-cells.

Hyper susceptibility.— Various observers have reported phenomena sug-
gesting hypersusceptibility to tumor growth in animals receiving grafts,
emulsions, or saline extracts of tumors, but the data are insufficient to
establish the existence of a specific hypersensitization (Woglom, Lit.).

The mechanism by which the resistant animal aborts the tumor graft
offers suggestive evidence regarding the nature of the immunity factors.
In resistant animals the unsuccessful graft fails to excite the specific stroma
reaction and remains unprovided with the necessary channels of nutriment.
Russell examining grafts in refractory animals at intervals found that the
surviving cells continued to proliferate for 7-10 days but instead of exciting
an active growth of fibroblasts they became sharply separated from the
host's tissues. He concluded that there must be present in resisting animals
something which inhibits the chemotactic influence of the cancer-cell upon
the connective tissues of the host. Inflammatory reaction has also been
shown to be responsible for the failure of grafting in resistant animals.
v. Dungern and Coca, studying the inoculation site in immune animals, and
in regressing sarcoma in the hare, observed that the necrosing graft gathered
large numbers of macrophages in vessels and tissue spaces, as well as many
lymphocytes and plasma-cells, which attacked and absorbed the tumor-
cells. Since this reaction failed in susceptible animals they interpreted it
as a phenomenon of hypersusceptibility or allergic, provided by the previous
immunizing dose. Burgess examining grafts in non-susceptible Japanese
mice observed at first the formation of the usual vascular stroma but after
a week an inflammatory reaction ensued yielding polynuclears, eosinophiles,
lymphocytes and plasma-cells, which shut off the blood-supply and induced
fibrosis. Da Fano also noted a rich exudate of lymphocytes and plasma-
cells about the inoculated tumor in immunizing animals. In splenectomized
animals Apolant finds that very slight immunity to tumors can be excited,
and Baeslack observed marked fall in the circulating lymphocytes in sus-
ceptible animals with growing tumors, and a steady increase in resisting
subjects with regressing tumors. Murphy finds that the chicken embryo
possesses no means of preventing growth of implanted rat tumor until ^the
chick hatches and develops spleen and lymphocytes, but if the embryo receives
a fragment of adult chicken spleen or bone-marrow along with the tumor
graft the latter fails to grow. After subjecting the rat spleen to the .T-ray
he found that the animal supported the growth of alien tumor-tissue for &
considerable period and until the spleen recovered its lymphocytogenic
function.

148 NEOPLASTIC DISEASES

All these observations lend important support to the view, long since
established in human pathology, that the lymphocyte is an important
agent of defense of the organism against tumor growth.

Some light but no complete elucidation of the nature of tumor immunity
has been furnished by collateral studies on tissue immunity.

Antibody production has been demonstrated against various tissue
cells injected into foreign species; as tracheal epithelium (V. Dungern);
or spermatozoa (Metalnikoff). These observations may justify the use of
antisera prepared in lower animals against human carcinoma tissue or its
derivatives.

Antibody production has been demonstrated against an animal's own
tissues, injected either into the same individual or into other animals of the
same species. Thus Adler prepared an autospermatoxin in guinea-pigs and
Halpern showed, by complement deviation, the development of antibodies
against an animal's own kidney, pancreas and spleen. These observations
further support the view that a human tumor-bearing subject may to some
extent be immunized by injections of his own tumor-tissue.

A certain relationship has been found between the same organs in differ-
ent species of animals, as with the testis (v. Dungern and Hirschfeld Schenk),
and with the sexual cells of fish (D unbar).

Nevertheless in the sera of animals rendered immune to transplantable
tumors there has been no satisfactory demonstration of specific cytolysins,
agglutinins, or precipitins. Nor have complement deviation tests in' such
sera been clearly successful.

Lambert and Hanes were able to cultivate rat sarcoma cells in the plasma
of rats immunized against this sarcoma, although the sera of immunized
alien animals inhibited the growth while the normal alien sera did not.

The serological evidence therefore points to some other form of immunity
and this is apparently to be found in the local and general hypersensitization
produced in the immunized animals elicited by absorption of regressing or
inoculated tumor-tissue, v. Dungern and Coca with the hare sarcoma,
and Weil with the Flexner-Jobling rat carcinoma demonstrated anaphylactic
reactions in the inoculated animals and a local inflammatory allergetic
reaction to inoculation. This conception of tumor immunity is in accord
with the fact that complete resistance to implantation of a virulent sarcoma
may exist in animals bearing an actively growing tumor of the same sort.

SPECIAL ONCOLOGY

CHAPTER X
FIBROMA

Fibroma is a term applied to tumors composed chiefly of connective
tissue.

Many of these tumors are composed exclusively of connective tissue and
are designated as pure fibromas. More of them are covered by hypertrophic
lining epithelium, as in papillary fibroma, or contain glandular structures,

FIG. 25. — Benign pigmented nbro-epithelial wart. (Photo by B. H. Buxton.}

adeno fibroma. In the nerve- trunks they may show atrophic nerve-fibers
for which, and on account of their origin, they are called neurofibroma.
Blood-vessels may be very abundant or the lymph-vessels may be in excess,
in angioflbroma and lymphangio fibroma. Neoplastic connective tissue is
also observed in various other benign and some malignant tumors as in
fibrolipoma, fibrochondroma, etc.

The gross appearance of true nbromas is usually characteristic. They
are circumscribed, encapsulated, usually lobulated, firm or soft tumors, and
on section exhibit a grayish translucent appearance. The blood content
varies but is usually slight. Secondary changes yield corresponding altera-

149

150 N EOF LA STIC DISEASES

tions in texture. Multiplicity is a striking feature of neurofibromas both
in the skin (fibroma molluscum) and in the organs. From this character-
istic appearance there are all gradations merging toward the products of
chronic inflammation. In some very early fibromas of breast and kidney the
isolation of the tumor nodule is imperfect although the later stages of such
growths are well encapsulated. There is no sharp dividing line between
chronic productive inflammation and fibroma, although characteristic exam-
ples of each are widely separate. The inflammatory nodule merges insen-
sibly with the surrounding tissue,, its histology lacks the definite features
of a neoplasm and it occurs under clinical conditions which supply the inflam-
matory agent, as in chronic mastitis, and chronic rhinitis. Yet, as Ribbert
remarks, the longer an inflammatory nod ale persists the more in some cases
it may approach the quality of a neoplasm. It must be admitted that
chronic productive inflammation may pass insensibly into fibroma, a fact
most frequently illustrated with some forms of local elephantiasis.

The structure of fibromas varies greatly but it commonly presents
fibroblasts, fibrils, blood- and lymph-vessels.

Soft fibromas contain a considerable proportion of cells lying in a soft
matrix which is often edematous. Much vascularity also reduces the con-
sistence. Hard fibromas contain fewer cells and firmer more abundant
matrix which is often hyaline. In very dense fibromas arising from perios-
teum and tendons very few cells may be present and wide areas of hyaline
matrix are observed. The consistence is also affected by calcification,
mucoid degeneration, and the formation of cysts.

The cells of genuine fibromas are usually larger and more numerous than
in adult connective tissue. In actively growing fibromas the chromatin
content of the nuclei is also increased and the tissue has a distinctly neoplastic
character. Even in some hard fibromas as in keloid, the cells may be of
large size throughout, but in many cases the active cells may be limited to
the periphery or to isolated foci chiefly about vessels while the main portions
of the tumor are acellular. The arrangement of the cells is uniform and is
determined by pressure or by the presence of originating structures as blood-
vessels or nerve-trunks, or gland alveoli.

With an increasing proportion of cells, diminution of matrix, and
irregularity in size and shape of the cells, the tumors show more active growth
and a tendency to recurrence, and to these tumors the term fibro sarcoma is
given. In distinguishing fibroma from sarcoma Borst relies chiefly on irregu-
larity in size and shape of the cells as well as overgrowth of nucleus and
absence of definite stroma. When the bulk of cells greatly exceeds the matrix
the tumors are usually of active growth and require careful removal to pre-
vent recurrence.

The matrix of fibromas varies greatly. In many cases it has the charac-
ters of embryonal connective tissue; in keloid it is hyaline; in dense tumors
it may be very firm but fibrillar; and it is often edematous and infiltrated
with leukocytes.

The fibroglia fibrils of Mallory are regularly present and may be very long
and quite abundant. They are best demonstrated in material promptly
fixed in Zenker's fluid and stained by a mixture of anilin blue, 0.5; orange
G, 2.0; oxalic acid, 2.0, water, 100. The bundles of wavy collagen fibrils are
abundant chiefly in hard fibromas. Ribbert regards the matrix of fibromas
as a product of cell activity but not as a derivative of cell processes. The
fibrils he considered to be the result of cell activity upon a secretory product
which has many of the qualities of fibrin but with an altered staining reaction.
This origin would explain the great length of many fibrils, the great bulk of

FIBROMA 151

the matrix, and the presence of many fibrils and much matrix with very few
cells. Elastic fibrils are usually scanty.

Secondary changes occur in the matrix, including hyaline transformation,
calcification, fatty and mucoid degeneration, edema, and necrosis, and in
connection with bone, ossification. Also the remnants of invaded structures
may be included in fibromas, as fat-cells which may be incited to prolifera-
tion, gland alveoli, muscle-cells and nerve fibrils. By metaplasia portions of
fibromas may be converted into cartilage or bone.

Blood-vessels occur in normal form and number, or as irregular thin-walled
spaces, or as sinuses lined by endothelium alone. In angiofibroma the vessels
are very abundant. They appear as irregular spaces and canals lying in the
connective tissue, they are lined by a moderate number of flat or cubical
endothelium, but the connective tissue is the predominant element. Some
authors include among fibromas the majority of angiomas. It seems better,
however, to separate from fibromas all very vascular tumors in which blood-
vessels form a predominant organoid unit. Fibroma is a histioid, not an
organoid tumor.

Lymph-vessels are commonly present in fibromas. In keloid the lymph
spaces are so prominent as to suggest for this tumor the term lymphangio-
fibroma. In local elephantiasis which is closely related to fibroma the dilated
lymph-vessels are numerous. Edema and lymph-cysts form from obstruction
to the lymph flow.

The natural history of fibroma is that of a slowly growing tumor progress-
ing steadily or intermittently over many years. In many instances, as in
neurofibroma, there is a natural tendency for the tumor to reach a certain size
and then to remain stationary, probably from mechanical interference writh
blood-supply. In very large fibromas as of breast, skin and ovary, hyaline,
calcific and necrotic areas bear witness to the regressive tendency that over-
takes this type of tumor. A spontaneous cure may thus be accomplished.
In a large fibroma ' of the quadriceps tendon I have seen almost complete
destruction and permanent arrest of growth by central softening. Many
mammary fibromas surfer hyaline change and arrest of growth after 15 to 20
years. Kosinski has reported complete spontaneous atrophy of neurofibro-
mata. Sarcomatous transformation is very rare but occurs with neuro-
fibroma. In the mixed adenofibroma of breast cancerous changes may de-
velop in the epithelium. Recurrence after operation is characteristic of keloid
but usually consists of an extension of the tumor process over formerly intact
areas.

Origin of Fibromas. — The exact point of origin of most fibromas is still
undetermined. That many of them arise from misplaced islands of tissue,
according to Cohnheim's theory, is very probable. Chiari. observed a con-
genital polypoid fibroma at the perineal raphe, and Ribbert has seen a fibroli-
poma in the same situation. Arnold described a congenital chondrofibroma
of the skull which he referred to a disturbance in the development of the
cranium. In several reported fibromas of the testis there were elements
suggesting that the tumor represented a one-sided development of a teratoma.
Certain fibromas in the adult appear in the region of embryonal clefts where
superfluous cells may be supposed to exist. In the breast, Williams found
evidence that 14 per cent, of the adenofibromas of this organ arise from
embryonal rests, and the frequent association of chondroma and osteoma
with fibroma, especially in the dog's breast, favors this view.

For other fibromas one must apply the theory of local irritation and dis-
turbance of nutrition, as in keloid which commonly follows scarring; in
papillary fibromas and adenofibromas of mucous membranes which are

152

N EOF LA STIC DISEASES

associated with catarrhal inflammation; and in fibromas of periosteum and
joint areas which may follow repeated trauma.

In a third group the clinical features point to a congenital or acquired local
predisposition, of which multiple neurofibroma is the best example. Ele-
phantiasis seems to exhibit a general predisposition often combined with the
effects of recurring inflammation.

It is especially in the second and third etiological classes that one encoun-
ters the less definite tumor-like processes which it is sometimes difficult to
classify, and in which one must recognize the cumulative influence of inflam-
mation and chronic disturbance of nutrition and the passage of inflammatory
into self-perpetuating neoplastic processes.

FIG. 26. — Fetal fibro-adenoma of breast in a girl of 18 years. The tumor grew rapidly,
measured 9 cm., was soft, bluish, resembling sarcoma.

Clinical Types of Fibroma.- — The clinical types of fibroma are numerous
and some of them form characteristic clinical entities which not only illus-
trate the peculiarities of this group of neoplasms but throw light on the nature
of tumors in general.

CUTANEOUS FIBROMAS

Fibroma Molluscum. — The most frequent fibroma of the skin occurs in
multiple form, as fibroma molluscum. Recklinghausen showed that this
tumor arises from the cutaneous nerve filaments, a conclusion which had been
suggested by some previous writers and has been fully verified by many latei
studies. The peculiar clinical characters of the disease were fully described
by Kolliker, 1860; Hitchcock, 1862; Virchow, 1863; Murray, 1873; Atkinson,
1875; Balzer, 1879; and Winiwarter, 1876; but Recklinghausen in 1882 traced

FIBROMA 153

degenerating nerve-fibers in several characteristic cases and stated that all
these tumors arise from nerve-trunks or filaments. An extensive literature
has accumulated on this subject and has been reviewed by Recklinghausen
and more recently by Bruns, Sarazanes, Verocay, and Herxheimer and Roth.

Two main types of neurofibroma are commonly distinguished, although
both may be observed in the same patient, (i) Pigmented multiple neuro-
fibromas, typical fibroma molluscum, and (2) plexiform neurofibroma.

In typical fibroma molluscum the tumors are multiple, and they may
become so numerous as to nearly cover the entire surface of the body. They
may be as small as pin-head, more often of the size of a pea, occasionally they
reach the bulk of an orange, and rarely they attain large dimensions. They
may become pendulous (fibroma pendulum). All portions of the integument
may be affected from the scalp to the soles of the feet, while in some cases the
mucous and serous membranes and internal organs are involved. A In the

FIG. 27. — Structure of a recurrent neurofibroma of skin.

skin they lie just beneath the epidermis, or beneath the derma, or they follow
up the nerve-trunks. They are movable laterally. They are sometimes
painful and when they are not palpable this symptom 'readily suggests
erroneous diagnoses. They may affect any nerve'and as a rule they are not
symmetrically placed. Pigmentation of the skin over the tumors or else-
where is often marked, so that many authors speak of the disease as pigmented
neuro fibromata sis.

In structure the tumors are usually cellular and soft. The growth sur-
rounds the nerve or involves one side or is connected with the nerve-trunk
by a thin pedicle. The nerve-fibers show all stages of atrophy. The larger
tumors frequently involve other structures of the skin as the 'sebaceous and
sweat-glands. They may be quite vascular and many authors trace a con-
nection between neurofibroma and many angiofibromas and nevi. They are
sometimes associated with xanthoma (Delore, Poncet), and rarely with
multiple lipoma (Vallas, Mouchet). Some early lesions suggest an origin
from the connective tissue about sweat-glands, but even here the process

154

NEOPLASTIC DISEASES

has been traced to nerve filaments belonging probably to the sympathetic
system.

Plexiform neurofibroma (Rankenneurome. Neurofibroma cirsoides.
Brims). — The plexiform neurofibroma is larger and the tumors are less
numerous than with fibroma molluscum. Their chief features are well
illustrated by the case of Bruns, of a boy of 18 years who presented a pendu-
lous fibroma 15 cm. in diameter, together with many small-pigmented tumors
of the type of fibroma molluscum. The grandparent and three brothers
suffered from fibroma molluscum. The congenital and hereditary tendency
is pronounced.

The tumors are composed of an agglomeration of many soft lobules
surrounding nerve-trunks which may long be preserved and appear as

irregularly coiled or straight nerve bands
traversing the tumor. On dissection many
of the coiled and thickened nerve-trunks may
be unravelled. In neurofibroma cirsoides
which appears chiefly in the face and scalp
the blood-vessels are abundant. The peri-
pheral zone is usually dense fibrous tissue,
enclosing more cellular connective tissue, while
the core is occupied by the nerve-trunk. Sar-
comatous changes have occurred in several
cases of plexiform neurofibroma and in those
of Genersich and Herxheimer there were
metastatic nodules in the lung. Local recur-
rence is very frequent. Many other pecu-
liarities are illustrated in the cases collected
by Recklinghausen and later writers. It is
probable , that the great majority of actively
growing fibromas and fibrosarcomas of the
limbs are of neural origin.

Visceral Neurofibromatosis.— The internal
nerve-trunks and filaments may be the seat of
large plexiform or small multiple fibromas. In
the intestinal form the tumors may occur at
any point from the lips to the anus. Certain
cases of macroglossia have been found to be
diffuse neurofibromatosis and related to ele-
phantiasis especially of the lymphangiectatic
type (Virchow). Sarazanes has collected cases
FIG. 28.— Hard recurrent in which the tumors occurred in the tongue,
fibrosarcoma of popliteal space, stomach, jejunum, ileum, colon, vagina and

bladder. In Robin's case there was a large
tumor of the solar plexus. Lotzbeck has de-
scribed several large tumors pressing upon the lumbar spine and arising from
the lumbar plexus, and Czerny observed a case involving both lumbar and
sacral plexuses. Pomorski describes a remarkable case in which multiple
tumors projected into the pleural cavity arising from the intercostal nerves.
Herxheimer and Roth describe a remarkable case presenting multiple
fibromas of skin of upper half of trunk; fibromas of intercostal and lumbar
nerves ; small sarcoma of lumbar plexus passing into a large pelvic tumor ;
tumor-like thickenings of terminal filaments of the sympathetic and lumbar
intervertebral ganglia; tumor mass with chromaffine cells in adrenal medulla;
multiple subserous nodules in jejunum; miliary endotheliomas of spinal dura.

FIBROMA 155

In a well-defined group of cases the sympathetic system is the chief or
exclusive seat of the lesions (Czerny, Adrian). In the case of Simon and
Hoche the mesentery was much thickened and beset with many fine nodules.

Several cases with adrenal tumors and pigmentation serve to explain the
long-suspected relation to Addison's disease (Chauffard, Suzuki, Hoffmann,
Kawashima, Vignolo-Lutati). The tumors of the adrenal are composed of
medullary chromafiine cells. Gliomas of the central nervous system have
been observed in a few cases (Verocay).

The exact nature of the cells involved in these tumors is not easily de-
termined and probably not uniform. Herxheimer and Roth conclude that
the small dermal tumors are chiefly fibromas. In larger growths they find
that the cells of the sheath of Schwann and of the endoneurium multiply.

, x ^ *

^ "• ',v** ' '
FIG. 29. — Markedly fasciculated structure of a neurosarcoma. Xeurofibroma of skin.

Concentric groups of cells which are so characteristic of this tumor they inter-
pret as endothelium of the nerve sheaths. In the ganglionic lesions the
endothelium in the capsules of the ganglion-cells multiplies actively. In
fact all the elements of the nerve filament or trunk except the ganglion-cells
and fibrils participate in the tumor process.

According to Verocay's conception the tissue of neurofibroma is not con-
nective but consists of nerve-cells or their embryonal equivalents which have
not been properly employed in the development of the nervous system. He
therefore suggests the term neurinoma. The validity of this view depends
on the nature of the cells of the sheath of Schwann. If these are specialized
nerve or glia cells, Verocay's interpretation would seem acceptable.

Elephantiasis. — It has long been recognized that there exists a close con-
nection between multiple tumors of nerve-trunks and some forms of ele-
phantiasis. The nature of this relation remains ill-defined but it is strongly
suggested by the occurrence of multiple fibromas in many cases of elephan-
tiasis, by the hereditary and congenital character of both conditions, by the
occasional presence in both of pigmentary changes in the skin, and by the

156 N EOF LA STIC DISEASES

partial histological resemblance of the structure of the affected tissues. The
result of recurrent inflammation and lymph stasis are the two main factors
which separate non-parasitic elephantiasis from fibromatosis.

Elephantiasis or diffuse fibromatosis affects the skin over large areas, as
of an entire limb, or occurs in more circumscribed form when its neoplastic
characters are more distinct. It is acquired and sporadic or congenital and
endemic. Beginning early it produces a soft mucinous thickening or in
later periods the tissue is firmer or sclerosed (elephantiasis molle and durum).
The lymph-vessels are commonly increased, enlarged, or may be cystic (ele-
phantiasis lymphangiectatica).

Hygroma cysticum (Wernher) is a circumscribed form of congenital
lymphangiectatic elephantiasis appearing in the neck, sacral and perineal
regions of fetuses, infants, and children. The blood-vessels are sometimes

FIG. 30. — Neurofibromatosis. Detail of process in nerve-filaments. In the center
proliferation of sheath-cells; in intermediate zone, endothelial cells; in peripheral area,
fibroblasts. (After Herxheimer.)

much increased (elephantiasis telangiectatica, elephantiasis angiomatosa).
In some remarkable cases the skin of the entire limb was greatly swollen,
dark blue, and composed of many thickened varicose veins often containing
phleboliths (Rokitansky, Pitha, Leisrink, Unna). All structures of the skin
may be involved and there is increase of connective tissue diffusely and about
nerves, vessels, and glands. The sweat-glands may be hypertrophic. The
epidermis may be thickened, pigmented and corrugated, and in the remark-
able form of congenital ichthyosis it is hypertrophic and extensively horni-
fied. In cases reported by Naegeli and by Morgan elephantiasis was associ-
ated with tumor-like thickening of the nerve-trunks supplying the area. In
several cases reported by P. Bruns the elephantiasis was associated with
definite neurofibromatosis. In certain cases usually congenital the thick-
ened skin falls in overlapping folds like drapery (Mott) and for these cases
the terms pachydermia or pachydermatocele are employed. Jordan dis-
tinguished two types of congenital elephantiasis, one of which is chiefly a

FIBROMA 157

diffuse neurofibromatosis, the other involving nerves, other cutaneous struc-
tures, and the muscle-tissue. In each case the blood-vessels gave origin to
the new tissue.

In most cases of acquired elephantiasis the nerve-trunks play a subordi-
nate part and the process involves all the cutaneous structures, yet in many
cases of long-standing neurofibromatosis similar extension of the hyperplastic
process is observed. The clinical history indicates that this extension is
chiefly owing to recurrent inflammation and lymph stasis. Thus the disease
commonly progresses with repeated attacks of erythema or erysipeloid, and
it may develop in the course of chronic suppuration. These observations
early led to the assumption that elephantiasis was of infective origin and
confusion arose between elephantiasis arabum (diffuse fibromatosis) and
elephantiasis graecorum, which was true leprosy. Carter has pointed out
many points of resemblance between the two types, especially in the nerve
lesions, and shown that true elephantiasis may complicate leprosy. To-day,
both leprosy and filariasis may be readily separated from the other causes
of elephantiasis.

These clinical relations of elephantiasis as well as the histological structure
demonstrate that the process is not a true neoplasm but belongs in the class
of fibromatoid reactions of predisposed subjects to chronic disturbance of
nutrition.

Neuropathic papilloma ( Gerhard t), Nevus unius lateris (Barensprung),
Nevus linearis (Unna), Nerve nevus (Simon) . — -This lesion occurs as multi-
ple flat or bean-shaped, warty outgrowths of hyper trophic dermal papillae.
They follow the distribution of definite cutaneous nerves like herpes zoster
and may be more numerous along Voight's lines bounding the distribution
of the nerves (Philipson). They may occur on any portion of the body and
even in the buccal mucosa (Pott). In some cases they are extensively pig-
mented (Schonberg).

The condition is hereditary (Haegele), and often congenital, but may ap-
pear as late as the 2yth year. The onset may be rather acute as in Beigel's
case, but the course is chronic, reaching a standstill or spontaneously re-
gressing (Neumann). Pain may be pronounced, and paresis and paralysis
may develop.

The histology shows an acute stage followed by chronic connective over-
growth of dermal papillae, but the structure varies greatly and there are no
reports to indicate that the process is a true tumor. In Elliot's case there
was cystic distention of the cutaneous glands. The overlying epithelium
may be hypertrophic. Recklinghausen states that the growth affects the
terminal filaments of the nerves, that it follows neuritis and is related to
ichthyosis with which it may be associated. Unna doubts this relation. Al-
though the condition is vaguely defined it appears to represent most clearly
the influence of nervous disorder upon fibromatosis.

General Etiology. — In the origin of the foregoing types of cutaneous
fibromas, many complex factors seem to be concerned, most of which center
in the nervous system. Together they constitute a somewhat definite clin-
ical entity or dyscrasia to which the term neurofibromatosis may be applied.
The congenital and slightly hereditary character is prominent in all the forms
of fibromatosis, suggesting the existence of abnormal qualities in the connect-
ive tissues of these subjects. The unfolding of the dyscrasia often proceeds
in a somewhat orderly manner. Thus Debove observed pigmented placques
at birth, small tumors of the skin at five years of age, and tumors of the nerves
at eight. Yet in most cases the pigmentation and the tumors appears simul-
taneously at a later age, 10 to 30 years (Marie). French authors, especially

158 N EOF LA STIC DISEASES

Sarazanes, emphasize the nervous symptoms observed in many cases, and
point to the pain, anesthesia, defects of special senses, neuroses, epilepsy,
mental disturbances, idiocy, fragility of the bones, and infantilism and mal-
formations, as evidence of general and especially of nervous deficiency in the
subjects of neurofibromatosis. Various digestive disturbances, jaundice,
urobilinuria, and alterations of nitrogenous metabolism have been cited in
support of the theory of general dyscrasia. Feindel and Oppenheim describe
marked forms of neurofibromatosis, in which the general symptoms are
present with punctate or lenticular pigmented spots in the skin while
the tumors are absent, scanty, or appear later.

For general fibromatosis various theories of origin have been assumed, as
the theory of recurrent or chronic infection as suggested by the recurrent
inflammatory processes in elephantiasis and its resemblance to leprosy. The
theory of auto-intoxication is suggested by many constitutional symptoms
and especially by certain cases of neurofibroma which clinically resemble
Addison's disease (Chauffard, Bernard). Feindel points out that the pig-
mentation and tumors may date from pregnancy, and alcoholism and over-
use of arsenic have been reported as exciting causes. Brickner has de-
scribed in pregnancy a peculiar punctate pigmentation of the skin which
seems to fall with neurofibromatosis. It is generally assumed that the vic-
tims of fibromatosis are the subjects of a congenital malformation of the ec-
toderm which under a great variety of exciting causes may slowly or rapidly
develop one or more of the manifestations of the disease. The great mass of
data that has accumulated in this field seems to call for a general assent to
this hypothesis, but there is danger that the conception of the scope of this
dyscrasia may be extended over too many pathological phenomena.

Keloid. — Keloid (/c^Ary, tumor) or Cheloid (x^Xiy, claw) is a peculiar
overgrowth of hyaline connective tissue developing in the skin of predisposed
subjects after trauma or scarring. The traumatic origin is usually obvious,
as in the extensive scarring of burns. More localized keloids occur in which
it is difficult to trace the probable traumatic origin and these are called
spontaneous.

The subjects of keloid may exhibit a special predisposition to overgrowth
of connective tissue after injury and in the negro this predisposition is racial.
The character of the trauma is diverse. Extensive burns by heat or escha-
rotics are specially prone to develop keloid, but needle punctures (Gumbel)
scratches, vaccination, repeated pressure of heavy weights and surgical
wounds, have preceded the condition.

The typical keloid has a characteristic structure and consists of anasto-
mosing strands of thick, hyaline, collagenous matrix between which lie many
well-nourished fibroblasts. Small well-developed blood-vessels are present,
and lymph spaces may be so prominent as to lead to the use of the term
lymphangiofibroma for some cases of keloid. Elastic fibers are missing.
Glandular structures of the skin are pushed aside and this fact leads Goldman
to conclude that the growth of the tumor is chiefly central. The periphery is
not well defined but is often more cellular with thinner fibers than the cen-
tral portions. Yet this feature is not so pronounced as to deprive the growth
of its circumscribed character or to invalidate the statement of Ribbert
that keloid grows largely from its own resources. Secondary changes are
chiefly those of increasing hyalinosis.

Keloid occurs in the form of a broad flat elevated firm thickening of scar
tissue which gradually extends over a considerable area, or as more circum-
scribed projecting or even polypoid outgrowths. The overlying epidermis
is usually shiny, atrophic and separated from the tumor by a thin layer of

FIBROMA 159

cutis. The natural history is of a slowly progressive growth which tends to
involve the whole area of affected scar tissue, or remains limited to the seat
of a trauma. After extirpation it often develops anew in predisposed tissues,
but never produces metastases. It may be made to disappear under
pressure.

The neoplastic properties in keloid are not pronounced. Especially at
its inception it belongs in the group of fibrous overgrowths which depend upon
chronic disturbance of nutrition. Yet it sometimes possesses considerable
momentum of growth, its cells exhibit nuclear hypertrophy, and especially
in the so-called spontaneous circumscribed forms, it may sometimes be re-
garded as an imperfect neoplasm. The remarkable case of Porter's in which
a very bulky keloid of face and arm developed in ten months after a burn
suggests both the neoplastic nature of the process and a predisposition to
the disease.

FIG. 31. — Tumor-like keloid following needle puncture. Remained stationary after a few
months of rapid growth. (After Brenizer, A. S. 61.)

Xanthoma. — Xanthoma, or xanthelasma as named by Wilson and Smith,
is a common brownish-yellow tumor of the skin appearing most frequently
in the eyelids (92 per cent., Poensgen) but occurring in multiple form in other
regions (xanthoma multiplex, generalized xanthoma). It may appear
first in the eyelid, later in other localities (Korach) and like multiple
fibroma often follows the course of cutaneous nerves, especially along Voight's
lines (Kobner), and symmetrically along folds of the skin. Apparently
similar growths have been described in the respiratory and pharyngeal mu-
cosa, the serous membranes, endocardium, tendon sheaths, on the cornea,
and in the pancreas in diabetes. According to Unna generalized xanthoma
is sharply separated anatomically from xanthoma palpebrarum.

In the skin the growth is flat (xanthoma planum) or beanshaped (xan-
thoma tuberosum) or polypoid and pendulous. Usually of small size, they
occasionally reach considerable dimensions (Poensgen, Ehrmann). They
are often congenital, but rather more frequent in adults and old persons.
It was shown by Chambard that general xanthoma may develop in the course
of icterus or with other diseases of the liver and with diabetes (xanthoma dia-
beticorum). Not a few subjects of early xanthoma later develop diabetes,
yet Johnston and Torok separate the skin affection in diabetes from the com-
mon xanthoma vulgare. The" diabetic lesion may be transitory while the
other is permanent.

In some cases xanthoma tuberosum is associated with nevi, vascular and

160 N EOF LA STIC DISEASES

pigmented, illustrating a congenital predisposition, and this fact may support
Borst's conclusion that the two conditions are anatomically related. Xan-
thoma may also be associated with multiple lipomas (Ehrmann). Vir-
chow regarded xanthoma tissue as intermediate between connective and fat
tissue and employed the term fibroma lipomatodes, believing that the cells
were derived from fibroblasts. The histological and clinical features point
to the existence of a peculiar formation of lipoids in the cells of a fibroma under
the influence of a local nervous and a general metabolic disorder. In
xanthoma palpebrarum the deposit of lipoids precedes the tumor growth
and first appears as yellow streaks along the blood- and lymph-vessels, and
muscle-fibers.

The structure of xanthoma is characterized chiefly by the great abundance
of lipoid globules in large swollen polyhedral and smaller spindle-shaped cells.
This material is an orange yellow lipochrome; more of it is stained by Sudan
III than by osmic acid, and Stoerk, with Pinkus and Pick, have showed that
the globules are doubly refractive and of myelin nature or probably a choles-
terin fatty acid ester. The central cells may become greatly distended
with this material, while the peripheral cells may show the spindle shape
of growing fibroblasts. Much fatty detritus may accumulate in these tumors
and giant-cells similar to those in epulis and containing or surrounding fatty
crystals or masses may form (Touton). In such cases the tumor may resem-
ble a spindle- and giant-cell sacroma. I have seen such a tumor from the
peroneal tendon sheath of a diabetic subject who also showed xanthoma
palpebrarum.

Waldeyer early showed that the first changes in xanthoma palpebrarum
consist in the appearance of fatty globules in certain perivascular groups of
star-shaped fibroblasts. Many authors, including Borst, trace the xanthoma
sells to the lymph endothelium and he also finds a close structural resem-
blance between some xanthomas and pigmented nevi. Hallopeau and Torok
consider the cells as equivalent to embryonal fat-cells which they may
strongly resemble. Waldeyer found many plasma-cells about the vessels
of the eyelid and believes that these become infiltrated with fat. Hebra,
Wilson, Geyer, and others have observed a proliferation of the sebaceous
glands, and Knauss of the hair follicles, sweat-glands and blood-vessels.
Pollitzer in cases of xanthoma palpebrarum traces the fatty cells to degen-
erating fibers of the orbicularis muscle, and he would separate this lesion
from xanthoma multiplex, which he regards as a fibroma or keloid undergoing
fatty degeneration. Unna also traces a close connection between the
fatty cells of early xanthoma palpebrarum and the muscle- fibers of the orbicu-
laris which lies close to the skin, but he considers the fat to be a deposit
from the lymph- vessels.

It thus appears that many different anatomical elements maybe concerned
in the clinical lesions of xanthoma, and that not all of the clinical forms
have a relation to tumors. Some of them, however, are certainly neoplastic
and fibromatous. Since the fatty change seems to be identical in nature
wherever it occurs there would seem to be room for the term xanthomatosis
as applying to this process wherever it occurs and without limitation to a
specific anatomical lesion.

FIBROMA OF BONES, PERIOSTEUM, AND FASCLE

Tumors of this class are comparatively rare, but of very general distri-
bution. From the maxillae, especially the superior, fibromas arise and reach
moderate dimensions, projecting into the mouth with ulceration of the mu-

FIBROMA 161

cosa, or beneath the skin. In the interior of the maxillae fibromas may develop
from disturbances in the formation of the teeth (Blauel). The long bones are
occasionally the. seat of hard fibroma for which a history of trauma is common,
[n the fasciae especially about the joints are encountered hard fibromas which
may reach a considerable size. The osteal and periosteal fibromas frequently
exhibit areas of calcification, chondrification and true bone formation, in
which processes characteristic osteoblasts engage. Bone also forms in fi-
bromas apart from any connection with periosteum. In the large fascial
fibromas hyalinosis, calcification and central softening may occur leading to
arrest of growth.

FIBROMA OF GLANDULAR ORGANS

Breast. — The fibromas of the breast are usually complex fibroadenomas
and will be considered under epithelial tumors.

Kidney. — Small fibromas of the kidney are of frequent occurrence.
They are single or multiple, often bilateral, hard, opaque, homogeneous

FIG. 32. — Fibroma of ovary.

nodules which project under the capsule, or appear in the cortex or more
frequently in the medulla at the bases of the pyramids. Many of them con-
tain smooth muscle-fibers and in the cortex they usually inclose compressed
or cystic renal tubules. These small tumors arise from disturbances of de-
velopment of the kidney. According to Genewein they are not true neo-
plasms but tumor-like nodules resulting from superfluous tissue (Albrecht's
hamartoma).

Large fibromas occasionally grow from the capsule or in the hilus of the
kidney, but they are generally associated with fat and smooth muscle-tissue,
and exhibit myxomatous changes. Under the term myxoma fibromatosum
Tillmann described a large tumor weighing 10 Ib. which he extirpated from a
woman of 28 years and which soon recurred. Claus, Wilks, and Busse and
Reinach have reported large tumors of capsule, cortex, or hilus of the kidney
which were nearly pure fibroma or mixed with lipoma, myxoma, or myoma.
In a large tumor of this class I found lobules of nearly pure fibroma, with
n

162 NEOPLASTIC DISEASES

others of fat and myxomatous tissue. These growths must owe their origin to
some developmental disturbances of the kidney, the nature of which is un-
determined. Small fibromyomas or nearly pure multiple leiomyomas are
not infrequently seen and have been described by Lartigau and Larkin.

Testis.- — Pure fibroma of the testis is very rare (Langhans), but I find
that tumors chiefly fibromatous have been described as occurring in the tunica
albuginea, testis, epididymis, or cord. On close examination most of these
tumors disclose evidence of complex composition, as in Chevassu's case.
They have sometimes reached a large size. Their origin has been referred to
the interstitial tissue of the affected locality, but that some of them are re-
lated to teratoma is very probable.

Fibroma in the ovary presents several features of interest, (a) The dif-
fuse tumors arise chiefly at the lateral pole and involve much or all of the or-
gan. They are capable of reaching enormous dimensions. A frequent
accident is strangulation by torsion of the pedicle. The structure varies
greatly in richness in cells, or vessels; from admixture with myoma; from sec-
ondary changes toward myxoma, osteoma, chondroma; and from necrosis,
and cystic softening. Adler describes an ovarian intracanalicular adeno-
fibroma. Ovarian hematoma may be connected with their origin (Brothers),
and a special type develops about corpora lutea (Rokitansky). Others may
be of teratomatous nature.

(b) Papillary fibroma appears as multiple warty outgrowths of one or
both organs.

(c) Ovarium gyratum is a form of superficial fibrosis of both ovaries which
obliterates the cortical structures and transforms the organ into an enlarged,
hard, very opaque mass, with wart-like surface. The condition was so named
by Adler and is not infrequent.

FIBROMA OF THE NARES. NASAL POLYP

Although there has been much debate over the relation of nasal polyps
to true neoplasms, here as elsewhere it is impossible to draw a sharp line be-
tween the products of chronic inflammation and tumor processes, so that
there is some justification in the current usage by rhinologists of the term
fibroma for these common growths (Bosworth, Lit.). Nevertheless, it is
quite clear that in the nares more than in any other mucus membrane the
polypoid outgrowths of chronic inflammation lack the histological features
of an autonomous new growth. In fact, as Chiari claimed in 1887, many of
them consist of nothing more than localized edematous areas of mucous
membrane rendered protuberant by mechanical means, but without other
changes. Once established, however, these masses are subject to various
grades of hyperplasia of their elements which render them not only persist-
ent, but often progressive, and in such cases there may be considerable
change in the appearance and proportions of various cells. Since this change
is seldom pronounced, the groups of nasal polyps must stand among the
purest examples of pseudoneoplasms of inflammatory origin.

Nasal polyps are probably always preceded by chronic rhinitis and
Tissier traces an unbroken series of cases from simple chronic rhinitis through
hyperplastic rhinitis to polypoid inflammatory outgrowths. The tumors
appear chiefly in young subjects and infants, rarely after 30 years, generally
at the ostia 'of the mucous sinuses opening into the nares. Empyema of
these sinuses is a common antecedent. They are commonly multiple,
sometimes very numerous, and they occasionally reach a large size, pressing
on adjacent structures, and widening the bridge of the nose, with obstruction

FIBROMA 163

of passages and various anatomical and clinical sequelae. Heymann pictures
a very large nasal polyp which filled the nasopharynx. They are soft in
the early stages, firmer if old, gorged with blood, or gray and translucent
from edema, with smooth warty or papillary surface. They may begin
as numerous low elevations of the mucosa, but soon tend to become
pedunculated.

Histologically three somewhat different varieties are described by Zarniko,
fibroma edematodes simplex, adeno fibroma edematodes, and fibroma edematodes
cysticum.

Fibroma Edematodes Simplex. — This tumor is composed of loose con-
nective tissue with few or many spindle- or star-shaped fibroblasts. The
stroma contains loose collagen and some elastic fibers. The grade of edema
varies but is usually pronounced, sometimes leaving wide spaces, or if
slight, as in old cases, yielding rather firm cellular areas. Lymphocytes
may be abundant, beneath the epithelium, about the vessels or in small foci.
Eosinophile cells, Charcot-Leyden crystals, and even extensive pigmentation
may form the sequel of hemorrhages. Nerve-fibers losing themselves in
the stroma have been demonstrated by Billroth and by Kalischer. Blood-
vessels are abundant especially in the pedicle but tend to disappear. In
some old cases they are very numerous and cellular suggesting angioma.
Dilated venous sinuses add to the bulk of many cases. Lymph sinuses are
less numerous. Areas of calcification and islands of true bone suggest an
influence of the neighboring periosteum. The lining epithelium is hyper-
trophic, ciliated, or transitional, or squamous from attrition. The edematous
fluid is an albuminous transudate, but may contain considerable traces of
mucin. Hyaline globules may also be present.

Adenofibroma Edematodes. — In some polyps new gland formation is
prominent and much of the tissue is composed of various slightly distended
alveoli lined by several layers of hypertrophic epithelium. Goblet cells
may be very numerous. In some cases the epithelial hyperplasia is pro-
nounced but it rarely suggets a true neoplasm.

Fibroma Edematodes Cysticum. — Most of the large and some smaller
polyps owe their bulk to the formation of cysts which arise from distended
alveoli lined with overgrowing cells, or if ducts are occluded, with flat cells.
The contents are serous fluid, mucus, pus, degenerating epithelium, fatty
detritus, or hyaline or calcific deposits.

The derivation of all these features and many other details in the structure
of nasal polyps have been fully traced by Heymann, Zuckerkandl, Wright,
"Zarniko and many others.

The natural history of nasal polyps is that of a persistent and slowly
progressive pseudoneoplasm. They seldom spontaneously disappear, except
through accidental expulsion. They are frequently found as a complication
of malignant tumors, but malignant transformation of a benign polyp is
extremely rare, Heymann finding only three somewhat doubtful cases.
They do not recur after complete removal which is sometimes difficult, but
new tumors often succeed those removed. In the etiology a special pre-
disposition may possibly exist, but the growths are adequately explained as the
result of chronic inflammation and the irritation of retained secretion.

Choanal Polyp. — Arising from the posterior nasal orifice very cellular
firm tumors occur which lack the edema of the intranasal growths, but yet
attain large dimensions, reaching into the pharynx or, as in Storck's case,
to the larynx. Zaufal removed such a tumor weighing 112 gm. Zarniko
observed extensive bone formation in one case with marked hyperplasia
and metaplasia of the epithelium. Some of these growths show more definite

164

NEOPLASTIC DISEASES

neoplastic characters than the intranasal growths. The choanal polyp
often originates from the mucosa of the accessory sinuses, maxillary and
antral, ethmoidal, or sphenoidal. These tumors are characterized by a
tendency to reach a large size, by the presence of a long pedicle, and by recur-
rence after removal of the tumor without the pedicle. After repeated
recurrence it is usually found necessary to open the sinus and attack the
growth at the base, and many rhinologists employ the radical method at
once in dealing with these polyps (Moore, Byrne).

Juvenile Nasopharyngeal Fibroma. — This rare and peculiar tumor occurs
chiefly in males and almost invariably between the ages of 10 and 25 years.
It is a very firm almost cartilaginous tumor which appears in the vault
of the pharynx and grows in several definite directions. According to
Bensch it produces an intrapharyngeal tumor when arising from the basilar

FIG. 33. — Malignant angiomyxoma growing from superior nares in a child.

fibrocartilages, the upper cervical vertebrae, or the internal lamina of the
pterygoid process; or an extrapharyngeal growth when arising from the
cartilage of the foramen lac. ant., or the sphenopalatine fossa. The intra-
pharyngeal tumor extends forward into the nares and the adjacent sinuses,
causing atrophy of the bony structures. From the sphenoidal origin the
growth extends down between the masse ter muscle and the mucosa; or it
pushes between the pterygoid and styloid muscles into the temporal fossa
and forward into the malar region; or through the inferior orbital fissure
it extends into the orbit, or by way of the superior orbital fissure or lamina
cribrosa it reaches the cranial cavity. From these points the courses from
the two seats of origin overlap.

In structure the tumor is composed of dense fibrous and elastic tissue

FIBROMA 165

which rarely shows calcification, cartilage or bone. The cells are round,
spindle- or star-shaped fibroblasts which are rather scanty except in certain
foci of young connective tissue where they may be so numerous as to suggest
fibrosarcoma. Mast cells and plasma-cells may be present. The vessels
are numerous (pharyngeal angiofibroma) and sometimes cavernous. Involu-
tion changes follow thickening and hyalinosis of vessel-walls, the stroma
becoming hyaline and the tumor undergoing necrosis or fatty degeneration
(Ballo).

The course is of an actively growing tumor which disturbs various
functions by pressure, leads to anemia from hemorrhage, suffers ulceration
and local infection, and may prove fatal in this way, or from cerebral dis-
turbance. Metastases are not observed. A remarkable feature of this
tumor attested by many observers is its complete spontaneous regression
after partial removal (Bensch, Grimwald, Konig, Bruns, Zarniko). This
event seems to occur chiefly toward the end of the period when the tumor
may develop, i.e., the 25th year. There is thus illustrated a form of natural
immunity, which may be referred to natural anatomical changes at the point
of origin from which alone the nutrition of the growth is maintained. Ac-
cording to Bensch the development of the male and female face and skull
at puberty explains the predominance of the tumor in males, while the
completion of the cranial development at the 25th year determines the
spontaneous disappearance of the tumor. It is not clear that this tumor
is always of fibromatous structure. Naab observes that chondroma and
sarcoma may appear under much the same conditions. I have seen a tumor
corresponding in many particulars to the above description but showing
the structure of a sarcoma with indistinct chondromatous qualities. Con-
fusion with chondroma seems possible. Many of the tumors are myxo-
matous or myxosarcomatous and these recur persistently and are commonly
fatal.

CHAPTER XI
MYXOMA

Myxoma is a tumor composed of mucous tissue.

Primary myxoma, a tumor which probably arises from embryonal mucous
tissue, is rare, but mesoblastic tumors such as fibroma, lipoma, and chondroma
which contain myxomatous portions are not infrequent. It is often difficult
to determine whether the myxomatous portion of a complex tumor is origi-
nally of this type or represents a degeneration of the more adult tissue. In
the former case one employs the terms myxofibroma or myxolipoma, in
the latter case the myomatous degeneration is indicated by the suffix myxo-
matodes as chondroma myxomatodes.

When mucous tissue is present in a neoplasm three possibilities as to its
significance must be considered. The mucous tissue may be developed
directly from embryonal mucous tissue and the tumor may be a primary
myxoma. Or the tissue may represent a metaplastic product of other tissues
and the tumor is a secondary myxoma. Or the tissue may result from chronic
edema of other structures and represent a form of spurious mucous tissue,
such as is seen in edematous nasal polyps and in atrophic fat tissue. These
theoretical deductions cannot always be established in the practical examina-
tion of tumors.

Since mucous tissue does not exist in the adult body a primary myxoma,
according to the above definition, must be rare and always embryonal.
Fully developed mucous tissue exists in the embryo only in the umbilical
cord and although a few myxomas of the navel have been described which
probably arose from cord tissue the chief source of myxomas must be sought
elsewhere. Such a source may be found in the early undifferentiated con-
nective tissue of the embryo which has a mucous quality. Such mucous
tissue is widely distributed in the embryo especially in the subcutaneous
areas. It is genetically related to fat tissue into which it is extensively
transformed during normal growth. It may be assumed that many primary
myxomas arise from islands of such embryonal tissue. Since such islands of
mucous tissue may readily be associated with cartilage and fibrous and fat
tissues, which are normally developed from the embryonal mesoblast, it is
reasonable to explain the occurrence of many myxolipomas, fibromas and
chondromas by assuming their origin from islands of tissue which are partly
differentiated, or which become so during the progress of the growth. It
does not appear that pure myxomas ever tend to differentiate into fibroma
or lipoma. It is not so easy to decide to what extent other mesoblastic
tumors become transformed into true myxoma. Fibroma, lipoma, and
chondroma undoubtedly become transformed by degeneration or imperfect
growth into tumors containing areas of typical mucous tissue. The group
of secondary myxoma develops in this way.

Virchow considered myxoma to be very closely related to lipoma and as
occasionally arising from embryonal fat tissue. Certain myxomas of bone
he believed might arise from cartilage. Ribbert, however, regards such sec-
ondary changes as spurious myxomas, on the ground that already differen-
tiated tissues cannot become transformed into true mucous tissue. This

166

MYXOMA 167

objection seems to me adequate to separate the primary from secondary
myxomas, but not to eliminate the latter class from the general category of
myxoma.

In the sense that primary myxomas are foreign to the type of tissue in
which they arise they may be regarded as always heterologous. Yet this
character is not equivalent to that of many other heterologous tumors which
arise from tissues widely displaced and genetically unrelated to the tissue in
which the tumor occurs.

Myxoma is to be sharply distinguished from epithelial tumors undergoing
mucous degeneration. Here the mucus is a form of hypersecretion, while in
myxoma it is an integral part of the living tissue.

Anatomical Characters. — Myxomas are soft, lobulated, polypoid, or
papillary tumors, which on section are smooth, translucent and gelatinous.
The lobulation is determined by the growth about blood-vessels which v.
Rindfleisch finds on injection are of relatively large caliber with few capil-
laries. The encapsulation of myxomas is seldom complete, the mucinous
material tending to infiltrate surrounding tissues. On this account complete
extirpation is sometimes difficult and recurrence follows from persistence of
widely disseminated mucous material and cells. In some cases the condi-
tions suggest a transformation of normal tissues into myxoma under the in-
fluence of the mucinous material. Virchow observed the gradual extension
of the myxomatous tendency from a recurrent tumor of the ulnar nerve over
the greater part of the brachial plexus.

On extraction with weak alkali myxomas yield a solution of mucus which
is precipitable by acetic acid. Alcohol precipitates mucus in membranous
or reticulated form resembling fibrin.

The structure of myxoma presents typical features of spindle- and star-
shaped cells with processes anastomosing or disappearing in the matrix,
and cytoplasm usually containing fatty and watery droplets. Hydropic
degeneration may be extreme in edematous tumors.

The cells may be grouped chiefly about blood-vessels which when abun-
dant may call for the designation "telangiectatic," or, "cavernous." Or
they may be more numerous in the capsule in cases showing peripheral
growth. Various admixtures of connective tissue, fat, cartilage, or bone
occur and may deserve suitable recognition in the terminology. Cystic
myxoma results from local edema, or hemorrhage, and in one definite group
of cases dilated lymph spaces or vessels yield cysts. Very cellular myxomas,
pure or combined with other tissues, and primary or secondary, constitute
the important group of myxosarcomas.

The matrix of myxomas varies greatly in bulk and in structure. It may
be very abundant widely separating the cells, and appearing as nearly homo-
geneous or faintly fibrillated or granular but always basophilic material.
In rapidly growing tumors and in cellular areas it may be very scanty. The
bulk of the matrix depends much on the capacity of the mucinous material
to absorb water. In the secondary myxomas the gradual transformation of
fibrous tissue, fat, cartilage and bone may often be traced, the matrix of these
tissues becoming transformed into mucous tissue and the cells assuming
spindle and star shapes. Similar changes may sometimes be observed on
the edges of infiltrating myxomas but the invaded tissue is usually passively
displaced by the tumor.

Epithelial and endothelial cells may become incorporated in the advancing
myxoma and rendered indistinguishable from the tumor-cells. In some endo-
theliomas myxomatous changes may be so complete as to greatly obscure
the true nature of the growth. The myxosarcomas exhibit many more

168 NEOPLASTIC DISEASES

cells, usually more vessels, and less matrix than the simple myxomas. As a
rule the mucous tissue is associated with areas of fine spindle-cells often
grouped about blood-vessels. In a bulky myxoma of the fascia of the thigh
I found that all the spindle-cells could be traced to the walls of very numerous
capillaries. This tumor was strictly a myxo-endothelioma. Myxomatous
tissue is often combined with fat tissue, cartilage, bone, or other neoplastic
elements. When the formation of mucous tissue in such a tumor is the pre-
dominating feature the growth may be designated as myxosarcoma, but
when mucous degeneration affects only small areas the term sarcoma myx-
omatodes is employed. The former group constitutes a numerous class of

bL V <•*** Y- x- I'M \ V .^rQi

FIG. 34. — A vascular myxoma of superior nares.

tumors among which the lipomatous and chondromatous varieties are most
numerous. The malignancy of myxosarcoma depends chiefly on its local
effects, metastases not being very. common. According to Malherbe, myxoma
of striated muscle, fasciae, and of certain viscera is usually malignant and
equivalent to sarcoma, while in the nares, breast, bone, and nervous system it
is almost always benign.

The clinical course of myxoma is of a slowly growing tumor which pro-
duces no symptoms except local swelling and pressure. After complete
extirpation they do not recur, but thorough removal is not always readily
accomplished and local recurrence of this benign tumor is not uncommon.
In the skin and nerve-trunks they are frequently multiple and new tumors
develop after extirpation of the old. Yet Virchow refers to two cases of
myxoma of cheek, and of labium, which recurred after operation and eventually
produced many myxomatous metastases. As a rule, malignant myxomas
fall readily in the class of myxosarcoma.

Simple myxoma rarely attains a large size and the onset of myxomatous

MYXOMA

169

changes usually marks a partial limitation of the growth capacities of a tumor.
Yet the myxolipomas grow to very large size and for some of the diffuse forms
of this tumor Virchow suggested a relation to elephantiasis. Such a case
affecting the leg and thigh is reported by Barling. In certain situations the
pressure symptoms of myxomas become serious (nares, brain, cord).

The location of myxomas is chiefly the subcutaneous and intermuscular
tissue of localities where the structure is loose and much fat is commonly
present. The regions most affected are the thigh, neck, cheek, leg, and peri-
toneum, and less frequently, the bones, meninges, nerve-trunks, mucous and
serous membranes, and hilus of the kidney. I have seen a myxoma as large
as an orange involving three lobes of the placenta.

FIG. 35. — Myxoma of portion of placenta.

Certain clinical forms of myxoma are rather well defined. Myxoma of
the nervous system affects the peripheral nerves, meninges and brain tissue.
In the nerve-trunks single and multiple primary myxoma occurs under much
the same conditions as multiple fibroma and probably represents a more
embryonal form of this tumor. Some of the cutaneous myxomas are prob-
ably of neural origin. They arise in the endoneurium and perineurium
probably from foci of embryonal tissue, and produce rounded or elongated,
soft but often painful tumors. After extirpation new tumors may develop.
Wilms observed a large cystic myxoma of the ulnar nerve.

The optic nerve is especially susceptible to myxoma, which here tends to
pursue a characteristic clinical course (Sattler, Parsons, Salzmann). The
tumor occurs chiefly in young subjects, produces a fusiform swelling of the
whole nerve-trunk, blindness results, but the eyeball is usually not invaded,

170 N EOF LA STIC DISEASES

and extirpation of the tumor is usually successful. In a case studied in this
laboratory with Knapp the central portions of the tumor were softened and
cystic, the nerve-fibers were nearly all destroyed, while the capsule presented
the structure of an angiosarcoma. In the meninges several soft myxomas
have been described, especially by the older authors, of which Virchow col-
lected a series. In the brain tissue Virchow described as myxoma certain
tumors which were probably gelatinous gliomas.

In the mucous membranes polypoid outgrowths in many regions present
some of the features of myxoma. They are chiefly edematous fibroadenomas
or inflammatory hyperplasias and contain little or no mucin.

In the bones Virchow described both primary and secondary myxoma.
The primary tumor he derived from the mucous tissue of the bone-marrow
and believed that from this origin the tumor caused absorption of the bone
and distended or ruptured the periosteum. A variety of secondary ni) xomas
arise in the bones and represent mucous degeneration of fibroma, chondroma,

pIG 26. — Lobulated myxoma of right auricle. (After Ribbert.) A and B, Main lobes of
tumor. D, elongated portion. V, vena cava sup. T, tricuspid.

and osteoma. They may be surrounded by a bony shell laid down by
the periosteum and portions of the original bone tissues may be found in the
substance of the tumor.

Congenital myxoma or myxosarcoma of the navel is described by
Kaufmann with the report of a case and review of the literature. I have
observed a cystic myxoma of the umbilical cord and navel measuring 10 cm.
in diameter, and associated with congenital malformation of the kidneys.

Myxoma of the Heart.— The endocardium is the seat of a series of tumors
which' include small fibromas, larger soft myxomas, and more cellular
myxosarcomas. The interpretation of any one of these tumors should be
influenced by our knowledge of the entire group.

Brenner collected 33 reports of cardiac myxomas, of which 20 were located
in the left auricle, chiefly on the septum, 10 on the heart valves, 2 in the

MYXOMA 171

right ventricle, and one on the apex epicardium. The smaller tumors offer
little difficulty of recognition since they usually take the form of typical
fibromyxoma. With increasing growth they assume a lobate, papillary,
polypoid or even villous form and the structure is greatly altered by edema,
hemorrhage and progressive thrombosis of blood with organization on the
surface. In this form they are difficult to distinguish from organized
thrombi. In fact Czapek, Thorel and others regard most of the reported
cardiac myxomas as organized thrombi. The tumors are as small as a pea
or as large as a hen's egg, and while they usually produce no symptoms
some seriously obstruct the circulation. They are usually covered with
blood-clot organized portions of which are fused with the tumor. Fibrin
emboli may be detached, and Marchand found a growing tumor embolus
in a cerebral vessel.

The structure of the tumors is rather uniform but varies as the original
myxomatous tissue is altered or replaced by edema, hemorrhage, perivascular
infiltration with round-cells, and organization of secondary thrombi. The
framework consists of a system of blood-vessels radiating from the pedicle
which support the overabundant mucinous material composing the bulk
of the tumor. The vessels are usually thin arterioles or venules or capil-
laries surrounded by lymphocytes or large mononuclear cells. Muscle-
fibers may be drawn into the pedicle from the myocardium. An abundance
of elastic fibers is a common element which Brenner attributes to the mechan-
ical influence of cardiac contraction upon the tumor stroma. In one of
Czapek's cases the stroma was nearly cartilaginous. The separation from
organized thrombi may be based on the highly mucinous character of the
stroma, on the presence of orderly radiating blood-vessels and elastic fibers,
and on the absence of masses of blood detritus undergoing organization.
While many of the larger tumors may be difficult to identify (as in
Oppenheimer's case) it seems unlikely that a simple organizing blood-clot
can reproduce the positive features of the true myxoma. Hence the great
majority of the reported cases of cardiac myxoma are probably genuine.

The origin of the tumors has been referred to superfluous embryonal
tissue in the region of the foramen ovale where many of the growths are
attached. Curtis expressed the view that the process is not a genuine
neoplasm but a result of chronic inflammation of rheumatic nature producing
nodular outgrowths of the endocardium wrhich continued to grow because of
the mechanical influences to which they are exposed.

Primary sarcomas of the heart are probably connected in origin with the
myxomas. Binder collected 15 cases, of which eight were located in the right
auricle. They reach large dimensions, grow into the veins, occlude the heart,
but rarely give metastases. The composition is chiefly of spindle-cells,
but giant-cell, and round-cell tumors also occur.

Apparently pure myxomas have been observed in the mesenten7 (Borst)
and in the thymus (Winogradow).

Chondromyxoma may make up the bulk of the mixed tumor of the
parotid, and in the fourth recurrence of an original cartilaginous tumor
of the parotid I have found pure myxoma. Certain of the nasopharyngeal
polyps which are of cartilaginous origin may appear, especially in recur-
rences, as pure myxosarcoma. In other organs also, as testis, mammae
and bones, it seems probable that certain myxomas represent imperfect
growth of cartilage in embryonal chondromas.

In several notable cases the intramuscular metastases of cartilaginous
or choriomatous teratoma testis have appeared in the form of myxoma. In

172 X EOF LA STIC DISEASES

fact there is reason to believe that the condition of nutrition of intravascular
tumors strongly favors the myxomatous type of growth in many tumors.

The combination of myxoma and lipoma occurs in certain tumors of
clinical importance and many of these growths reach a large size and prove
malignant. In the retroperitoneal region, in the hilus of the left kidney, and
in the spermatic cord, are encountered locally malignant myxolipomas. In
the eleventh recurrence of an original lipoma of the spermatic cord which
I was able to follow over a period of 15 years some lobules were pure
myxoma. Robertson, in an analysis of 51 cases of lipoma myxomatodes
found that 43 per cent, developed in the muscles of the lower extremities,
33 per cent, in the retroperitoneal region; one reached a weight of 65 Ibs.,
and 33 per cent, were malignant.

In the etiology of myxomas special factors must be considered for different
groups and an etiological classification becomes of interest.

A congenital origin has been established for myxomas of the navel which
probably arise from foci of umbilical cord tissue, and for the mesenteric
tumor described by Borst. The general source of myxomas must be sought
in superfluous or aberrant foci of embryonal connective tissue, fat and carti-
lage. Virchow regarded myxoma as arising indifferently from several
embryonal mesoblastic tissues, and from glia-tissue. Ribbert would limit
their origin rather strictly to embryonal connective tissue. The conditions
which give rise to secondary myxoma, may apparently represent an embry-
onal reversion of connective tissue, fat or cartilage, or it may result from
chronic edema and a true mucous degeneration.

Special embryonic disturbances do not seem to be connected with
myxomas, although Marchand suggested that abnormalities in the con-
struction of the cardiac septa might be responsible for myxoma of the
endocardium. As already stated an intravascular position favors the ap-
pearance of myxomatous changes in a tumor. Chronic inflammation and
edema lead to the growth of myxomatoid polyps of mucous membranes.
Finally in the testis, spermatic cord and possibly in the kidney myxomas
are probably of teratoid origin, and in some other regions as parotid, breast,
they represent mixed tumors.

Sanarelli and Splendore have studied a filterable virus which on inocula-
tion produces multiple tumors resembling myxoma in the skin and organs
of rabbits. Rous' tumor of chickens which he was able to reproduce by the
inoculation of filtered extracts has a myxomatous character.

CHAPTER XII
LIPOMA

A lipoma is a tumor composed of fat tissue.

The gross appearance of most of these tumors is characteristic. They
form firm, elastic, rounded, usually multilobulated growths, which, without
encapsulation, are sharply circumscribed from the surrounding tissue.
Their size varies from that of a pea to masses weighing many pounds which
produce serious results from weight and pressure. The consistence is usually
that of normal fat tissue, lipoma molle, but this density may be reduced by

FIG. 37. — Lipoma of forearm in adult, containing fetal fat tissue.

secondary changes, or, more often increased, by admixture with fibrous
tissue or by forms of metaplasia. In many situations they become pendulous
and by constriction of the pedicle spontaneous atrophy may result. The
color is usually that of normal fat tissue, but xanthomatous changes may
yield an orange yellow tint, or various secondary processes may give cor-
responding alterations. Very cellular areas with imperfect fat formation
are recognizable by a lighter opaque color, while the fully developed tumor
tissue is yellow and translucent.

173

174

N EOF LA STIC DISEASES

Lipomas exhibit a striking connection with the nutrient blood-vessels,
each of the multiple lobules growing about a branch of the main vessel.
Lateral anastomoses of these vessels are scanty so that the tumor grows
expansively and is readily shelled out of its position. With pure lipomas
appositional growth is not observed, but this rule is less rigid for mixed
lipoma and liposarcoma.

The microscopical structure resembles normal fat tissue, but the lobules
vary greatly in size and the supporting stroma is irregular in distribution.
The cells may be overdistended with fat, or may produce the smaller type
of embryonal fat tissue, and often there are areas of polyhedral cells in which
the fatty deposits are incomplete. It is from such cells lying in isolated
foci or along the vessels that the growth of lipomas chiefly occurs. In some
of these foci an alveolar structure may be produced by polyhedral cells

* 4ir*£y *v- r^V^^v*--^ « -Jr:-:f >^: •

FIG. 38. — Subcutaneous lipoma. Gross texture of orange tint. Lipoid material appears

in granular form as in xanthoma.

with incomplete fat deposits. Occasionally the young cells contain granular
lipoid pigment and strongly resemble xanthoma cells, and this character
may be diffuse throughout rather large lipomas, especially about the kidney.
The blood-vessels are usually overabundant and many cellular arterioles
are found in the stroma running out into the lobules and dividing into capil-
laries. Extensive overgrowth of blood-vessels leads to .the formation of
vascular fatty tumors, lipoma telangiectaticum or cavernosum, so that it is
sometimes difficult to distinguish between vascular lipoma and angioma.
Lymph-vessels also may be overdeveloped, and Borst observed the trans-
formation of a lipoma into a fibrous lymphangioma.

Secondary changes in lipomas are common in advanced stages of growth.
One of the more frequent is a mucinous degeneration which occurs in atro-
phic or edematous areas and may reach extensive proportions without

LI POM A 175

constituting a true myxolipoma. Diffuse mucinous degeneration produces
a peculiar tumor-tissue designated by Miiller as collonema. Mucinous
changes are more common in liposarcomas, where they usually represent a
true myxolipoma. Borst has observed the transformation of the fat in
portions of lipomas into a waxy material. Beriel and Delachanal followed
the myxomatous and sarcomatous transformation of a lipoma of the sciatic
sheath which eventually produced lipomatous and sarcomatous metastases
in lymph-nodes and lung. Calcification either of isolated foci or of the
entire capsule may occur and is rarely followed by ossification (Lipoma
petrificiim ossificans, Virchow).

Cysts form in lipomas from the fluidification of the central portions of
large lobules producing areas of fluid fat (oil cysts) which are said to result
chiefly from trauma. In mucinous and edematous lipomas irregular cystic
areas may form containing mucous or serous fluid, fatty crystals and cal-
cific deposits. Lymph-cysts with clear fluid are occasionally observed.

Lipomas may exhibit an excess of fibrous tissue resulting from atrophy
of fat and fibrous replacement or from admixture with true fibroma (fibro-
lipoma). More frequently true myxoma is combined with lipoma, and occa-
sionally chondrolipomas are observed. In a considerable class of tumors all
the cells are abundant and one has to deal with various types of liposarcoma.
In the abdominal cavity of a dog I have observed a large tumor composed of
adult fat, embryonal fat, myxoma, chondroma and large areas of osteoma.

Many interesting features are occasionally observed in the clinical course
of lipomas. Some internal growths, as in the thorax, abdomen, or cranium,
reach such a size and exert such pressure as to cause serious symptoms or
even death, with symptoms referable to the affected organs. Very large
lipomas seem to be capable of diverting the nutrition of the body and inducing
emaciation. This feature is prominent in many of the retroperitoneal
tumors collected by Voeckler. The limit of growth of simple lipoma is often
considerable, but in many of the very large tumors portions of the growth
become more cellular and exhibit sarcomatous structure. The occurrence
of multiple lipomas, even hundreds (Virchow), is evidence of a peculiar
dyscrasia of the fat tissues of these subjects, in whom the tumors may appear
in the lungs and liver where fat is normally absent. A remarkable case is
that of Broca, in which, in a man of 31 years, after extirpation of a large lipoma
of thigh, hundreds of small tumors appeared over the body and persisted for
40 years. The patient finally suffered from dysphagia, with regression of
most of the tumors, but at autopsy a large fatty tumor surrounded and
compressed most of the esophagus. Persistent local recurrence of lipomas
is rare and usually associated with a cellular and vascular or sarcomatous
structure. Yet in a case of recurrent lipoma of the spermatic cord extir-
pated many times in the course of 15 years, the structure was never very
cellular and varied little throughout the course.

The capacity of the organism to appropriate the fat of lipomas has been
investigated by Wells, who found no peculiarity in the chemical composition
of the fat of lipomas, no deficiency of lipase, and no ground for the common
assumption that the fat of these tumors is beyond the reach of the fat-mo-
bilizing factors of the body. Since many lipomas have continued to grow
while the body was emaciating, and not a few remain unaffected during the
loss of body fat in phthisis (Madelung), or gastritis (Kuster), it is necessary
to assume that local conditions, possibly the character of the circulation,
prevented the absorption of the lipoma.

Into the etiology of lipoma many factors seem to enter. An hereditary
influence was recognized in a family observed by Murchison in which the

176 N EOF LA STIC DISEASES

father and three daughters had multiple symmetrical lipomas while nine
sons were free. In Blaschko's case only the male members were affected and
the tumors appeared at puberty. Other hereditary cases are recorded by
Meerbeck and Petren.

The occurrence of multiple symmetrical lipomas has suggested to many
a connection with the peripheral nerves (Payer, Kottnitz). In a group of
cases the tumors have been painful and associated with other lesions of the
nervous system. Alsberg found several neurofibromas with many lipomas
in the same case and he traced nerve-fibers into certain lipomas. Both
xanthoma and multiple lipoma have also been observed with multiple neuro-
fibroma. Yet the occurrence of lipomas with multiple neurofibroma is
extremely rare and it has not been possible to establish for lipoma such a
relation to the peripheral nerves as exists with fibroma. Grosch and others
have argued that multiple lipomas may originate in connection with the se-
baceous glands, as the result of a trophoneurosis, but later observers have
been unable to find support for this theory (Lit. Goebel).

Virchow described as capsular lipoma certain limited but sometimes bulky
growths occurring in atrophying organs as the kidney and breast. A similar
growth of fat tissue replaces the atrophic thymus and bone-marrow and is
very often seen in the atrophic lymph-nodes of cachectic or emaciated sub-
jects and with chronic mastitis. Askanazy was able to show that in several
cases of small multiple lipomas the tumors were located in atrophic lymph-
nodes, and he suggested that this was a common origin of lipomas. The term
replacement lipomatosis seems more applicable to this process which may
produce fatty growths of moderate dimensions but not true lipomas.

Multiple lipomas have been observed in many cases of disease or atrophy
of the thyroid gland in cases of obesity and in alcoholism, but it does not appear
that these constitutional conditions have any direct bearing on the etiology
of true lipoma (Curling, Madelung, Kottnitz). They seem more clearly
connected with the forms of diffuse or regional overgrowth of fat tissue which
bear the same relation to lipoma as diffuse fibromatosis holds to fibroma.
In such conditions disturbances of the thyroid and pituitary glands seem to be
an important factor.

A congenital tissue predisposition seems to be an essential facor in the
origin of most lipomas. This predisposition may take the form of a dis-
turbance of development of the fat tissue. It has been shown by Kolliker
and Toldt that the fat lobules have a certain independence in development
which constitute them a sort of primitive organ. The comparative isola-
tion of the blood-supply of these lobules reappearing in lipomas suggests
that the anomaly predisposing to lipoma is connected with the distribution of
blood-vessels in the fattv tissues.

A more definite embryonic disturbance is probably responsible for the
origin of many lipomas of the internal organs, as in the kidney, where mis-
placed islands of capsular fat are held to give rise to tumors (Selter, Lu-
barsch, Manasse, Muller).

More complex embryogenic anomalies are concerned with those lipomas
which arise in the cranial cavity with cholesteatoma, where complex epidermal
tissues are involved (Bostroem); with spina bifida (v. Recklinghausen,
Arnold); with a rudimentary cervical rib (Volcker); in the uterus (Merckel).

Certain lipomas result from predominance of fat tissues in mixed tumors.
Such is probably the nature of the recurrent lipoma of the spermatic cord.
(Sazarin, Ehrendorfer, Porges).

Trauma of many types has acted as an exciting factor with many soli-

LI POM A 177

tary superficial lipomas in subjects in which a local or general predisposition
must be assumed to exist.

In the general etiological classification of lipoma and lipomatoid processes
one must recognize many different forms of hypertrophy of fat tissue as fol-
lows: (i) Obesity; (2) localized overgrowth of fat tissue, lipoma annul are colli;
(3) replacement lipomatosis, as in atrophic organs, marrow, kidney, capsular
lipoma, lymph-nodes; (4) homologous lipoma, a group including the ma-
jority of solitary subcutaneous lipomas; (5) heterologous lipoma from mis-
placed groups of embryonal tissue cells; (6) overgrowth of lipoma in mixed
tumors and teratomas.

Clinical Types of ~Lipoma..— Subcutaneous. — The subcutaneous tissue is the
commonest seat of lipoma, and the back, neck, shoulders, axilla, and abdom-
inal wall are most frequently affected. According to Grosch who has plated
a large number of subcutaneous lipomas, these tumors occur in inverse
proportion to the number of glandular structures in the skin. The cutaneous
lipomas are single or multiple, unilateral or bilateral and symmetrical,
small or large, and polypoid, or pendulated. They arise in the derma,
beneath the superficial fascia and in the deeper fascias.

Small congenital lipomas occur beneath the skin on the volar side of the
fingers and hands. They arise from the deep fascia and may be connected
with the tendon sheaths.

Lipoma annular e colli is a diffuse form of lipomatosis occurring in the^neck,
producing* great enlargement of this region, and involving the fat tissues of
the skin and subcutaneous and intramuscular structures (Madelung). It
is not a true lipoma but a localized overgrowth of the abundant fat tissues of
this region. Somewhat similar overgrowths of fat tissue may occur in the
hips and thighs (Shattock). More general hypertrophy of fat tissues is
seen in adiposis dolorosa (Dercum). Subcutaneous lipomas often reaching
considerable size occur in the scrotum and labia.

Synovial. — Lipoma and lipomatous processes affect the joints. Soli-
tary lipoma may arise within the joint cavity through rupture of the syn-
ovial membrane and protrusion of the subcapsular fat which then goes on to
continuous hyperplasia (Konig). Solitary lipomas may also arise in the
joint from overgrowth of fat in synovia! fringes (Otterbeck, Filter.) Ex-
tra-articular lipomas arising from the subcapsular fat occur about the knee
and hip. Lipoma arborescens is a characteristic extensive papillary outgrowth
from the fat tissues of the synovial membrane and joint capsule of the knee
which fills the joint spaces and interferes with function. It occurs with
simple chronic and with tuberculous arthritis in which case it is probably
of inflammatory origin with overgrowth of synovial fat (Kaufmann), but it
occurs apart from any inflammatory processes as a true tumor of pure fat
tissue in which the characteristic relation of lobules to branching subcap-
sular blood-vessels is observed (Borst, Ribbert).

Inter muscular. — In the cheek a congenital lipoma arises from a mass of
fat in the canine fossa, on inner surface of masseter muscle, long known as
corpus adiposum males (Bichat), pushes its way beneath the skin and appears
as a subcutaneous tumor of moderate dimensions. Several tumors of this
origin have been collected by Bruns and Ransohoff. They may readily
be mistaken for tumors of the parotid with which they are in intimate
connection.

Beneath the pectoralis lipomas arise probably from extensions of the
axillary fat which cause protrusion of the breast (Billroth). Deep lipomas
are also observed in the orbit, at the base of the tongue, and in the larynx.
Grosch has collected many lipomas occurring about the cranium.
12

178 N EOF LA STIC DISEASES

Cranial.- — In the cranial cavity lipomas have been observed in various
situations in most of which small collections of fat tissue are normally pres-
ent. The chief locations include the surface of the corpus callosum, the base
of fithe cerebrum, the brain stem and cerebellum, the ventricles, and the roots
of the cranial nerves (v. Sury, Lit.). They invariably arise from the pia
although many appear to be imbedded in the brain tissue. Taubner
argued that they may arise from the glia-tissue.

Virchow mentions six lipomas of the pia, one of the raphe of the corpus
callosum, and four at the base. In the choroid plexus and nourished by its
vessels they have been observed by Virchow, Wallmann and Hackel. Rind-
fleisch saw small multiple lipomas of dura and ventricular ependyma. Fere
and Francillon report symmetrical lipomas. Garnier's lipoma was attached
to the crus cerebri. Small lipomas of the corpora quadrigemina are reported
by Bernhard and Taubner. The most characteristic type is the lipoma which
is nourished by the vessels of the corpus callosum, grows along this structure
and largely replaces the nerve tissue (Virchow, Benjamin, Coats). Peri-
neural lipomas inclose the roots of the cranial nerves or olfactory bulbs
(Shouppe). A central nucleus of bone has been found by Benjamin, Chiari,
Ernst, and v. Sury.

Many of the tumors are small and fail to produce symptoms, while not
a few reach sufficient bulk to cause atrophy of adjacent nerve tissue. Weil
removed at operation a lipoma, 10 X 10 X 4 cm. from the temporal fossa.
Wurth's lipoma of the basal pia extended into the left hemisphere and caused
epilepsy and hemiplegia. From the studies of Bostroem who collected 28
cases it appears probable that most intracranial lipomas originate from epi-
dermal inclusions although no dermal elements have been found in them.
Nippe found a lipoma of the parietal lobe surrounded by gliosarcoma which
he attributed to trauma.

Lipomas may develop in connection with defective development of the
spinal canal and meninges. A series of tumors, some of which were pure
lipoma, others composed of fat, fibrous tissue or cartilage, have been observed
in connection with spina bifida and with scantily developed meningocele
(v. Recklinghausen). Arnold's hairy fibrolipoma of the scalp appears to
have originated from imperfect closure of a cranial suture.

Renal.' — In the kidney small circumscribed multiple lipomas occur be-
neath the capsule or replacing a portion of cortex, or reaching to the medulla.
The structure of these tumors varies. Some of them are composed of pure
fat tissue; others contain considerable fibromatous tissue, so that Virchow
and others have spoken of them as fibrolipoma. In either case the light
yellow translucent color seems, to distinguish them from the more common
struma suprarenalis of Grawitz, which is opaque and of an orange tint.
In not a few cases smooth muscle-tissue has been found in such tumors and
Selter, Lubarsch, and Manasse have described them as myofibroma; while
in other cases sarcomatous features are observed as in the case of Mliller's
(myoliposarcoma). I have observed a very large liposarcoma of this
type, in one lobe of which xanthomatous changes were pronounced. Borst
and Selter describe symmetrical lipomas of the kidneys chiefly of the upper
half of the organ. In Borst's case double myolipoma was associated with
nbro-muscular tumors of the same portions of both kidneys. All these
features point to a congenital and embryonal origin of these tumors, but the
exact nature of the embryogenic disturbance is undetermined. That they
may be connected in some way with Grawitz' struma suprarenalis is indicated
by the presence of adrenal tissue in Muller's case, and by the occurrence of
curious, complex, chiefly liposarcomatous tumors of the kidney, in one of which

LIPOMA 179

I have observed areas of perithelioma mingled with liposarcomatous tissue.
Somewhat similar myolipomatous growths occur along the spermatic cord.

Partial or complete replacement lipomatosis of the kidney has been ob-
served in a series of cases reported by Lacrampe-Loustan. Rayer and Ep-
stein have described such cases in which no trace of renal tissue remained while
the intact capsule of the organ inclosed pure fat tissue. Selter called atten-
tion to the fact that in most of these cases a single large calculus occupies the
renal pelvis. The proliferation of fat begins in the pelvic adipose tissue,
and follows atrophy of the renal parenchyma.

True pelvic lipomas probably develop from such capsular tumors which
early project into the cavity. Warthin described a very large peduncu-
lated intrapelvic growth over which the mucosa and atrophic kidney tissue
was widely stretched, while a tongue-like mass extended several inches into
the ureter.

Perirenal lipomas containing connective tissue, mucoid areas, and often
sarcomatous areas occur in infants and adults and may reach very large di-
mensions. In advanced stages they pass as retroperitoneal lipomas. Lau-
wers describes a tumor arising at birth and reaching a weight of 6 Ib. at seven
years. Windle's liposarcoma weighed 50 Ib. Adami described two very
large tumors composed of adult fat tissue with cellular stroma. The growth
is usually slow but with sarcomatous structure the progress maybe rapid and
recurrence is frequent.

Gastrointestinal.- — In the gastrointestinal tract lipomas are of rare occur-
rence. They arise from the submucosa and from the appendices epiploicae
of the colon. Dewis collected 44 cases in nine of which the tumor was expelled
spontaneously while intussusception occurred in 21. The subserous lipomas
may be worked loose in the peritoneum. Ehrlich has collected 52 cases of
intestinal lipomas. In the gastric submucosa small fatty tumors may occur.
I have observed a large fatty tumor 4X 10 cm. surrounding the appendix
which was the seat of chronic suppuration. Very large retroperitoneal
lipomas have been observed. (Madelung, Waldeyer, Adami.)

Mediastinal.- — In the mediastinum localized overgrowth of fat tissue is
not unknown, especially in alcoholic and obese subjects. True lipomas of
the mediastinum may reach large dimensions and cause pressure symptoms
from the thoracic organs. Arising from many different points in the sub-
pleural fat, mediastinal lipomas may project into the pleural cavity or along
the intercostal spaces (Rokitansky). Or the growth may perforate the
chest wall and appear externally in the back (Czerny), beneath the breast
(Gussenbauer) or on the front of the chest (Cruveilhier, Conner). In the
writer's case the tumor encircled nearly all the structures in the thorax.
In Fitz's case there was congenital hypoplasia of the left lung. Carless
observed a large lipoma of the thyroid region of which the pedicle was traced
into the mediastinum and which was associated with other multiple symmet-
rical lipomas. I have seen one mediastinal liposarcoma with tumor fragments
in sputum and metastasis in deltoid muscle.

Cardiac. — In the heart lipomas have been described by Ribbert, Orth,
Petrocchi, Spalty, Hagedorn and others. They may originate in misplaced
islands of epicardial fat tissue. Dittrich's tumor was congenital.

Uterine.- — In the uterus Orth has observed a polypoid lipoma and Wer-
kel two intramural lipomas, while lipomatous areas of mixed tumors of the
uterus are described by Gebhart. Pollak thought his intrauterine lipoma
originated from a portion of omentum protruding into a wound of the uterus.

Myelogenous.- — A true lipoma of the marrow of the fibula in a young girl
has been recorded by Wehrsig.

CHAPTER XIII
CHONDROMA

Localized overgrowth of cartilage occurs in several forms between which
it is sometimes difficult to draw sharp distinctions. Limited outgrowths
of preexisting cartilage occur on the ribs, in the larynx, and about joints,
which exhibit the characters of a simple hyperplastic process, and are called
ecchondroses. True progressive neoplasms composed of cartilage appear
in the same situations and also in tissues not normally containing cartilage
and these are called chondromas or enchondromas. That many ecchondroses
possess some of the properties of tumors is indicated by the occasional
occurrence of large chondromas as a sequel of ecchondrosis. Thus chondro-
mas as large as an apple occur at the chondrosternal junction. In a case
of Weber's there was striking symmetry in the location of multiple chondro-
mas and ecchondroses.

Virchow classed as ecchondroses the smooth diffuse outgrowths of
permanent cartilage, and as enchondromas the large circumscribed lobulated
tumors of transitory cartilage. Between these main classes are many
intermediate forms which display more or less clearly the neoplastic qualities.
The ecchondroses are usually small, multiple, smooth and nodular or
diffuse outgrowths of preexisting cartilage. After reaching a certain stage
their growth tends to culminate, often with the natural growth of cartilage
in the body, after which they may remain quiescent or undergo secondary
changes, chiefly calcification or ossification. Amyloid deposits may also
occur.

In structure the ecchondroses copy normal hyaline and fibrocartilage
according to their points of origin, and show few of the atypical features
of true chondroma. They are usually surrounded by normal perichondrium
from a portion of which, according to v. Rindfleisch, they originate.

Ecchondroses are not extremely common but rather widely distributed.
The most familiar examples occur at the costochondral junctions where
they appear as smooth multiple nodular swellings which tend to calcify or
ossify. Virchow and others believed that these and most other ecchondroses
were a sequel of rickets and this origin probably applies to the ecchondroses
arising in early life and soon tending to calcify.

A well-known form of ecchondrosis appears on the inner surface of the
symphysis pubis, and may reach such dimensions as to obstruct labor
(pelvis spinosa). About the epiphyses of any of the long bones small nodular
outgrowths of cartilage may appear.

Localized cartilaginous outgrowths of the cricoid and thyroid cartilages
have been described by Virchow and many later writers. They project
inward with deformation of the larynx but with rare exceptions do not
obstruct breathing. The entire cricoid cartilage may be diffusely thickened
by multiple ecchondroses. From the upper and lower surfaces of the tracheal
rings multiple cartilaginous nodules may develop. They are connected
with the rings by strands of fibrous tissue or perichondrium, and they may
become so numerous as to cause fusion of many adjacent rings (Virchow,
Recklinghausen, Mischaikoff) . Ecchondroses usually of small size develop
from the intervertebral discs and project outward or into the spinal canal.

180

CHONDROMA 181

In the joint cavities multiple ecchondroses are a frequent result of chronic
arthritis with osteochondritis. The modes of origin of these growths and
the manner in which they become detached, forming joint mice, have been
exhaustively discussed by Virchow.

Enchondroma. — The true chondroma is a rather common tumor, the
varied features of which, perhaps more than any other benign tumor, il-
lustrate the peculiarities of neoplasms. This result is perhaps dependent
upon the facts that cartilage is essentially an embryonal and transitory tissue,
and that cartilage cells although encased in a firm matrix have rather active
proliferative powers, possess ameboid properties and are readily subject
to metaplastic changes. For the most striking display of these characters
one must pass to the tumors of lower animals with which chondromas are
more common than with man.

The chondroma produces a hard, rounded, lobulated tumor which often
reaches large dimensions. The lobulated structure is referred to the expan-
sive growth from multiple centers, as a result of which the surrounding tissues
are pressed aside. In this way large tumors may form, composed of con-
voluted masses resembling the convolutions of the brain. Such growths are
commonly encapsulated by perichondrium and are cartilaginous throughout
at all stages. Other chondromas are imperfectly encapsulated, encroach
upon surrounding tissues as a malignant tumor, and invade blood-vessels.
In such cases one finds many stages of the formation of the perfected cartilage
from more cellular tissue, the nature of which is not always clear. The
nutrition of the solid chondromas is maintained by a system of lymph
spaces from the periphery. Rindfleisch and Borst have traced a rich system
of lymphatics from the periphery of a submaxillary chondroma and com-
municating with the pericellular spaces. Through most of these growths
there are irregular bands of connective tissue carrying blood-vessels and this
feature becomes pronounced as the tumors tend to calcify or ossify. About
many chrondromas there is an excessive development of blood-vessels to
which Virchow and v. Recklinghausen ascribe an important and primary
influence in the development of the tumors. Such growths have been termed
angiochondroma and a few of them have been deeply pigmented by diffusion
of extravasated blood pigment (Siegert).

The capsule of subperiosteal chondromas may consist chiefly of the
thickened periosteum which may go on to produce bone, and a bony capsule
may surround chondromas developing in the marrow cavities.

While most chondromas are solid, many become softened by mucinous
degeneration, and cysts filled with mucinous, serous or fatty material may
form. The skin over a chondroma may atrophy, and ulceration, excavation
of portions of the tumor, and suppuration may be established. Although
the chondromas are usually localized and benign they sometimes grow
extensively in the blood-vessels, filling the lumen with nodular or solid masses
and extending over wide areas. In a case reported by Ernst a chondroma
of the lumbar spine invaded many of the abdominal and" pelvic veins, traveled
up the vena azygos and vena cava, filled the right ventricle and continued
into the pulmonary artery. Discontinuous metastases also occur especially
in the lungs, occasionally in the lymph-nodes.

The multiple character of certain chondromas has been a striking feature,
and in some cases nearly every bone in the body has been affected. In
the notable case reported by Recklinghausen, the hands, feet, knee, elbow,
and ribs were the seat of very numerous chondromas.

The location of skeletal chondromas is usually in the diaphyses of the
bones near the epiphyses. They may project externally, pushing outward

182 N EOF LA STIC DISEASES

the periosteum, or growing in the medullary cavity they distend the cavity
and are surrounded by the thin bony shaft.

The structure of chondromas reproduces that of the various normal
types of cartilage, chiefly the hyaline variety. Ranvier classified chon-
dromas, according to their structure, in four groups, (i) A single lobe of
hyaline cartilage. (2) Several lobules of hyaline cartilage separated by
fibrocartilage. (3) Fetal cartilage. (4) Cartilage with stellate cells.
The cells may be more or less numerous than in normal cartilage. They
vary greatly in size and usually lack the orderly arrangement into groups of
cells with opposed surfaces flattened. Peculiar vacuoles are common in
these cells and were described by Virchow under the term "physaliden."
The cells are usually rounded and lie in distinct spaces, but with imperfect
formation of chondrin matrix they become stellate with mucinous degenera-
tion, fusiform as they approach the connective tissue type, calcine granules
may be deposited in them, and in some cases they show all transitions up to
the bone cell in osteoid and osseous areas. The cells usually contain glycogen
and fat granules and well-marked fatty degeneration may occur.

The growing cells of a chondroma are not as a rule those inclosed in the
matrix but rather those on the periphery of the tumor. The matrix of the
chondroma is usually hyaline, but may be fibrillated or may contain elastic
fibrils. Ernst noted" very active production of the elastic fibrils in a rapidly
growing tumor. The matrix is not an integral part of the cells but a product
which is deposited under cellular influence (Ribbert). The chondrin is
usually deficient and irregularly distributed and various types of secondary
change are frequent.

Calcification with the deposit of phosphate and carbonate of lime affects
first the matrix, producing an irregular network of densely basic staining
material which is composed of granules compacted together and becoming
homogeneous. The borders of the cell spaces may be first affected and from
this point the deposit appears in the cells so that in advanced stages both
matrix and cells may become heavily incrusted. In such areas the cells
assume a stellate form approaching the character of bone cells.

Ossification of chondromas occurs under several conditions. An im-
perfect formation of islands of bone may take place at different points
throughout chondroma, this change being preceded by increased vascularity
of the septa, and by calcification and final ossification.

More often the connective tissue in and about the chondroma having
first laid down cartilage goes on to replace it by trabeculae of well-formed
bone surrounded by typical osteoblasts. In this process the normal events
in the production of bone in cartilaginous matrix take place.

About central chondromas which invade the shaft of a bone the peri-
osteum may be incited to the production of a bony capsule which is of
inflammatory origin and not a part of the tumor.

In many chondromas the formation of cartilaginous matrix is imperfect
and a simple hyaline or partly fibrillated or mucinous material takes its
place. This imperfect chondrification is much more common than any
form of softening of chondrified matrix. In the soft matrix the cells may
attain large size and lie in very large round spaces, or, in myxochondroma
they become stellate and the matrix fibrillated. Some of the soft chondromas
are composed of a shell of perichondrium from which spring papillary fringes
of poorly chondrified cartilage while the central portions are filled with
mucinous fluid (cystic, papillary chondroma).

Distinctly malignant cartilaginous tumors, chondrosarcomas, occur in
several forms. Medullary chondromas may perforate the shafts of long

CHONDROMA

183

bones and destroy the epiphyses, proving malignant from mechanical fac-
tors. Infiltrating chondromas in which very cellular peripheral portions
invade surrounding tissues and produce nodules of cartilage are properly
called chondrosarcoma. There is a considerable group of chondromas occur-
ring in mixed tumors and teratomas, which are usually very cellular,
containing other tissues besides cartilage, and which invade tissues, lymph-
nodes, and blood- and lymph-vessels. Invasion of veins is not confined to
the embryonal or teratoid chondromas, for in Virchow's case of tumor of
fibula and in Ernst's case of fibrochondroma of spine there were extensive
intravascular growths, while the pelvic chondromas in several cases have in-
vaded blood-vessels and lymphatics (Foerster, Weber, Biesiadecki). In

FIG. 39. — Structure of the wall of a cystic chondroma.

this group the malignant properties are often out of proportion to the cel-
lular quality. In a group of sarcomas of long bones composed of cartilage,
bone, and cellular tissue, the local destructive effects and recurrence after
operation lead to their designation as osteochondrosarcoma.

While in general the more cellular and softer tumors, as myxochondroma,
are the more malignant, both clinical and histological features should be
regarded in applying the term chondrosarcoma. The metastases of chon-
dromas exhibit most of the characters observed with other malignant tu-
mors and a special capacity to invade the large veins must be ascribed to
them. Invasion of the lymphatics also occurs. The structure of these
invasive chondromas does not always suggest malignancy. In Ernst's case
the intravascular cartilage was provided with firm hyaline matrix, but this

184

NEOPLASTIC DISEASES

tumor did not produce embolic nodules. To account for the invasive prop-
erties one must assume that the active growth and infiltrative properties
reside in the undifferentiated cells of the periphery of the cartilaginous nod-
ules and in some cases extensive continuous growths in vessels and embolic
metastases have consisted almost exclusively of such undifferentiated cells.
By such changes a chondrosarcoma may lose much or possibly all of its chon-
dromatous character. This possibility also suggests that certain tumors
originating from the mother tissue of cartilage may never show pronounced
chondromatous features but appear as simple sarcoma or myxosarcoma.
Certain nasopharyngeai sarcomas (polyps) are probably of this character.

Etiology. — The majority of chondromas occur in early life and about
puberty. Some are congenital, and multiple chondroma of the spine is
hereditary and congenital. Many of them are located at the growing ends
of bones and in not a few there is a distinct tendency toward standstill and
regression at the period when the development of the skeleton is complete.
All of these facts point to an origin from disturbances in development of the

FIG. 40. — Island of superfluous cartilage in periosteum of rib. (E. Muller.)

cartilaginous elements in the formation of bones and joints. An inherited
predisposition has been emphasized by Weber, who observed many chon-
dromas and ecchondroses in several members and three generations of the
same family. In the French family of Pellerin members of three generations
were affected with multiple chondromas of tibia, ribs, and humerus (Ernst).

Virchow, Recklinghausen and many others have shown that rickets is an
important factor in the disturbance of the growth of bones that leads to
chondroma. Borst has found widely misplaced islands of cartilage in ra-
chitic bones and believes that these may give origin to chondroma of limited
growth, but doubts the general applicability of the rachitic theory of skele-
tal chondroma. Ribbert also fails to find in this theory a sufficient ex-
planation of any large group of chondromas and thinks the disturbance must
result from some unknown fetal disorder of the bones. E. Miiller has de-
scribed superfluous islands of cartilage in the periosteum of the ribs and sug-
gested that these structures may be the source of chondromas.

In the remarkable case of Recklinghausen's in which multiple chondromas
of feet and hands were associated with angioma, the author assumed that
congenital aplasia of the blood-vessels subsequently leading to passive dila-

CHONDROMA 185

tation and angioma, prevented the normal progress of replacement of car-
tilage by bone and resulted in overgrowth of cellular cartilage. The tumors
ceased to grow at 22 years.

For the large group of distinctly heterologous chondromas of breast, pa-
rotid, neck, uterus, etc., various embryonic disturbances must be assumed to
exist, in most of which complex masses of tissue are involved. Chondroma
of the sex glands results from the one-sided development of teratomas and
it is probable that in other localities certain chondromas have a similar origin.

Trauma and inflammation are frequent causes of ecchondroses, and
trauma is not infrequently reported as preceding chondroma and chondrosar-
coma (50 per cent. Weber), especially of the long bones, in which cases it
must be assumed that there is also a local or general predisposition.

Clinical Types of Chondroma.- — The skeletal chondromas are the most
frequent forms of this tumor. They occur most often as single or multiple
tumors of the hands and feet but may affect any of the bones (Nasse, Lit.).
They arise from periosteum or in the medulla, usually near the diaphysis
and regularly before puberty, tending to become stationary at that period.
They deform the shafts of the bones and the joints. From the pelvic
synchondroses they may grow to very large size, a case of Weber's having
reached a diameter of two feet. These tumors as well as the pubic ecchon-
droses may obstruct labor. In a girl of 15 years Pfeiffer observed a pelvic
chondroma which measured one meter in circumference and weighed 27
pounds. Most of these large pelvic tumors have shown rapid growth
(Ernst).

Pronounced cases of multiple osteochondroma represent a somewhat
specific malady which is probably related to chondrodysplasia and other
disturbances in the growth of bone (Ashurst, Lit.). It is responsible for a
variety of skeletal deformities, as depicted by Hagen. The disease some-
times exhibits hereditary tendencies, being transmitted by affected males
and females and by unaffected females. The tumors may appear at birth,
or be delayed until the 5oth year, and one tumor may be growing while
another is regressing. There is generally a limit of growth about puberty.
The growth of the long bones may be so inhibited that the subject is dwarfed.
Growth of radius over that of ulna may produce a deformity resembling
dislocation of the radius, and growth of tibia over fibula results in pes valgus.
The :v-ray shows osteoporosis of the ends of the bones, and often a cystic
appearance, while the compact bone of the ends of shafts may be very
deficient. At various points, usually about the joints, the multiple
outgrowths appear. The structure shows a persistence and overgrowth of
poorly ossified or calcified cartilage, in which the cells are irregular in size
and form (Carman, Fisher). The ordinary epiphyseal line is irregular or
obliterated. Late ossification leaves the bone deformed and covered with
osteophytes. Lenormant collected a series of cases in which osteosarcoma
appeared to develop on the basis of the early lesions.

Chondroma of the scapula arises from various portions of the bone, and
exhibits the structure of the benign chondroma or that of chondrosarcoma,
often myxomatous. The great variations in the structure and course of these
tumors is fully presented by Deganello in a study of 39 cases. Osteoid
chondroma is a peculiar form of skeletal chondroma arising beneath the
periosteum of the long bones. As the growth enlarges the bone assumes a
thickened spindle form. The structure is that of hyaline acidophilic osteoid
tissue in which the cells approach the form of bone-cells, and true bone may
form in them. Many of the osteosarcomas correspond to this description.

186

N EOF LA STIC DISEASES

Virchow describes an extensive case, largely ossified, arising in the soft
intercostal tissues and producing metastases in the lung and pleura.

Branchio genie chondromas occur in the neck from misplaced islands of
cartilage derived from the branchial clefts. They are located in and about
the sternomastoid ligament and muscle with branchiogenic cysts and fistulas,

FIG. 41. FIG. 42.

FIG. 41. — Multiple congenital ecchondroses in a negro girl of n years. (After Ashurst,
A. S., 63.)

FIG. 42. — Multiple congenital osteochondroma. X-ray photograph of bones of forearm.
(After Carman and Fisher, A. S., 61.)

and near the parotid gland. Zahn has collected twelve cases in which mis-
placed islands of cartilage were discovered in this region, and Bidder observed
a congenital tumor arising from such an island. Recklinghausen's chon-
droma of the thyroid may have arisen from such a tissue rest. Symmetrical

CHONDROMA

187

islands of cartilage and bone have been found in the tonsil but do not seem
to have given rise to tumors (Deichert).

An auricular chondroma is described by Virchow as springing from a
misplaced portion of the fibre-elastic cartilage of the ear.

The chondromas of the hyoid region described by Boeckel and Spisharny
seem to have been connected entirely with abnormalities of the hyoid bone.
The various embryological disturbances giving rise to cysts, rests, and tumors
in this region will be discussed elsewhere.

Chondroma of the respiratory tract occurs in the trachea, bronchi, and
lungs, apparently arising from the same structures that lead to ecchondroses.
Virchow has described multiple chondromas of the lung, located at the root,
in the parenchyma and on the pleura. While often purely cartilaginous, they

FIG. 43. — Structure of multiple osteochondroma. Section through outer bony shell. A,
Hyaline cartilage with atypical cells and calcium deposit. B, bone trabeculas. C, mucoid
connective and fat tissue. (After Carman and Fisher.)

may become calcified or ossified. In the lung rare tumors occur as multi-
lobed growths of hyaline cartilage, subpleural or deep within the lobe, and
their association with connective and fat tissue points to an origin for some
of them from a complex mass of tissue. In Siegert's case the chondroma
projected from the bronchial wall into a dilated bronchus. Chronic thicken-
ing of the pleura may yield flat plates resembling cartilage but composed of
hyaline or calcified connective tissue. Yet Kramer has described a lobulated
chondroma of the pleural surface of the diaphragm.

In the breast pure chondroma is occasionally observed but more often the
cartilaginous growth is a portion of a mixed tumor usually of epithelial
type.

It is commonly assumed that in all instances these tumors arise from
isolated masses of tissue which include a skeletal portion giving rise to the
chondroma, but the correctness of this view is not demonstrated. It is
possible that some of the cartilaginous tumors arise by metaplasia of other

188 NEOPLASTIC DISEASES

tissues. In the dog a large proportion of mammary cancers contain cartilage
and the histological structure strongly suggests its formation by metaplasia
from other tissues. Williams has collected many reports of cartilaginous
and bony tumors of the breast and argues in favor of the origin from mis-
placed masses of complex tissue.

In the uterus, especially in the cervix, cartilaginous and bony tumors
are occasionally observed (Williams, Lit.). It seems probable that they arise
from misplaced islands containing skeletal tissue. Thus Meyer found a
bony nodule in the cervix associated with a remnant of the Wolffian duct.
Miller found an osseous tumor replacing the corpus in a subject in whom
the vagina was absent. In several uterine myomas cartilage has been found
(Williams).

In the mixed tumors of the salivary glands cartilaginous areas are very
common, and especially in the submaxillary the tumor may be nearly pure
chondroma. Here the cartilage is of imperfect hyaline variety and often
of myxomatous type. In recurrences of these tumors there may be a tend-
ency toward elimination of all but the cartilaginous elements. The various
questions that concern these tumors will be discussed elsewhere.

Teratoid chondroma. A considerable group of chondromas, including
many of those which invade the vessels and prove malignant, represent
one-sided development of the cartilaginous portions of teratomas. Most
of these chondromas arise in the sex glands, ovary and more especially the
testis, but with the extensions of the limits of occurrence of teratomas it
seems probable that chondromas of this origin may be more numerous than
now appears. In the testis these tumors are solid or cystic, and other
elements besides cartilage are usually present in abundance. The cartilage
may be reduced to very minute traces which escape detection in many tumors
or tridermal type (Ewing). In several notable cases extensive intravascular
growths and metastases occurred (Paget, Ohkubo, Lit.).

Chordoma.- — A remnant of the chorda dorsalis, a specific entodermal
embryonal tissue about which the spinal column develops, regularly persists
in infants in the centers of the intervertebral discs (Kolliker). It was
shown by H. Mtiller that portions of chorda tissue commonly persist at the
base of the skull and in the coccyx, and that this tissue probably gives
origin to certain peculiar tumors which Virchow first described as ecchondro-
sis spheno-occipitalis. Ribbert found chorda remnants in the bony tissue and
flat plates beneath the dura mater of the Clivus Blumenbachii, and held
that they produced tumors only when misplaced and lying outside the bony
encasement. He found the tumors in about 2 per cent, of a series of
subjects, in the form of bean-shaped masses which perforate the dura and
become adherent to the basilar artery with which they may be torn away in
removing the brain. By careful sectioning he was able to show that the
small intradural tumors are connected by a pedicle with the underlying
bone in which their roots are imbedded. They seldom reach a large size
and being soft do not produce pressure or other symptoms. Yet Grahl
observed a lobulated extradural chordoma of the sella turcica which produced
fatal pressure symptoms. A large chordoma lying in front of the upper
cervical vertebrae has been observed by Klebs. Hassner's tumor measured
5.5 X 6.5 cm. and had produced pressure symptoms for four years.

In structure chorda tissue is composed of groups of large vacuolated
cells lying in soft homogeneous basic staining matrix, and the tumors accu-
rately reproduce this structure. Virchow described the peculiar vacuolated
cells of these growths under the term ecchondrosis physalif ora, and since some-
what similar vacuolation occurs in chondroma, he was inclined to regard

CHONDROMA 189

all of them as chondromas. Although chorda tissue does not produce
cartilage and there can be no transition forms between chondroma and chor-
doma, yet it may at times be difficult to distinguish between them.

Malignant Chordoma.— The exact limits of the occurrence and possible
variations in structure and course of chordoma have not been determined.
It would seem likely that a tissue as extensive as the chorda dorsalis might
persist at various points along its normal location, and that it might give
origin to structures varying from that of the simple chordoma.

Nebelthau has shown that remnants of chorda tissue may occur at several
points along the base of the skull. Fischer has described a malignant chor-
doma arising beneath the dura of the clivus B., invading the spinal canal and
compressing the cord. A small vein was invaded by polyhedral tumor-cells.

£-« •*vZ. :•••-'•

-•••• &

.- :*. *-;;<••••

-'•^?. ;• /. : ss.

r ' -*i •.-:•' <.' V,. -.

FIG. 44. — Sacral chordoma. (From a section received from Dr. Mallory.}

The structure corresponded to that of chordoma but some areas resembled
cartilage.

Link obtained portions of a tumor in the pharyngeal vault, which affected
the internal ear and compressed several cranial nerves and which he believed
arose from the clivus B. Besides the usual chorda-like tissue it contained
groups of polyhedral tumor-cells so that Linck recalls the entodermal origin
of the chorda and discusses the question whether the malignant chordoma
should be called sarcoma or carcinoma. Coccygeal chordomas are described
by Feldmann and Vecchi, and in the latter case the growth recurred after
operation. Albert describes a coccygeal chordoma which involved the
rectal wall and recurred promptly after operation.

The positive identification of chordoma is not readily accomplished. Two

190 NEOPLASTIC DISEASES

common tumors closely simulate or even duplicate the structure attributed
to chordoma — viz., myxochondroma and colloid carcinoma of the intestinal
canal. The gross relations of the tumor should be given first consideration in
the diagnosis. Especially in the sacral region chordoma is difficult to separate
satisfactorily from chondroma or colloid carcinoma. Feldman analyzes in
detail the features which distinguished his tumor which eroded the sacrum,
from colloid carcinoma, but I have seen all these features, except the broad
attachment to the sacrum, in colloid carcinoma of the rectum. In the
pharyngeal region atypical chondromas are rather common and must be
considered a more probable occurrence than chordoma.

CHAPTER XIV
OSTEOMA

Circumscribed overgrowth of bone occurs under such a wide variety of
conditions and the distinctions between inflammatory and neoplastic hyper-
plasia of the tissue are so often obscure that it has never been possible to
exactly define the limits of osteoma. True progressive neoplasms wrhich
adhere to Virchow's criteria and in which bone is the essential and not the
secondary or accidental product, are not common, but chronic processes
which result in bone formation from trauma, inflammation and disturbances
of nutrition are numerous. Volkmann concluded that all exostoses that
arise from cartilage are true tumors, others not. Borst, who separates from
the tumors all the bone-producing processes which are self-limiting or clearly
associated with trauma and inflammation has little to say about true osteoma.
Virchow and Ribbert largely agree in recognizing neoplastic qualities in many
processes in which trauma and inflammation are originally concerned, and
which, whether true tumors or not, illustrate the complex etiology of
neoplasms.

Bone formation in necrotic tissue (brain, eye, kidney, aorta) ; in the floors
of ulcers; in the course of syphilis, tuberculosis and chronic suppuration in
and about bones; after fractures, in chronic arthritis; at the insertion of the
overused tendons; in bursae; in the muscles of riders — are some of the proc-
esses in which neoplastic qualities are least prominent. Yet in all of them
the size of the resulting bony mass, the long duration of the process, and its
eventual independence of the original exciting factor occasionally reveal
definite neoplastic characters. Hence in discussions of osteoma it is custo-
mary to include all forms of overgrowth of bone, thus securing an effective
comparison of true and partial bony neoplasms.

Histological study fails as a rule to distinguish simple hyperplastic
growth of bone from true osteomas. When originating in bone both processes
show a participation of some or many osteoblasts which surround the edges
of the newgrowth and add to its substance from one or many sides. Both
processes yield dense lamellated bone with few Haversian canals or spongy
bone with many vessels and abundant marrow spaces and cells. Bone
forms in connective tissue without the appearance of many osteoblasts,
the fixed cells being passively incorporated in osseous matrix, but this
character does not always distinguish self-limiting from extensively pro-
gressive osteosis.

The gross and clinical features seem to form the best criteria by which to
separate osteoma from simple hyperostosis.

Spontaneous or traumatic but non-inflammatory origin, progressive
course, circumscribed form, active participation of osteoblasts, and derivation
from cartilage, are features which are more prominent in true osteoma,
while an inflammatory origin, self-limitation, multiplicity, diffuse form,
reduced numbers or absence of osteoblasts, and origin from connective or
other soft tissues, belong to the less definite or spurious bony neoplasms.

Terminology. — Osteoma is the term applied to tumors composed of bone.
Strictly speaking, it should be limited to true neoplasms.

191

192 NEOPLASTIC DISEASES

Exostoses are circumscribed masses which project above the bony surface.

Enostoses lie within compact or cancellous bone.

Hyperostoses are more diffuse enlargements of bone. Osteophyte is the
general term applied to inflammatory periosteal bony deposits.

The new tissue may be ivory-like with solid lamellae with few or no
Haversian canals (extososis eburnea) ; or spongy with cancellous tissue (ex-
tososis spongiosa); or it may contain wide marrow cavities or spaces (ex-
tososis medullaris). The growth may affect bony structures or other tissues,
and is thus hyper plastic or hetero plastic.

The osteophyte is an inflammatory cortical or supracortical deposit of
bone from the periosteum. It appears as a flat, often extensive plate
or more circumscribed mass deposited on preexisting bone from which it
may usually be detached. Microscopically it consists of many small islands
and thin trabeculae of bone lying in the cellular and vascular connective
tissue of the thickened periosteum and continuous with the preformed bone
from which it springs. Many stages of the process of ossification are visible
in early cases.

Any area of periosteum which is affected by chronic inflammation may
produce osteophytes. They are most frequently observed on the shafts of
long bones; in the neighborhood of chronic sinuses or ulcers; as a prominent
feature in the course of chronic arthritis; on the maxillae about inflamed teeth;
and beneath the dura of the frontal or occipital bones in gestation.

The course of inflammatory periostea! bony deposits varies with their
etiology. Most cases reach a standstill as the inflammation subsides, leaving
deformities and interference with function. Ankylosis of joints may result.
In not a few cases osteophytic growth seems to have led to progressive over-
growth and the production of extensive tumor-like processes. In the case
of Forcade's son, cited by Virchow, suppuration in the lachrymal region led
to progressive enlargement of many bones of the face and skull continuing
for 33 years, and resulting in extensive leontiasis ossea.

Hyperostosis. — Diffuse hypertrophy of large portions of bones, or whole
bones, or several bones, occurs under many conditions. The most familiar
form of hyperostosis results from osteomyelitis, periostitis, and arthritis.
While the hypertrophies of this class may be extensive they are readily
separated from neoplastic growths. In acromegaly there is diffuse over-
growth of bones of skull and extremities resulting from disturbance of func-
tion of the hypophysis (leontiasis ossea). The old and frequently cited case
of Sancerotte of general leontiasis ossea is unique but of uncertain nature.
The bones of the face and skull are specially prone to diffuse enlargement
from local factors, trauma, inflammation, and rickets, and not all cases of
craniosclerosis can be referred to acromegaly. Virchow collected many
cases of diffuse enlargements of temporal, sphenoid, maxillary, and malar
bones, and head of femur, apparently resulting from varied causes, not dis-
tinctly inflammatory. He considered these overgrowths of bone as com-
parable to elephantiasis of the skin and lipomatosis.

Exostoses. — The circumscribed tumor-like masses projecting from the
surface of bones and intimately connected with the shaft, present a varied
form, course, and etiology. They are flat or tuberous, nodular, globular, or
pointed or ragged growths, which appear in many striations, at epiphyseal
junctions or on the shafts of long bones, and at the insertions of tendons and
fascia. They are flat, smooth and ivory-like as is usually the case with
exostoses of the skull (ex. clavata) ; or spongy with cancellous spaces com-
municating with those of the shaft. The porous exostoses may later become
solid. They are usually multiple, often symmetrical, and some notable cases

OSTEOMA 193

are recorded in which there was a prominent hereditary tendency transmitted
through the males (Heymann, Reinecke). In a case of hereditary multiple
exostoses E. Miiller found very numerous islands of cartilage in the perios-
teum of long and flat bones.

In advanced forms the general development of the bones has been retarded
and even dwarfism has occurred (Virchow). As a rule exostoses occur in
young subjects before puberty during the period of active growth of the
bones (exostoses de croissance).

Exostoses usually arise from overgrowth of subperiosteal bone and these
must be attributed to an irritation affecting the periosteum. Yet the entire
thickness of the shaft may be involved and new cancellous spaces of the
exostosis communicate with the old. Or the newgrowth may lie within the
bone shaft or marrow cavity (enostosis). In other cases the process is
entirely superficial and periosteal and some of these may lie within the perios-
teum and apart from the shaft (parosteal exostosis). Trauma, with or with-
out misplacement of a fragment of periosteum, or fracture, is often the ex-
citing cause of such growths. About the ends of long bones portions of
cartilage may be found in exostoses (ex. cartilaginea). An origin from a
misplaced island of cartilage is probable, and may be referred to trauma,
rickets, or preexisting ecchondrosis. Microscopically exostoses usually begin
with proliferation of the inner vascular layer of the periosteum and the forma-
tion of a network of osteoid tissue. This matrix may at once become eburn-
ated, or vascular channels may persist and the tissue remain spongy. The
underlying bone becomes sclerosed and fused with the newgrowth, or it
becomes rarefied and the adjacent marrow spaces communicate with those
of the exostosis. According to Virchow the former process may be called
histioid, the latter organoid.

Clinical Groups of Exostoses. — The largest class of exostoses are those
which form at the ends of long bones and are connected with disturbances of
growth. They are multiple, tend to grow less rapidly as the subject reaches
puberty and rarely they may spontaneously disappear (Hartmann). The
long bones, the vertebrae, pelvis, scapula and the skull are the chief sites
affected. Partly cartilaginous exostoses occur about joints and may possess
a synovial covering which is derived from and may communicate with the
joint (exostoses bursata) . Some of these are probably originally intra-articular
and gradually become separated from the joint cavity (Bergmann, Volkmann).

Multiple exostoses occur on the bodies of the vertebrae and involving the
intervertebral discs. In the cervical region they may produce palpable
tumors.

Traumatic exostoses constitute a well-defined class. They occur at the
seat of fractures when excessive callus forms and after single or repeated
trauma of the periosteum or bone and along the alveolar borders after ex-
traction of teeth. Virchow cites two cases where broken splinters of bone
hypertrophied, forming exostoses of moderate size. The great toe is the seat
of a subungual exostosis which may occasionally develop into a true osteoma
or osteochondroma. Continuous mild trauma is also responsible for the
discontinuous exostoses which form in the deltoid in soldiers where the gun
rests on the shoulder, and in the adductor muscles of riders.

In nearly all these situations occur larger growths with more distinct
neoplastic characters suggesting that the small exostoses may occasionally
give origin to true osteomas.

In the trachea Ribbert and Mischaikoff have fully described the multiple,
round, flat or ragged nodules and plates of bone which grow in the submucosa,
and have found that most of them, like the tracheal ecchondroses, are con-
is

194

NEOPLASTIC DISEASES

nected with the perichondrium of the tracheal rings. In a very advanced
case described by Heyman, with extensive ossification in the larynx, there
were many bony masses with marrow spaces throughout the trachea.

TRUE OSTEOMA

Osteoma of Facial Bones and Antra.— The bones of the face are the seat
of a variety of bony overgrowths which are difficult to classify.

In the maxilla osteosclerosis and hyperplastic bone formation occurs? *in
connection with dislocated and inflamed teeth producing exostoses or enos-
toses, or hyperplastic masses some of which project externally or into the
antrum of Highmore. Many of these must be regarded as inflammatory,
while others are true'osteomas,

«•

FIG. 45. — Growing osteoma of antrum.

In the orbit bony growths arise from any of the bones of this cavity, usually
from the upper and inner segment.

They not infrequently appear as congenital tumors in young girls.
Virchow concluded that they arose as enostoses of the orbital wall 'and grew
either into the orbit or nares or into the cranial cavity. He described four
cases, in some of which cysts were found lined by ciliated epithelium. Many
bony tumors have been described as arising from the ethmoid, frontal, and
superior maxillary bones, projecting into the cranium, nares, frontal sinus,
or antrum of Highmore.

LaGrange has collected 148 cases. Their origin appeared to be from the
periosteum or, as Lesser states, from embryonal cartilaginous portions of the
ethmoid. Projecting into the sinuses they present a covering of inflamed

OSTEOMA

195

and often cystic mucosa (Panas). The chief site is the upper inner wall
of the orbit. They may penetrate the skull, but seldom cause grave cerebral
symptoms, while only two such cases were fatal. Knapp has reported two
enucleations, in one of which the growth was broadly attached over the upper
wall of the orbit.

Osteoma of the frontal sinus is believed to arise from fragments of carti-
lage connected with the ethmoid. It produces a characteristic swelling over
the orbit and progresses steadily until extirpated. Its structure is usually
solid and lamellated. Most of the osteomas of the nares and antrum of
Highmore also arise from the ethmoid (Bornhaupt). Tillmanns collected
several cases in which these tumors were found loose in the nasal cavity or
antrum (dead osteoma).

FIG. 46. — Osteoma of orbit. (After Knapp.)

Secondary Osteoma. — Osteoma occurs as an 'element in many other
tumors where it appears as a result of secondary ossification of the connective
tissue. Here it may signify a terminal product in a series of transformations
of the tissues of fibroma, lipoma, sarcoma (Borst). In periosteal fibroma
bone is a natural end product of the growth (fibro-osteoma).

In certain cases it represents an integral part of a mixed tumor. In' the
common breast tumors of dogs, bone formation may be very active and ex-
tensive, producing complex osteo-chondro-carcino-sarcomas. In the ovary
osteoma occurs in several forms ( Kroemer, Lit.) . True bone with periosteum
and marrow spaces is observed in connection with dermoids and teratomas.
Ovarian stones composed of a thick shell of bone about a central cavity arise
from ossification of cysts, some of which are from corpora lutea. They are
usually preceded by active inflammation. Metaplastic bone formation
occurs in ovarian fibromas and chondromas, either in small foci or throughout
the tumor.

196 NEOPLASTIC DISEASES

Osteoma in the Nervous System. — In a considerable portion of cachectic
subjects, especially of the insane and epileptic, there are multiple nodules of
bone in the cerebral or spinal arachnoid. Zanda finds that these nodules
form about small vessels through degeneration, exfoliation and sclerosis of
endothelial cells and connective tissue, which form hyaline, then osteoid and
finally bone tissue. From these nodules or over large areas, especially in the
falx cerebri and cerebral and spinal dura, larger masses of bone may form
with cellular and fatty marrow spaces, yielding bony plates which are smooth
and incorporated in the dura externally, and rough internally where growth
progresses (Zanda, Ziegler, Borst).

Larger tumors compressing the brain or cord and lying within the brain
tissue or arising from the membranes have been described by several authors
(Virchow, Meschede, Ebstein, Bidder, DeVecchi).

The intracerebral growths were referred by Virchow to osteogenesis by
the glia-tissue. Some are associated with encephalitis with softening.
Others doubtless originate from misplaced islands of the bone-forming matrix
of the dura.

Heteroplastic Bone Formation. — In heteroplastic bone formation the
process begins either in a cartilaginous or a fibrous matrix. The cartilage
becomes more vascular and ossification occurs about the small vessels through
the activities of osteoblasts. In connective tissue the stroma becomes
hyaline, calcification occurs under the influence of osteoblasts with the
appearance of osteoid and finally osseous tissue. Here one must conclude
that the process is metaplastic, the fibroblasts acquiring the function of
osteoblasts.

Several factors may be regarded as tending to call forth osteoblastic
properties in fibroblasts.

1. Proximity to Bone. — Some authors have assumed that bone formation
always results from osteoblasts that have wandered out from periosteum
(Busch). In myositis ossificans this theory finds a certain support as the
process begins in the periosteum.

2. The presence of calcific deposits figures in many instances of ossification
of necrotic tissue.

3. An active productive inflammation with organization of dead tissue and
blood-clot, is probably essential in the ossification of muscle-tissue after
trauma (Busse, Berndt, Rapke, Lit.).

4. A special predisposition to calcification and ossification, possibly con-
nected with disturbance of calcium metabolism, must be assumed to exist
in certain cases, notably in those of reticulated osteoma of the lung.

In many cases heteroplastic -bone formation occurs without the appear-
ance of many osteoblasts, the fixed cells being passively incorporated in
osteoid and osseous matrix.

Clinical Forms. — The lung is subject to an interesting and rare type^ of
bone deposit through the progressive ossification of inflammatory connective
tissue. This condition was first described by Luschka and may be termed
reticulated osteoma.

The condition appears in three forms which are probably stages of the
same process. It first produces multiple nodules or tuberosities in the con-
nective tissue of one or several lobes.

In early cases in young subjects both lungs throughout presented about
fifty pea- to bean-sized nodules with much new connective tissue (Wagner,
Heschl). In later stages one or more lobes are the seat of extensive reticu-
lated bony deposits radiating in stalactite form from the root of the lung
(Forster, Bostrom, Picchini, Triboulet, Arnsperger). In a few cases one

OSTEOMA 197

lobe is transformed into a nearly diffuse mass of bone while nodules appear in
other lobes (Port, Cohn).

Bone masses in the wall of a cavity with nodules in other portions of the
lung were observed by Rullier, Browning and LeDiberder.

Microscopically the process begins as an interstitial gro\vth of connective
tissue, in the septa, walls of bronchi and alveoli, and about the large vessels,
all of which are inclosed and eventually occluded by ossifying connective
tissue. The vessels may show endarteritis obliterans (Picchini). The
islands of bone are surrounded by numerous osteoblasts and marrow spaces
filled with fat and marrow-cells may appear.

The majority of observers have concluded that the process, at least
at its inception, is an ossifying interstitial pneumonia. In advanced stages
it seems to acquire certain neoplastic characters, and Virchow regarded
the diffuse form as a true osteoma. The reticulated osteoma is to be dis-
tinguished from ossifying chondroma of the lung but in advanced cases
this may be difficult to accomplish.

Simple calcification may occur in the walls of cavities (Krauss, Nusser)
and the lung is a frequent seat of metastatic osteosarcoma (Gross).

In the penis of a subject 42 years old, Lenhossek has described the for-
mation of bony and cartilaginous plates which probably resulted from the
changes in inflammatory tissue in the fibrous septum and sheath. Konig
refers to similar cases.

In the skin multiple nodules of compact bone appear in the epidermis
or derma, sometimes about cartilaginous matrix (Virchow).

Coleman has described osseous plates in the sole of the foot.

In the eye, the sclera and choroid, are occasionally seen bone plates which
result from metaplastic changes in inflammatory connective tissues.

Bone formation in necrotic tissue occurs in many situations, as in phthisis
bulbi (Virchow), in the wall of the sclerotic aorta (Cohn, Klotz), in the walls
of abscesses. and in chronic pleurisy, and in advanced stages marrow spaces
and cells may appear. After ligation of the main vessels of the kidney
there may be extensive formation of bone and cellular marrow in the necrotic
organ of the rabbit.

Myositis Ossificans. — Spongy bone may form as a result of trauma in
the muscles of working people and has been observed in the biceps, digastric,
vastus externus, adductor magnus, and diaphragm (Virchow). In these
cases the ossification is self-limiting but in not a few cases of traumatic
origin there is a certain progressive tendency suggesting a relation to myositis
ossificans.

The progressive ossification of one or many muscles, first fully described
by Munchmayer and called progressive myositis ossificans, arises spon-
taneously, chiefly in young subjects and pursues a chronic intermittent
course. It affects the shoulder, face, trunk and limbs, and may become
quite extensive. In the early exacerbations there may be local congestion
and pain.

Once established it tends to progress until the affected muscle is com-
pletely ossified and immobile. Yet Elliott observed complete resolution
of the preliminary myositis. According to Ribbert the ossification emanates
from the periosteum, spreading along the fascia, tendons and the peri-
mysium and endomysium, with atrophy of the muscle-fibers.

Lexer finds first, increase of connective tissue, then chondrification and
finally ossification, constituting three stages in the process.

Since the disease occurs at an early age in subjects with deformities of
fingers and toes, is associated with multiple exostoses, and progresses inde-

198 N EOF LA STIC DISEASES

pendently of any originating trauma or other known factor, Ribbert regards
the process as blastomatous. Since the intermuscular connective tissue
may be regarded as a part of the skeletal system and intimately connected
with the periosteum (Koester), it may be supposed that in these cases the
former tissue retains more of the periosteal character than is normal, thus
constituting a tissue predisposition toward bone formation (Mays). The
occurrence of very similar lesions in tabes and syringomyelia suggests that
a spinal trophic influence may be concerned in some cases (Kaufmann).

CHAPTER XV
MYOMA

Myoma, a tumor of muscle-tissue, occurs in two types, leiomyoma con-
taining smooth muscle-tissue, and rhabdomyoma composed of striated muscle-
tissue. In both cases supporting connective tissue and blood-vessels usually
accompany the muscle-cells and the structure is organoid. Yet pure
leiomyoma occurs in the gastro-intestinal wall and the early stages of many
myomas contain little or no connective tissue. According to the rule with

FIG. 47. — Structure of simple benign myoma uteri.

benign tumors, myomas are easily recognizable as such, and metaplasia
and inflammatory factors play a very subordinate role in their history.

LEIOMYOMA

Leiomyoma occurs in the form of single or more often multiple, miliary
or voluminous, firm and opaque, or cystic tumors chiefly in preexisting
smooth muscle- tissues. Some contain much connective tissue and are

199

200

NEOPLA S TIC DISEA SES

quite hard, leiomyoma durum \ others are succulent and edematous,
leiomyoma molle; rarely dilated blood-vessels are prominent, leiomyoma
cavernosum; and occasionally cysts of dilated lymph-vessels, glandular
structures, or softened edematous areas may form. Extreme congestion
may render them dark and mottled, and after strangulation of vessels
they become black. Fatty degeneration may produce yellowish soft areas,
and calcification may transform entire tumors into stony masses.

On section leiomyoma presents characteristic striated or convoluted
markings from intertwining bands of muscle-cells. The tumor is more

FIG. 48. — Multiple myomas of uterus, one cystic.

opaque than normal muscle-tissue and is usually sharply circumscribed,
often shelling readily out of its bed. The curved markings often center
about blood-vessels from which the growth appears to originate. In injected
specimens Ribbert finds the blood-vessels small amd scanty as compared
with surrounding tissue, and the nutrition is maintained largely by lymph-
vessels. Hence myomas grow slowly and are very subject to standstill
and regression.

The structure of leiomyoma presents a system of intertwining bundles
of muscle-cells supported by septa and fibrils of connective tissue. In

MYOMA 201

some cases the muscle bundles are definitely related to small blood-vessels
or glandular structures but more often no such relation is apparent. The
edges of the tumor are usually sharply defined but may grade insensibly into
the surrounding tissues. The tumor-cells are thicker and shorter than
normal smooth muscle-cells, the cytoplasm grows less acidophile and the
nuclei are larger and richer in chromatin. In actively growing tumors
there is increase in the neoplastic characters of the cells, especially in their
size, and in malignant leiomyomas very large spindle-cells appear, giant-cells
form of enormous dimensions, and the connective-tissue stroma disappears.

The diagnosis between leiomyoma and spindle-cell sarcoma is often
difficult and may be based on the clinical history, the acidophile character
of muscle cytoplasm, the long oval nuclei, the arrangement of the cells
and the presence of many adult collagenous fibrils running between the cells.
Both cells and nuclei are more uniform in size and exhibit more evenly rounded
ends than fibroblasts. Special stains facilitate the diagnosis. The ap-
pearance of cross-sections of muscle bundles with nuclei embedded in
acidophile fibers, alternating with longitudinal sections, is usually quite
characteristic.

The connective-tissue stroma is acellular, often edematous or infiltrated
with round-cells. Two types of blood-vessels are found in most myomas.
In one the walls are normal, while the others participate in the neoplastic
process, the walls are composed chiefly of hyper trophic muscle-cells and
the adventitia is deficient or absent.

Regressive changes are frequently present. Fatty degeneration affects
individual cells in moderate degree, and extreme fatty and hydropic degenera-
tion or necrosis with edema produce softened areas. Hyaline degeneration
may overtake small areas or an entire tumor. Calcification follows fatty
degeneration or hyaline change and may become universal. Inflammatory
changes in myomas are usually slight. Round-cell infiltration of the stroma
is associated with edema, and about the included glandular structures of
some myomas there is adenoid tissue, or lymph-follicles may develop. Mast
cells may be very numerous (Reich, Gottschalk). Occasionally myomas
become infected and infiltrated with polynuclear leukocytes, and cystic
myomas may be found distended with pus.

The course of leiomyoma is slowly progressive over a period of years
and the symptoms are mainly of mechanical origin, or referable to associated
conditions. There is a natural tendency for many leiomyomas to reach a
standstill after a long period of growth or to regress with atrophy of muscle-
fibers, replacement fibrosis, hyaline degeneration and calcification.' In
the uterus this tendency reveals itself especially at the menopause, but it is
not constant. On the contrary very rapid growth or sarcomatous trans-
formation may begin at the menopause. Gibson observed the appearance
of a uterine myoma and growth to the size of a child's head within seven
months after removal of both tubes and ovaries. Regressive changes may
be hastened by pedunculation, by hyaline changes in stroma, by closure
of vessels, by separation from attachments, and by inflammatory processes.
Acceleration of growth may result from abnormal adhesions.

Myoma Malignum. — In a group of cases now rather numerous,
leiomyoma has proved malignant, breaking its natural boundaries, and
producing metastases in liver, lungs, kidney, peritoneum, and lymph-nodes,
and thereby acquiring the designation myoma malignum. From the uterus,
stomach, esophagus, and intestine this usually benign tumor has developed
extensive local and general secondary growths and proved fatal. This event
has occurred in the later periods of the growth or after extirpation of tumors

202

N EOF LA STIC DISEASES

which had long remained benign so that it would appear that a malignant
change had taken place in the character of the tumor. The symptoms
observed are a rapid increase in the size of a long quiescent growth, signs
of secondary growths, ascites in the uterine cases, and cachexia. The main
tumor has usually been adherent, with cavernous, softened, or cystic areas.
In one of my cases the softening spread from a crater-like ulcer in the adherent
endometrium. In Schlagenhaufer's case it was limited to an angiomatous
area.

In most of the cases the structure of the soft pultaceous areas and of
the metastatic growths which probably emanate from these areas, differed
from that of ordinary leiomyoma. The cells were larger, the nuclei more
massive and hyperchromatic, mitoses were present, the fusiform cells became

FIG. 49. — Miliary myoma in a uterine vein. The tumor is benign.

shorter or rounded, giant-cells formed, intercellular connective tissue was
scanty or absent, and the walls of vessels were defective (Krische,
Langerhans, Williams, Beeston, Moser, Basso). In Hansemann's malignant
myoma of the stomach the cells were uniform but short or rounded and the
nuclei very rich in chromatin. In Eising's esophageal 'myoma islands of
adenocarcinoma were present and the muscle-cells much increased in size.
In one of Evelt's cases the sarcoma was apparently melanotic. In three
uterine cases I found the structural changes very marked. In one (3461)
there was extensive mucoid degeneration. In another (2287) the spindle-
cells and giant-cells reached enormous dimensions. In all the derivation
from muscle-cells was clear. So far as I have been able to learn no case has
been fully studied in which definite variation from the usual structure of

MYOMA 203

leiomyoma were wanting, although in several instances these variations have
not been very pronounced.

In one case^of large uterine myoma I found the peritoneum of the uterus
thickly beset with miliary myomas identical in structure with ordinary
myoma, and in a case of recurrent multiple nodular myomas of the broad liga-
ment the cells varied little from the usual type although they were shorter
and looser and the tissue was very vascular. In neither case were there dis-
tant metastases. Accordingly it may be said that the structure of malig-
nant myoma varies from that of the benign type.

Ribbert has protested against the term myosarcoma, employed by many
for the malignant tumors, on the ground that sarcoma implies a tumor of
connective tissues. Yet in a morphological sense this term seems admissible.
Objection has also been made to the interpretation of the above changes as
genuine sarcomatous degeneration of myomas. There has been a tendency
on the part of gynecologists to multiply the cases of this sort, and to search for
suspicious foci over wide areas of perfectly benign tumors. Some estimates
place the frequency of the change at 10 per cent, of all uterine myomas.
From the reports of Winter, Henkel, Hofmeier, and Flautau, in 1880 cases
of fibroids 48 or 2.5 per cent, were found to show sarcomatous changes. The
manner in which these statistics were obtained is perhaps fairly indicated in
the study of Winter. In his first series of 500 cases he examined only sus-
picious-looking areas and found 16 (3.2 per cent.) to contain sarcomatous foci.
In 253 later cases he examined all parts of the tumor and succeeded in rais-
ing the number of sarcomas to 1 1 (4.3 per cent.) . There were sometimes pres-
ent general signs of malignancy, as rapid growth, polypoid masses on the
main tumor, and changes in consistence, but local metastases occurred only
once and cachexia resulted chiefly from hemorrhage. In the same manner
Cullen has reported 17 cases of sarcomatous degeneration of uterine myomas.

These observations show that ordinary myomas vary in structure in
different portions and probably at different periods, and they seem to justify
the suspicion with which the gynecologist regards the entire group. But it
must be considered that these suspicious changes may not always be pro-
gressive but may signify merely a temporary or local acceleration of growth
which may subside and even regress. They do not seem to justify their
designation as sarcomatous transformations, for which much more exten-
sively altered areas or even general metastases might well be demanded.
Sarcomatous tendencies and precancerous changes do not constitute real
sarcoma or cancer. I have encountered three malignant uterine myomas
with general metastases and two with local Recurrence in 20 years, and
Winter found no case among 753, so that malignant degeneration of myoma
must be rare.

It has been claimed that certain myosarcomas arise through a malignant
transformation of the connective tisue of leiomyoma. (Ricker, v. Franque
and Hauser). In Ricker's case the change occurred in numerous foci
sharply separated from the muscle-tissue which was either infiltrated with
the sarcoma-cells or underwent atrophy. Yet the descriptions of these
authors are not entirely convincing that they were not dealing with the
ordinary type of malignant change in muscle-cells.

Clinical Types of Leiomyoma. — Uterine Fibromyoma. — The uterus is
the commonest seat of leiomyoma. The tumors are usually multiple, in
fact in several cases the entire uterus has been found to consist of a congeries
of discrete myomatoid masses (Cruveilhier, Williams, Stone). The lo-
cation is widely distributed, the posterior wall, anterior wall, sides, and cer-
vix appearing in the order named. From 5-8 per cent: of these tumors are

204

N EOF LA STIC DISEASES

cervical (Fehling). Extra-uterine tumors of the same type and significance
occur also in the broad ligaments, vagina, tubal junction, in the pelvic fas-
ciae, and in the round ligament as far down as the groin or labium majus
(Cullen, Aschoff). The position of the uterine tumor may be subserous,
interstitial, or submucous. Both subserous and submucous tumors tend to
become pedunculated or even separated from the uterus, being rarely dis-
charged per vaginam (Simpson), or lying free in the peritoneum (Turner),
or becoming attached to surrounding organs. Submucous tumors may gradu-
ally separate from their original site and become implanted on the opposed
mucous surface (Leyden, Kustner). Diffuse myomatosis may cause thick-
ening of a small focus or of a large area, or of almost the whole organ. Mil-

FIG. 50. — Structure of a multiple nodular recurrent myoma of broad ligament.

iary myomas appear in the peritoneum during the course of larger tumors,
while Hunter found at autopsy a single tumor weighing 140 pounds.

The form of uterine myoma is usually a rounded, sharply circumscribed
solid and elastic mass which projects prominently from the cut surface.
Many very early myomas and many adenomyomas are without definite
demarcation and the diffuse forms remain so, but with increasing age most
tumors show more and more isolation and some become encapsulated.
Cysts, multiple and superficial or large and central, form in many myomas
from dilated gland alveoli, or from chronic edema and mucinous softening.
Their contents are serous or mucinous fluid with cholesterin, or after infec-
tion they may become distended with pus. Some of the cystic myomas reach
a very large size (Martin), that removed by Severanu of Bucharest being one
of the largest tumors ever observed. They may contain pus or chocolate-
brown or bloody fluid. The uterus which is the seat of myoma, especially

MYOMA

205

of the submucous or interstitial varieties, enlarges with the growth of the
tumor and becomes extensively deformed. There is hypertrophy and hyper-
plasia of the muscle-cells as a result of contractions caused by irritation from
the tumor (Bertelsman), but Tillaux saw the uterus greatly enlarged with a
small tumor of the lower segment. The vessels about the tumor are enlarged
and the whole organ is hyperemic. Endometritis, interstitial or glandular,
commonly results, especially with submucous varieties, and mucous and bloody
discharge becomes a prominent symptom. Inflammatory hyperplasia may

FIG. 51. — Myoma of uterus, confined under pressure with edema, small cysts, and polypoid

growths into cysts.

be limited to the mucosa overlying the tumor (Wyder), or it may extend also
to the tubes (Fabricius) and ovaries (Bulius). Profuse hemorrhage between
or prolonging the menstrual periods marks the course of many forms of my-
omas, and sometimes proves fatal. According to the position of the tumors
the uterine cavity becomes elongated, irregular, or occluded. The stretch-
ing of the myometrium may produce peculiar rhombic spaces in the stroma
and the stretching has even led to rupture of fundus from the cervix (Len-
nander, Hedren) . Mural myomas may cause extensive torsion of the uterus,
and submucous tumors may lead to prolapse or inversion (Kuster, Kotschau).

206

N EOF LA STIC DISEASES

The gross section reveals the usual 'convoluted markings of myoma, or a
congeries of multiple tumors. Islands of adenoid tissue and the sections
of glands may be revealed by the hand glass. Multiple minute cysts appear
when the alveoli are moderately dilated. The tumor-vessels are usually
scanty while the surrounding tissue supports numerous dilated veins, but
small areas (Cullen), or the entire tumor (Virchow, Martin), may be telan-
giectatic. Dilated lymph-vessels were prominent in two myosarcomas de-
scribed by Menge. Submucous myomas are often traversed by glandular
tracts, the openings of which may be seen on the mucous surface.

FIG. 52. — Structure of a locally infiltrating myoma uteri.

Extensive degenerative changes frequently alter the appearance of uterine
myomas. Marked edema produces softening and cystic areas. Chronic
edema leads to extensive mucinous degeneration with increase in the size of
the tumor and formation of cysts. With increasing age there is a tendency
toward atrophy and fibrosis which may greatly reduce the size of. large tu-
mors and render others very hard. Fatty degeneration of muscle-cells is
associated with their atrophy and probably precedes calcification. Fatty
changes may become very active during gestation and Martin saw a large
myoma almost wholly transformed into fatty semifluid material during ges-
tation and the puerperium. Large tumors undergo fatty degeneration and
may be reduced to small nodules or entirely disappear (Duncan, Hewitt,
Gusserow). Hyaline degeneration may affect the blood-vessels, stroma, or
muscle-tissue, in small foci or in considerable areas. According to Ribbert

MYOMA 207

this change may precede calcification, the salts being deposited in the hyaline
material. Stratz saw amyloid degeneration about the vessels of a polypoid
myoma. Calcification overtakes fatty and atrophying myomas and com-
pletely transforms them into stony masses. Uterine stones of large dimen-
sions are thus found in the cavity, wall, or on the peritoneal surface of the
uterus (Henocque), and they have been discharged through the vagina or
intestine, or into the bladder (Payr). Everett found the composition to be
calcium carbonate 49 per cent., phosphate 29 per cent., sulphate 13 per cent.,
with traces of lithates and organic material. Turner and Wylie found a com-
plete separation from the uterus of calcified subperitoneal myomas. Throm-
bosis of vessels is not an uncommon event, especially with pedunculated myo-
mas, and leads to hemorrhagic infarction, necrosis, softening and even to
excavation and discharge of large portions of submucous tumors.

Sarcomatous changes, previously considered, occur in a small proportion
of uterine myomas. Carcinoma is sometimes observed with uterine myoma
and may result from several conditions. In adenomyoma, carcinoma may
develop from the epithelial elements in the tumor. A submucous myoma
may be complicated by carcinoma of the overlying and long inflamed mu-
cosa, and the carcinoma may penetrate the myoma. Or the carcinoma may
arise in a distant portion of the mucosa. Carcinoma of other organs has
been known to produce metastases in uterine myomas (Liebmann, Schafer,
Rolley).

The microscopical structure of uterine myomas reveals two forms of this
tumor, fibromyoma and adenomyoma. The great majority of the tumors
are of the former class and present the usual characteristic structure of fi-
bromyoma. At their inception these tumors are nearly pure myomas and
some remain so throughout most of their course but with increasing age there
is a tendency toward increasing development of connective tissue which in
atrophying tumors may exceed the muscular tissue. The connective tis-
sue is distributed in septa supporting vessels and as finer fibrils ramifying
between the muscle-cells. Gebhard observed a large, purely fibrous nodule
in the center of a solid myoma. The connective tissue does not participate
in the tumor process although some observers have claimed that it might
give rise to sarcomatous changes in myomas. The tumor-cells are larger,
thicker and more granular than normal uterine muscle-cells, and the nu-
clei are larger, more rounded, and richer in chromatin. During gestation
the cells of myomas increase in size. Their arrangement is in intertwining
bundles running in all directions and without definite relation to any struc-
tural unit. Certain large tumors are composed of a congeries of somewhat
discrete nodules in the centers of which are blood-vessels, and in some early
myomas the growth centers chiefly about blood-vessels from the walls of
which the tumor seems to spring. In such cases the adventitia of the vessel-
walls may be deficient (Rosger). It has been claimed that nerves have been
demonstrated in uterine myoma (Hertz) but they are insensitive, and their
existence has been denied.

In rare cases islands of bone have been found in uterine myoma (Lebert,
Freund); a nodule of cartilage has been encountered by Bennet; and in one
malignant case of adenomyosarcoma Kaufmann found both bone and car-
tilage. A fibrochondro-osteoma described by Kworostansky was possibly
an atypical myoma suffering extensive metaplasia.

Adenomyoma presents the usual structure of the muscle-tissue but it
contains glandular alveoli which appear in various forms. They usually
form small groups of acini lined by cubical or cylindrical and sometimes cili-
ated epithelium supported by lymphoid stroma. These acini are identical

208 NEOPLASTIC DISEASES

in appearance with fragments of uterine mucosa with which they are often
directly connected. Or the cells are more embryonal in type, with relatively
large nuclei, with or without cilia, and the lymphoid stroma may be present
or absent. Most observers have been unable to establish any constant dis-
tinctions between the epithelial structures in adenomyomas in different lo-
cations but the development of the glands varies widely from a few scanty
acini to large cystic tumors composed largely of epithelial lined cysts. Pap-
illary projections may grow into the cysts and Cullen saw adenocarcinoma
developing from the papillae. During menstruation there is congestion
and hemorrhage into the glands (Cullen), and Amos has described decidual
changes during gestation.

The occurrence of adenomyoma is relatively infrequent, but its distri-
bution is widespread. They may be submucous, interstitial, or subperito-
neal, and they have been found in the broad ligament, round ligament,
and groin (Cullen), cervix, vaginal wall, Fallopian tube and rectum.

Etiology. — Uterine myoma is the most frequent of all tumors, its occur-
rence being estimated at 50 per cent, of all women over 50 years of age (Klob),

FIG. 53. — Structure of adenomyoma of broad ligament.

and at 20 per cent, for those over 35 years. The incidence reaches its acme,
38.8 per cent., between the ages of 30 and 40 years (Gusserow). The
negress is especially susceptible. Before puberty it is extremely rare but
Tillaux reported in a girl of 19 a cervical myoma which had given
symptoms for six years. Leopold's statement that the rudiments of myomas
may be found in the uterus in children has not been verified. An hereditary
influence seems to have existed in certain families in which several members
suffered from myoma at an early age (Veit, Gusserow).

Sterility has long been held to be a factor in the etiology of myoma and
Veit concludes that abnormal excitation and congestion of the organ without
conception may excite tumor growth. It is highly probable that myoma
favors sterility from the mechanical and inflammatory effects of the tumor.
Both sterility and myoma are favored by the infantile type of uterus and by
misplacements and other defects in the organ which go with each of these
conditions. Virchow held that myoma is caused by local irritation. Many
authors have pointed out sources of such irritation and shown that these
act as secondary and exciting factors, which are not constant or essential.

MYOMA

209

The essential factor in the etiology of myoma is an embryogenic dis-
turbance in the structure of the uterus. The remarkable degree of isolation
of many myomas, their widespread occurrence apart from the uterine body,
and the presence in many cases of heterotopic inclusions, epithelial, carti-
laginous, osseous, fatty, and rhabdomyomatous, clearly point to an embry-
onal origin. Moreover, as Williams has emphasized, uterine myomas are

FIG. 54. — Diagrammatic representation of development of genito-urinary tract. (After

Heisler.)

The Miillerian duct and derivatives are jet black. The Wolffian body and derivatives
include all other structures except the sex glands, bladder, prostate and rectum.

_ i, Indifferent type. 2, Indifferent type, later stage, the Wolffian and Miillerian ducts and
primitive ureter now opening into the urogenital sinus. 3, Male type, lower ends of Mul-
lerian ducts fused to form the sinus pocularis. 4, Female type.

often associated with a large number of abnormalities in the genito-urinary
system.

The nature of the embryogenic disturbance varies with different tumors.

(a) It is generally agreed that the common pure fibromyoma results from

210 XEOPLASTIC DISEASES

a disturbance in the formation of the tubes, uterus, and vagina from the Miil-
lerian ducts, which split off from the Wolffian ducts at an early period^ and
fuse to form the genital canal.

The relation of certain early myomas to the blood-vessels of the uterus has
long impressed many observers and suggested that uterine myomas arise
from disturbances in the growth of the blood-vessels from the walls of which
the uterus and vagina originally receive their muscular tissue. Rosger,
Kleinwachter, Sobotta, and others have traced the development of early
myomas from the vessel- walls and concluded that the blood-vessels control
the origin and growth of uterine myomas. This view has much evidence to
commend it, although it is seldom possible to demonstrate such a relation
in advanced stages of the tumors. Yet in many pure, in adenomatous and
in telangiectatic myomas, the blood-vessels are composed of neoplastic
muscular-tissue. In a case of multiple recurrent telangiectatic myoma of the
broad liagment I found striking evidence of the origin of the tumor masses
from blood-vessels.

The cases in which the whole uterus is composed of a congeries of myomas,
or where a myoma replaces the cervix (Landau) or causes uterus didelphys
(Pick), strongly suggest an origin from misfitting vascular units which
go to make up the uterine muscle. Likewise single isolated myomas seem to
represent overgrowth of muscle from single vascular units which have not
fitted the general texture of the myometrium. Into many such tumors the
invasion of glands has been traced from the mucosa. There are many who
believe that the great majority of myomas of all types originate in this way.

(b) Regarding the origin of adenomyomas opinions are at variance and
it is probable that no single mode of origin can apply to all these tumors.

i. A Mullerian origin accounts most satisfactorily for the majority of
uterine adenomyomas, especially for the submucous, interstitial, and diffuse
varieties. Duplication of the duct, fetal budding of the epithelium, mis-
placements of islands of fetal mucosa, postembryonal misplacement of
gland tissue, and invasion of the myometrium by gland alveoli during in-
flammation, have been observed or suggested as accounting for the origin of
these tumors (Meyer, Pick, Hauser, Schroeder, Ruge).

In many submucous or deeper adenomyomas the epithelial structures
have been traced to the uterine mucosa, on the surface of which they some-
times open by patent canals (Ribbert, Cullen). The invasion of a tubal
myoma by glands of the tubal mucosa has been traced in serial sections by v.
Franque. The structure of the glands in most adenomyomas is an exact
duplicate of the uterine glands and they seem to functionate as does the
uterine mucosa.

. 2. Mesonephric Adenomyoma.- — The epithelial structures in certain adeno-
myomas were interpreted by Babes and by Recklinghausen as remnants of
the Wolffian body or mesonephros, and many have supported this view
(Ricker, Schroeder, Pick, Schickele, Ernst). Recklinghausen believed the
glandular structures in certain cases presented the characteristics of the meso-
nephros which forms a closed system consisting of a chief canal or ampulla into
which many parallel smaller canals open. The smaller canals, starting in
wide ampullae advance in the form of convoluted secreting tubules lined by
cubical epithelium and empty into the chief canal while lined by high or cili-
ated epithelium. Vascular polypoid projections of cellular tissue along the
canals in certain tumors he interpreted as pseudoglomeruli. Occasional
deposits of pigment he compared with the pigment of Giralde's organ (rem-
nant of lower Wolffian tubules).

Recklinghausen and Pick have attempted to divide adenomyomas into submucous

MYOMA 211

(central and ventral) and paroophoral (dorsal and peripheral), the former deriving its
glands from the endometrium, the latter from theparoophoron, the remnant of the Wolffian
body (lower tubules). Pick holds strongly to the dual origin of adenomyoma uteri, claim-
ing that the tumors located in the broad ligament are of Wolffian origin and may be des-
ignated as parovarian and paroophoral adenomyomas. Under the term adenomyoma
psammopapillare he describes a remarkable multiple papilrary tumor arising in the broad
ligament which well illustrates Recklinghausen's voluminous paroophoral adenomyoma.
As the chief histological distinction he states that lymphoid stroma usually but not always
accompanies uterine glands in adenomyoma while the alveoli of Wolffian origin lie in
immediate contact with muscle-tissue and lack the lymphoid stroma. Yet Cullen finds
such lymphoid stroma in tumors of the round ligament.

While it is probable that certain extra-uterine adenomyomas originate from the paro-
varium or paroophoron the majority of observers have not been impressed with the meso-
nephric characters of these tumors. Neither the location of the tumors nor the arrangement
of the ducts nor the character of the epithelium seem to be sufficient evidence to prove the
mesonephric origin, since very similar structures are seen in submucous tumors and in
others for which a Millie rian origin is extremely probable (Meyer, v. Franque). Cohen
saw the characteristic arrangement of tubules in a submucous tumor of which the epithe-
lium was clearly derived from the endometrium, and he found the pigment in adenomyoma
to be ferruginous while that of Giralde's organ is iron-free. Aschoff found no uniformity
in the location of the so-called paroophoral type of adenomyoma, and Kossmann and
Lockstadt found a general resemblance between uterine glandular tissue and the epithelial
structures in all adenomyomas. Pick states that there are both adult and embryonal
types of adenomyoma, and such a distinction appears to be not infrequent, but the dis-
tribution of these types does not accord with the other features which might separate
two varieties of adenomyoma. The predominance of muscular tissue is more readily
explained by a Miillerian origin, for muscle-cells are scanty in the Wolffian structures, and
Pick regards this element as quite secondary and unessential in the anlage of mesonephric
tumors.

3. Remnants of the Wolffian duct (Gartner's duct), seem to give origin to
certain extra-uterine adenomyomas. It has been shown by Recklinghausen,
Ricker, Pick, and others, that the whole region of the uterovaginal canal
may contain isolated epithelial groups which are probably derived from the
Wolffian duct. Borst found heterotopic Wolffian alveoli in the iliac lymph-
nodes. Klein traced a persistent Wolffian duct in two infants. The proxi-
mal portion traversed the broad ligament beneath the Fallopian tube to
the uterus, and terminated in the uterine muscle at the os internum. The
distal portion passed along the side of the uterus to the cervix, curved back-
ward over the fornix and passed downward in the wall of the vagina to the
hymen. The canal was lined by cubical epithelium and supported by smooth
muscle, and Klein concludes that this structure may give rise to various
tumors along its course, as cysts, myoma, adenomyoma, and adenocarci-
noma. Cervical and vaginal adenomyomas, especially, have been referred to
this origin (Breus, Herpf, Pfannenstiel). Yet, except for their unusual posi-
tion, the same difficulties exist in proving this origin as for the mesonephric
type, since the structure of these tumors does not differ essentially from that
of the Miillerian type (Cullen).

4. Besides the epithelial alveoli, subperitoneal myomas may contain
acini lined by cubical endothelium derived from inclusions of the peritoneum
(Aschoff, Meyer).

Summarizing the evidence one may conclude that simple myoma uteri
arises chiefly from a disturbance in the development of the tubes, uterus
and vagina from Muller's ducts, which often leads at the same time to gross
deformities and infantile characters in these organs.

Adenomyoma arises chiefly from the fetal or post-embryonal inclusion of
Miillerian epithelium in the tumor process. Extra-uterine adenomyomas in
the broad and round ligaments and cervix may also arise from the meso-
nephric elements or from the Wolffian duct, but neither the position nor struc-
ture of these tumors permits their positive identification in every instance.

212 N EOF LA STIC DISEASES

The growth of many myomas is controlled by their relation to blood-vessels
from which they are derived. The chief exciting factor is intermittent hy-
peremia connected with irregularities in the sexual functions.

Myoma in the Alimentary Tract. — The esophagus was the seat of small
multiple leiomyomas containing also striated muscle-fibers and ganglion-
cells in a case described by Pickler. A larger single tumor was observed by
Illig. Both were connected with the inner muscular coat. Eising's case
was complicated with adenocarcinoma.

In the stomach Miodowski observed a bulky myoma which led to
severe hemorrhage. He found two similar cases in the literature. Hanse-
mann has reported a malignant gastric myoma with metastases in liver and
pancreas. In a large tumor studied by Cohen there were islands of pancreas.
Laboulbene saw four small myomas in the same stomach. Many gastric
sarcomas are probably of myogenic origin (q.v.).

In the intestine leiomyoma is not uncommon. The tumors are single
or multiple. Nazzari saw 40 small tumors in one case and 120 in another.
Steiner found them either subperitoneal or submucous, the latter type caus-
ing stenosis or intussusception, the former producing diverticula. In Mer-
cer's case fatal hemorrhage occurred. Cohen found islands of pancreas in
an intestinal myoma which probably belonged with the adenomyomas of
Trappe. Both gastric and intestinal myomas are apt to be associated with
uterine myoma, and they appear to originate from isolated segments of the
musculature, connected with blood-vessels or epithelial structures. Accord-
ing to Boetticher and Lode three types of intestinal myomas may be dis-
tinguished: (i) Small multiple nodular or polypoid tumors arise from local
proliferation in the muscularis; the mucosa is free; (2) broad thick tumor
masses form in the muscle layers while the mucosa becomes adherent to the tu-
mor; (3) larger polypoid subserous myomas may project into the peritoneum.

Dermatomyoma. — A wide variety of myomas is observed in the skin.
They occur on the buttock and extremities, at embryonal fissures (Babes),
in the scrotum and labia (m. dartiques) (Besnier, Forster, Challard). They
may be associated with keloid (Babes), or lymphangioma (Axel, Key),
neuroma (Czerny), and xanthoma (Chambard, Gouilloud). Politzer has
shown that certain xanthomas result from fatty degeneration of smooth mus-
cle-fibers. In some cases the blood-vessels are very numerous and neoplas-
tic, producing angiomyomas (Hess). The tumors are usually small and
multiple, firm, movable, cutaneous or subcutaneous, nodules or masses.
They may be painful and tender. They usually occur in adults but Hess
observed early cases and Marc describes a congenital lymphangiectatic my-
oma. The origin has been traced to the arrectores pilorum (Judassohn,
Walters) or to the cutaneous arterioles (Hess, Marc). Borst suggests that
some of the dermatomyomas are really neurofibromas. Sobotka traced
the process from simple hypertrophy of the arrectores up to tumor growth,
followed by degeneration.

In the urinary bladder and passages myomas constitute a considerable
proportion of the tumors occurring in those organs.

In the bladder they may reach large dimensions and their location is
either subserous or submucous (Stein, Terrier, Hartmann). In an infant
Kaufmann found a myoma of the trigonum containing cartilage. A large
myocarcinoma is reported by Volkmann. In the ureter Buttner observed a
large pure myoma. In the testis Rindfleisch described a myoma which
contained nerve-fibers and ganglion-cells, and Becker reported one case of
doubtful nature.

In chronic prostatitis there is often extensive hypertrophy of smooth

MYOMA 213

muscle-tissue which may approach the neoplastic grade. True myomas of
this organ have not been clearly separated from this inflammatory overgrowth.
In the kidney small multiple myomas and myolipomas occur in capsule
or cortex and appear to be derived from fragments of capsule tissue (Miil-
ler, Larkin). Jacobsens has collected several cases which were associated
with cerebral sclerosis. In the breast leiomyoma has been observed by Ab-
ramow and Ribbert.

RHABDOMYOMA

Tumors of striated muscle are characterized by their rare occurrence,
embryonal type, and common association with other constituents in mixed
tumors. They occur in very wide distribution and, while the geni to-urinary
system furnishes the largest proportion, few muscular regions escape an
occasional development of rhabdomyoma, and the homologous growths are
fully equaled in number by heterotopic forms. They usually occur in early
life, some are congenital, and a few examples have been first noted in advanced
or old age (Wolfensberger, Fujinami).

In form they appear as single or multiple, nodular or voluminous, flat or
rounded, circumscribed or diffuse and even polypoid growths. They are
usually soft and grayish on section, and markings produced by muscle bun-
dles alternate with abundant connective-tissue stroma. Very cellular
forms are more opaque, yellowish or reddish, soft and often diffuse. The
mixed rhabdomyomas present the varied appearance of teratomas. A cys-
tic rhabdomyoma of the elbow has been described by Billroth.

The structure of rhabdomyoma presents chiefly a system of parallel
bundles or intertwining strands of striped muscle-fibers, supported by adult
or embryonal connective tissue. The fibers may encircle blood-vessels or
other structures but are more often diffuse. The cells of rhabdomyoma sel-
dom exhibit adult characters. They are usually thin and much elongated
and rarely they are branching (Zenker, Billroth). Both long and cross
striation may be pronounced or the cross striation may be present in a part
of the cell only or be entirely missing in embryonal and spindle-shaped cells
which still retain longitudinal fibrillation. Or the cells may closely resemble
smooth muscle-cells. In large vacuolated cells Ribbert describes concen-
tric striation of the perinuclear cytoplasm. In a testicular tumor he ob-
served long tubular fibers, the walls of which were of striated or hyaline mus-
cle fibrils and the core of granular sarcoplasm with many nuclei in axial
positions. The ends of the fibers may be swollen, rounded, and contain
multiple nuclei. In the more embryonal types the cells are spindle-shaped,
shorter, and even round, and they may lose their acidophile character and
all resemblance to muscle-cells. Yet such marked anaplasia is seldom if
ever universal, certain foci commonly retaining cells of definite myogenic
character. Even the round-cells of lymph-node metastases may retain
traces of striation (Wolfensberger, Eberth), or the metastases may consist of
cells showing no features of muscle-cells (Benenati). In many myomas the
cells contain an abundance of glycogen which is evidence of their embryonal
character (Marchand).

The nuclei follow a type of large vesicular chromatic bodies, single or
multiple, which lie in a central area of granular cytoplasm. Or they may
project from the cell border like nuclei of sarcolemma. A d'efinite
sarcolemma is wanting but traces of such a structure with its nuclei have
been seen in rare cases (v. Franque, Marchand). The stroma is either
loose adult connective, or embryonal, sarcomatous or myxosarcomatous,
and in the teratomas bone, cartilage and various other tissues may be present.

214 NEOPLAST1C DISEASES

Blood-vessels are usually abundant and sometimes, as in a large polypoid
vaginal tumor described by Kaschewarowa, they are overdeveloped.

In parts of certain rhabdomyomas it is difficult to determine whether one
has to deal with voluntary muscle-fibers which have lost their striation or
with genuine smooth muscle-tissue. The undifferentiated cells may closely
resemble smooth muscle. Moreover rhabdomyoma occurs especially where
smooth muscle-tissue exists (kidney, testis). To many observers it has
appeared that smooth muscle-tissue may give rise to striped muscle-fibers
in tumors (Eberth, Rindfleisch, Arnold, Marchand). In a myosarcoma
uteri v. Franque saw islands of striated muscle together with smooth muscle
and spindle-cell sarcoma and he concluded that the striped muscle arose by
metaplasia of smooth muscle. Yet Girode and Nehrkorn both saw islands
of striated muscle in the normal myometrium and the embryology of this
organ provides the possibility that portions of striped muscle-tissue may be
included in its structure. Arnold, in supporting a suspicion that metaplasia
of smooth may produce striated muscle, derived a rhabdomyoma testis from
the cremaster muscle, but the tumor lay within the albuginea, while this
muscle lies without the organ. The embryology of muscle-tissue, voluntary
muscle being derived from mesothelial plates and involuntary muscle from
the mesenchyme, does not favor the idea that one form may pass into the
other. While many earlier observations suggested the change of smooth into
striped muscle, most recent studies have not favored this view (Ribbert,
Hauser, Kolisko).

The course of. rhabdomyoma is usually progressive and in the
sarcomatous and teratoid forms it is rapid. The more adult types may
become encapsulated or assume the polypoid forms, but the embryonal
tumors infiltrate surrounding tissue, multiplying muscle-cells being often
preceded by a zone of proliferating connective tissue.

Degenerative changes, glycogenic, hyaline or amyloid may occur without
interfering with the growth. The malignant tumors of the kidney and
testis reach large dimensions and produce metastases and cachexia, but
the metastases are usually derived from other elements of the tumor.

CLINICAL FORMS OF RHABDOMYOMA

Adenomyosarcoma of Kidney. — The kidney is the commonest seat of tumors
containing straited muscle, but since none of them has yet appeared in pure
form they will be described under tumors of the kidney.

In the urinary bladder polypoid rhabdomyomas have been described
by Cattani, Vincenzi, Stumpf, and Monckberg. They occurred in children
or young adults, and formed movable growths about the urethral orifice
or trigone.

Rhabdomyoma uteri appears almost exclusively as an element in the poly-
poid vaginal sarcoma of children and adults (Sarcoma botryoides, Pfan-
nenstiel). This process affects the vagina in children and chiefly the cervix
in adults (Gow, Pick). It may exist at birth (Demme) and first appears
as a rather broad thickening of the submucosa which soon becomes polypoid,
v. Franque reported a somewhat similar tumor located on the fundus uteri
in a multipara. The symptoms are hemorrhage, fetid discharge, and
protrusion of a polypoid tumor from the vagina, with dysuria, pain, fever,
and cachexia. The vagina is eventually filled with ulcerating masses and
there are bulky extensions into the pelvis, and occasionally to regional
lymph-nodes, rarely to skin or lung (Kalustow, Rosthorn). In Demme's
case a benign polyp after five years suddenly became malignant. The usual

MYOMA

215

histology is that of a large spindle-cell sarcoma, with many blood- and lymph-
vessels, myxomatous tendencies, and areas of striated muscle.

Pfannenstiel believed he could trace the development of muscle-cells
from the spindle-cells. Kolisko found muscle-tissue in all of three cases and
believed it to be present in all cases. Islands of cartilage have been observed
in the primary tumors (Rein, Pernici) or only in recurrences. The remark-
able clinical characters of this tumor render it a very well-defined disease.
The early appearance and complex histological structure of the tumors
show that their origin must be referred to some embryogenic disturbance of
the cervix and vagina, but the nature of this disturbance has never been
clearly defined.

In the testis rhabdomyoma occurs in the form of nodular tumors as
large as a walnut or a child's head. They may replace the entire organ or
displace it to one side, or be found outside the tunica albuginea. In several
cases the muscle-tissue was associated with epithelial structures, and one
of Ribbert's cases was combined with carcinoma and sarcoma. Neumann
and Ribbert found many spindle- and round-cells which were not readily

FIG. 55. — Structure of congenital rhabdomyoma of heart. (From a section of Wolbach's

case.}

identified as myomatous, and Neumann suggests that some spindle-cell
sarcomas regarded as fibroblastic may really be of myogenous origin.
Benenati describes a large rhabdomyoma of an undescended testis with
round-cell metastases in the regional lymph-nodes. The tumor contained
spindle-cell and round-cell areas as well as striped muscle. Stoerk observed
a very malignant case with myomatous metastases in distant lymph-nodes.
Wood found cartilage and epithelial cysts as well as muscle. All these
observations lead one to accept the view that rhabdomyoma testis occurs
only as a one-sided development of a teratoma. Rokitansky and Neumann
derived their tumors from the gubernaculum of Hunter, but these growths
were attached to the lower pole of the tunica and were not strictly tumors
of the testis.

Congenital rhabdomyoma of the heart is a very characteristic condition

216

N EOF LA S TIC DISEA SES

of which twelve cases have been reported (Wolbach, Lit.). They occur
as multiple sharply circumscribed areas or tumors, lying within the wall
or projecting internally or externally. Ponfick pointed out that they are
associated with diffuse sclerosis of the cerebral cortex and with disturbances
of nutrition. Cesaris-Demel found also nodules in the kidney composed of
embryogenic renal tissue, and Wolbach observed multiple neuroglia rests
in the spinal meninges.

The structure of the tumor presents a peculiar spongy tissue in which
it is difficult to make out the relation of certain large vacuoles to cells and
fibrils. The vacuoles have been shown to lie in the very large cells of which
the tumor is composed (Seifert, Wolbach). The cells are large rounded
masses containing large nuclei and nucleoli, surrounded by partly striated

FIG. 56. — Rhabdomyosarcoma of voluntary muscle following fracture of femur. (After

Midler.}

cytoplasm which extends in many fibrils between the vacuoles to the cell
border. They resemble early embryonal heart muscle-cells (Kolisko), and
similar cells may be found in the fetal myocardium (Wolbach). The cross
striations are formed of fuchsinophile granules grouped in the sarcous
elements, and the long striations are made up of alternating sarcous elements
and basophile fibrillary material. Either of these elements may be in excess.
The resemblance of the cells to PurkinjVs cells and those of the conducting
bundles of the heart is mentioned by Knox and Shorer. That the tumors
arise from an embryogenic disturbance in the structure of the heart is
obvious. Kolisko mentions the early and extensive changes in the mor-
phology of the heart as favoring errors in development. Bonome traces
the pathogenesis to fetal malnutrition resulting 'in cerebral atrophy and
sclerosis, and to fibrous overgrowth in the heart which separates nests of
embryonal cells from which the tumors develop.

MYOMA 217

Miscellaneous Rhabdomyomas. — Tumors containing striated muscle
have been observed in isolated cases in many other organs and tissues;
in the esophagus (Wolfensberger, Glinski); in the stomach (Brodowski),
in the tongue (Pende), parotid gland (Prudden); in the breast (Billroth);
in the prostate (E. Kaufmann); in place of the left lung (Helbing).
Rhabdomyomas of the skeletal muscles in various parts of the body, orbit,
neck, pelvis, buttocks, and different portions of the extremities have been
collected by Fujinami from reports of various authors, and Benenati gives
an extensive chronological list of cases. Among the regions affected are
the spinal vertebrae and pectoralis major (Buhl), upper arm (Billroth), tibia
(Lambl), thigh (Fujinami), and nose (Erdmann).

Of 1 6 cases of rhabdomyoma derived from adult voluntary striated muscle
in which the cells were said to have retained cross striation, reported up
to 1913, Kuttner rejects six and regards the others as questionable. Tumors
composed of more anaplastic cells in which cross striation was lost and whose
origin from muscle-cells was established on other grounds, are very rarely
reported. Miiller has reported from this laboratory one such case following
repeated trauma of a long ununited fracture of the femur. The tumor was
composed of large acidophile spindle-cells, some of which approached the
dimensions of muscle-cells. A few cases of similar origin are reported.

CHAPTER XVI
ANGIOMA

' Angioma is a tumor composed of newly formed vessels. Both Wood- and
lymph-vessels are subject to neoplastic growth, giving the two classes of tu-
mors, hemangioma and lymphangioma.

HEMANGIOMA

The determination of the scope of neoplastic processes affecting blood-
vessels presents unusual difficulties. Vessels occupy an altruistic^ position

FIG. 57. — Plexiform angioma of skin. Slowly growing and benign

in the physiology of organs, subordinating themselves to more specialized
structures. Possessing less natural autonomy they may be expected to
display pronounced neoplastic properties. Thus practically normal blood-
vessels support highly malignant tumor-tissue. The supply of vessels in a
tissue or organ varies extremely in both normal and pathological conditions.
Not being composed of a simple tissue tumors of vessels must be organoid
in character. The growth of vessels is markedly influenced by the element
of mechanical pressure of the circulation, which is absent in other tumors.
Finally the nutrition of vessels, especially of those subject to tumor growth,
is provided in a different manner from that existing in other tissues. Thus
the physiology of vessels necessitates special standards in the interpretation

218

AXGIOMA 219

of tumor processes, and this peculiarity has led to much difference of opinion
as to what constitutes an angioma.

From the angiomas may at once be excluded several processes marked by
overgrowth of vessels.

Hypertrophic granulation tissue presents an extensive newgrowth of
vessels in sinuses, abscess walls, suppurating cysts, and in closed tissues,
with circumscribed enlargement of tissue. Yet it is self-limiting, regresses
upon removal of the irritant, and the structure of the vessels shows absence
of the histological signs of a neoplasm. In rare instances, however, without
clinical data it may be difficult to separate this process from angioma, but a
definite relation between chronic granulation tissue and any of the charac-
teristic vascular tumors can rarely be established. On the other hand there
are many indications that certain sarcomas arise from granulation tissue.

Chronic varicosities are established in veins and arteries in several con-
ditions which do not constitute tumors, as varicose veins in the limbs, sper-
matic cord, and broad ligament, and in diffuse aneurisms which follow trauma.
In hemorrhoids the varicosities are the result of venous stasis and chronic
inflammation. In inflammatory polyps extensive development of veins
often results from venous stasis.

Excessive development of blood-vessels occurs in many tumors as a
result of venous stasis or unusual demands for nutrition. Very often such
vessels present a normal or nearly normal structure and do not exhibit neo-
plastic growth. Such tumors are not true angiomas but their vascularity
may be indicated by the term " angioma tosum," as fibroma angiomatosum.
The demands for nutrition in rapidly growing cellular tumors may produce
a type of growth which is composed chiefly of blood-vessels sheathed by
masses of tumor-cells, and which is often called perithelioma, or telangiec-
tatic sarcoma. This rather characteristic structure is not confined to any
one class of tumors and it is not essentially a tumor of blood-vessels.

Over against these processes in which there is excessive development of
more or less normal vessels stands a large class of tumors in which a neo-
plastic process affects the walls of vessels and usually also the supporting
connective tissue, and these constitute the true angiomas.

In general angiomas are of congenital or early development, slow growth
and benign course, and they occur under rather characteristic clinical
conditions.

Hemangioma Simplex. Vascular Nevus (Telangiectasis). — This type of
angioma occurs in several forms.

J? evils vinos-us, or the port-wine stain, consists of a circumscribed or
diffuse dilatation and newgrowth of superficial capillaries and venules of the
derma over which the epidermis is usually thin and delicate. The dilated
capillaries lie immediately beneath the epidermis so that the color of the blood
is imparted to the skin. They are usually congenital and the face is the chief
locality affected. A similar process affects the subcutaneous tissue and fat,
where it fails to yield a discoloration of the skin. According to Unna
nevus vinosus is to be separated from the true angiomas of the skin, since it
consists of a simple telangiectasis of venous capillaries and does not progress
after birth. Nevertheless it and the deeper congenital nevi have often been
the source of extensive plexiform and cavernous angiomas. It may be classed
with Albrecht's hamartomas.

Plexiform angioma consists of a newgrowth of dilated capillaries in which
the length of the vessels is increased but the number of new cells is not in
great excess. Small veins and arterioles are also involved. This process
causes a definite enlargement and tumor of the subcutaneous tissue, with

220

N EOF LA STIC DISEASES

flat or warty projections of the skin. Circumscribed tumors of this class
occur in the skin of the face and especially in the eyelids of young children.
In a few cases multiple and diffuse tumors with considerable newgrowth
of connective tissue have occurred, chiefly in the arms and face of children
and adults, and have been described under the term elephantiasis hemangio-
matosa, or nevus vase, mollusciformis (Seifert, Fox, Kaposi, Unna). In
Jackson's case the process followed the course of the facial nerve. The plexi-
form angioma or deep nevus is located in the derma or subcutaneous tissue
or in the fat tissue and commonly extends from one to the other. It may
even invade the muscles and bones and eventually involve considerable areas

FIG. 58. — Simple cellular angioma, or angio-endothelioma.

and even a large portion of a limb. Occurring in embryonal fissures in face,
cheek, lip and neck, it has been called jissural angioma.

Angioma often begins in the vessels about the sweat-glands which may
become atrophic and fibrosed or hypertrophic. An imperfect formation of
lobules may be observed in relation to the cutaneous glands, or from natural
anatomical septa in the fat tissue. The new vessels have the characters of
arterioles rather than \enules, but many sizes and types of vessels may occur
in the same tumor. Cellular hyperplasia in the vessel-walls is constant.
The endothelium is much increased and appears in one or more layers.
It is sometimes exfoliated or degenerated, and dilated vessels may be lined by
giant-cells. Elastin is deficient or absent, and muscular tissue is usually
deficient.

Angioma of the muscles occurs in subjects under 30 years of age, chiefly
in the triceps femoris and forearm, occasionally in other regions. It produces

ANGIOMA 221

moderate enlargement of the part with turgescence and impairment of func-
tion. Muscatello describes four histological varieties: (i) Capillary and
progressive; (2) arterial, (j) venous, (4) cavernous. Pupovac observed
multiplication of lymph- as well as blood-vessels. In a series of 46 cases
tabulated by Sutter the above histological varieties were variously combined.
The process usually began with a proliferation of muscle-cells in the walls
of venules and in several cases there were polypoid myomatous outgrowths
into the lumen and fusion of contiguous vessel-walls with subsequent dila-
tation of channels. The atrophic muscle-fibers were replaced by fat-cells.
Angioma of muscles may extend to other tissues. I have examined a plexi-
form angioma involving the subcutaneous tissue, fat, and nearly all the mus-
cles of the forearm of a young girl.

Hemangioma hypertropkicum (Ziegler) is a cellular form of capillary
angioma occurring chiefly in the skin. Nauwerck described a very simila'r
tumor occurring in the femur. It consists of a large number of small vessels
lined by hypertrophic and neoplastic endothelium. The vessels usually
maintain a scanty lumen but the proliferation of endothelium may obliterate
the lumen and yield compact groups of cells. In this form the tumor is vir-
tually an endothelioma and in this and the transitional forms it may be des-
ignated as hemangio-endothelioma. Distention of the cellular vessels may also
occur giving a cavernous variety of the tumor. In many simple angiomas
especially in the growing edges and in fat lobules, the structure is that of
hemangioma hypertrophicum. Pure tumors of this type are usually pro-
gressive and if very cellular may exhibit local malignancy.

Histogenesis. — Ribbert has analyzed in detail the origin and growth of
simple angioma. By means of interstitial injection he finds that the vessels
have few or no lateral anastomoses, while the injection mass passes freely
into the efferent artery and afferent veins but not into the tissue surrounding
the tumor. This result indicates that the tumor process resides in an iso-
lated segment of the vessel-walls and produces elongation- and varicosities
in a more or less closed territory without gradual involvement of surrounding
vessels. Where the tumor forms a new lobule or invades fat or other tis-
sues it is not by extension of ttte tumor process to the healthy vessels of the
new area but by the projection of new vessels which grow out from the tumor
while the vessels of the invaded part are compressed and occluded. The mi-
croscopical structure shows that the process affects both the walls of the ves-
sel and the supporting connective tissue. In the invaded fat lobules Rib-
bert finds isolated tumor-vessels connected by long strands with the main
tumor, while between the fat-cells parallel rows of endothelial cells appear
which later become thickened and canalized. These new structures seem to
have no connection with the normal vessels of the invaded tissue.

Thoma refers much of the growth of angioma to mechanical factors.
Increase of blood-pressure and loss of support to vessel-walls from changes
in the surrounding tissue tend to excite new growth of vessels, while increased
rapidity of flow favors elongation and dilatation of the wall. Many authors
(Rokitansky, Borst) consider that many simple so-called angiomas represent
simple hypertrophy of vascular segments without neoplastic overgrowth.
These factors are doubtless important in determining the course of angiomas
but they cannot account for their origin, which must be referred to a develop-
mental anomaly in the structure of certain vascular segments which do not
fit into the circulatory system, and which retain embryonal characters.
The congenital origin of the great majority of angiomas speaks strongly in
favor of a tissue predisposition as a prominent factor in their genesis.

Virchow believed that angiomas result from the action of local irritation

222

N EOF LA STIC DISEASES

on imperfectly formed vessels, as those in embryonal fissures. Unna was
led to believe that nevus vinosus especially occurs in areas which have been
subjected to abnormal pressure during fetal life. The relation to nerve-
trunks has suggested to many a neurotic theory of origin. In not a few
cases a traumatic origin is clearly indicated (Lowenthal, Lit.).

Cavernous Angioma. — When the vascular channels are widely dilated
and the connective tissue septa are thin, the angioma is designated as cavern-
ous. This process is of frequent occurrence in many situations and in nearly
all tissues and organs. In the skin cavernous angiomas produce circum-
scribed or diffuse, flat or elevated lesions, involving the derma and subcuta-
neous tissue. If superficial they are dark red in color. If covered by cor-

FIG. 59. — Metastasizing angioma, secondary nodules in lung. (Borrmann.)

rugated and thickened epidermis, they become warty. Changes in the
circulation affect both the size and color of the tumors. Many of them are
distinctly erectile and pulsating. Thrombosis and the formation of cal-
cific phleboliths occur in dilated sinuses. The smaller tumors are usually
encapsulated and stationary but there are many cases of diffuse cavernous
angioma in which a capsule is missing and the limits of the process gradu-
ally extend over many years.

The cavernous angioma first appears as a circumscribed tumor developing
often on the basis of a congenital nevus and tends to enlarge steadily over a
period of many years. They may be observed at birth or appear at any age.
When allowed to progress they may attain very large dimensions, and
successively invade neighboring tissues and organs. In some of the older

AXGIOMA

223

cases, extraordinary results were produced. Gascoyen observed an angioma
of the parotid which progressed for many years, produced a large polypoid
tumor externally while a pharyngeal portion eventually caused death by
suffocation. Autopsy showed several nevi of the intestinal serosa and
mucosa and one in the liver. Cruveilhier described a cavernous angioma
involving the skin, muscles, tendons, synovial membranes, nerves, and
periosteum of nearly the whole arm of a 65-year-old hemiplegic. Falkowski
reports peculiar cavernomas of liver and spleen and angiomas of skin in an
infant.

The subcutaneous angiomas may gradually involve the skin and the
deep fascias, and some which first appear subcutaneously originate in much
deeper tissues, or they establish wide communications with deep venous
trunks.

Multiplicity of cavernous angioma is a prominent feature in some cases.
The minute senile angiomas of the skin usually appear in considerable num-

FIG. 60. — Structure of metastasizing angioma. (Borrmann.}

bers. Large multiple cavernomas of widely separated regions occurred in a
case of Hildebrand's. The smaller cavernous angiomas are often multiple,
as many as forty or even a hundred having been observed in one subject
(Esmarch, Schuh).

Sharply contrasted with the multiple benign cavernous angiomas is a
group of metastasizing cavernous or more cellular angiomas which exhibit
certain peculiar features of malignancy, and are eventually fatal, chiefly
through internal hemorrhage and anemia. Here belongs the remarkable
case observed by Borrmann in which angioma of the skin of the breast in a
subject of 23 years recurred repeatedly after operation and finally proved
fatal with numerous secondary tumors in both lungs. The original tumor
had the structure of simple angioma but the secondary growths were
more cellular.

In a case observed by the writer the breast was greatly enlarged by a
bulky cavernous angioma, several tumors appeared on the skin and mucous

224

NEOPLASTIC DISEASES

membranes, and there were evidences of pulmonary involvement. The
structure was very similar to that in Borrmann's case.

In Shennan's remarkable case, of six years' duration, marked by numerous
hemoptyses, there were found at autopsy cavernous angiomas involving
the whole of the spleen, much of the lungs, the thymus and mediastinal nodes,
liv^er and bone-marrow, while many miliary angiomas occurred in other
tissues. The structure was generally not malignant in appearance, but
the small tumors and some of the larger were doubtless metastatic, and
exhibited a local invasive tendency.

FIG. 61. — Metastasizing angioma of left breast. Note tumors of jaw, neck, under ear, and
at right axilla. There were tumors also in pharynx and lungs.

The course of cavernous angioma is usually slowly progressive. Begin-
ning in congenital nevi or in deep tissues, at any period of life, they slowly
enlarge by distention of the original vessels and by formation of new vessels.
The growth is sometimes accelerated at the menstrual period and during
gestation. Free anastomoses with large arteries or veins may become estab-
lished and severe, or fatal hemorrhage may occur. A capsule forms about
many tumors which are then apt to remain stationary. Spontaneous
regression may result from contraction of the capsule, thrombosis, inflam-
mation, or ulceration, or a cure may be affected by continuous pressure,
ligature of vessels, or excision. Very slight interference is sometimes
sufficient. Intercurrent diseases or cachexia may initiate the regression.

ANGIOMA 225

Recurrence after operation has often followed incomplete removal. A
certain local malignancy is also exhibited by tumors which extend from one
tissue to another, leading even to the erosion of bones, and occasionally
pressure symptoms become serious.

The structure of cavernous angioma presents chiefly a series of anastomos-
ing vascular channels inclosed by thin septa. The appearance on section
may be roughly compared to that of a sponge. Yet in less advanced cases
it is possible to recognize simple spherical sacculations, and tubular dilata-
tions, all connected with one main afferent and one efferent vessel. Large
cystic dilatations may occur, filled with blood or serous fluid. The walls
exhibit the structure of venules or less often of arterioles. Hyperplasia
of cells may lead to nodular growths of new tissue projecting into the lumen.

FIG. 62. — Cavernous angioma of liver.

Many authors have described the budding of new vessels on the advancing
edges of cavernous angioma. In progressing cases certain areas of the tumor
may show the numerous cellular vessels of simple or plexiform angioma,
so that it is not always possible to separate cavernous from simple angioma.

v. Recklinghausen and others locate the earliest stages of the cavernous
angioma in the walls of the veins, while many believe the capillaries are first
affected (Borst). I have drawn the impression that either veins or capillaries
may be involved in different cases.

Histogenesis. — In the development of cavernoma Rindfleisch and Borst
attribute chief importance to a fibrocellular growth in and about the walls
of the capillaries. The retraction of this new tissue tends to shorten the
vessel, dilatation resulting from mechanical pressure. The same relation
between connective-tissue growth and vascular dilatation is observed in
cavernous fibromas, so that the cavernoma has been likened to a fibroma

226 NEOPLASTIC DISEASES

with excessive development of vessels. Loss of muscular and elastic tissue
in the new or altered vessels must also greatly favor the dilatation. In
regressing cases a fibrous capsule forms or fibrous areas appear in the tumor,
the sinus walls thicken and contract, and eventually only scar tissue remains.

The question of the neoplastic nature of cavernous angioma has been
extensively discussed. When one examines a stationary cavernoma of the
liver it is difficult to recognize any definite feature of a tumor and many
have assumed that these and a considerable proportion of other localized
dilatations of vessels should be separated from the angiomas and referred to
mechanical factors. There is no doubt that simple varices may simulate
the structure of cavernous angiomas and have often been classed with this
tumor. The gross dissection of certain angiomas strongly suggests that
simple saccular and tubular dilatations of preexisting veins will explain
their origin. Yet Virchow traced the earliest stages of cavernoma of liver
to islands of proliferating connective tissue surrounding cellular capillaries,
and Ribbert finds on the edges of cavernoma new vessels which communicate
freely with those of the tumor but imperfectly with those of the surrounding
tissue. Local varices can usually be distinctly separated from angioma in
the same* tissue. The usual origin of cutaneous angioma is from congenital
simple or plexiform angioma which is admittedly a neoplasm. It is thus
apparent that in the growth of cavernous angioma there are essential factors
other than mechanical dilatation of vessels, and it is most reasonable to
regard these factors as partaking of the neoplastic order. Albrecht regards
cavernoma of liver as an ill-fitted but practically normal segment of tissue
which possess a limited capacity for aberrant growth. For this and many
other benign tumors he introduced the term hamartoma.

The clinical features of cavernous angioma fall into several rather well-
defined groups. The cutaneous tumors form the most numerous group.
They are located in the derma or subcutaneous tissues, chiefly in regions
where the skin is loose. While no region of the body escapes, the chief
locations are the fax:e, scalp, labia, scrotum, prepuce, extremities, and folds
of the knees, axilla, and buttocks. The influence of embryonal fissures
noted in the occurrence of simple angioma is observed also with the cavernous
type. The wide variations in the origin, growth, size, number, and complica-
tions of these tumors is elaborately set forth in the detailed reports of cases
collected by Virchow.

Submucous cavernomas occur chiefly in the buccal region. The gum
is the seat of a common cavernous tumor which may follow violent extraction
of molar teeth. It usually remains of moderate dimensions but may gradu-
ally extend until it involves a considerable portion of the alveolar tissues
and establishes connections with large veins. At this stage its extirpation
is difficult and has produced fatal hemorrhage.

In the tongue cavernous angioma arises usually in the tip of the organ
and may extend until it produces an erectile tumor of large dimensions
(Reiche) . Both lymph- and blood-vessels participate in the process in certain
cases of angiomatous macroglossia (Wegner). A form of angiomatous
ranula has been described by Delbeau. The lips are frequent seats of con-
genital nevi and of cavernous angiomas.

Orbital angiomas affect either eyelid and may involve the conjunctiva.
In the retroorbital fat a few diffuse and circumscribed cavernous angiomas
have been described (Morton, Schuh, di Ricci). These tumors may extend
along the optic nerve into the eyeball (Quackenboss).

Angioma of bone is rare, although overgrowth of vessels is a prominent
feature of many malignant bone tumors, and bone-tissues are often eroded

ANGIOMA 227

by extensions from angioma of adjacent tissues. The extensively cavernous
tumors of the long bones, especially of humerus and tibia, must be classed
histologically as sarcomas, although some of them may be successfully treated
by curettage or ligation of the main vessels. True cavernous angioma may
arise in the periosteum or in the marrow (Virchow, Kauffmann). They in-
vade the outer layers or cause absorption of the shaft. Extensive angiomas
of the skull have been observed by Kauffmann and by Schoene, and of the
vertebrae by Gerhardt, Kauffmann and Muthmann. I have studied one
cavernous angioma of the head of the humerus which appeared beneath a
thin shell of bone two years after trauma. In a case of slowly progressive
paraplegia I found a cavernous angioma of a dorsal vertebra, which permitted
collapse of the body and gave rise to a protruding tumor which compressed
the cord.

In the glands angioma occurred in the parotid in the case of Gascoyen,
and in several cases the breast has been extensively transformed into caver-
nous tissue by tumors arising in the fat (Virchow, Image, Borst, Hake).

In the internal organs cavernous angioma occurs chiefly in the liver,
rarely in the spleen (Albrecht), kidney, and uterus (Virchow). Dowd has
collected 13 cases of angioma of the spleen, illustrating small tumors found at
autopsy, very large growths removed at operation, malignant tumors produc-
ing metastases, multiple benign tumors in spleen, liver, omentum, and skin,
and a progressive anemia accompanying the large growths.

The common cavernoma of the liver is of much theoretical interest but
rarely produces symptoms. They are single or multiple, as small as a pea
or as large as a child's head (Ribbert), and usually lie just beneath or project-
ing from the surface. They are often associated with angioma of other or-
gans. Their frequency increases with the age of the subjects but congenital
cases rarely occur. Veeder and Austin describe a remarkably extensive
multiple congenital hemangioma of the liver. Virchow believed that they
might spontaneously disappear, leaving scars. The structure shows central
sinuses separated by thin fibrous or cellular septa which may contain
islands of liver cells. On the edges are smaller vessels communicating with
the sinuses. The tumor is sharply marked off from the parenchyma. Rib-
bert finds that interstitial injections of the tumor or of the surrounding
parenchyma do not pass from one tissue to the other, the tumor-vessels
showing a marked independence of the normal vessels of the organ. Yet
the tumor may be filled by injections through the portal or hepatic veins or
hepatic artery (Virchow).

The origin and nature of the cavernoma of the liver has long been a
subject of discussion, the later phases of which have been maintained by
Ribbert and by Schmieden. On the whole the argument seems to favor the
contention of Ribbert, that these growths are partial neoplasms originating
from embryogenic disturbances, through which a displaced segment of the
organ comes to possess a limited power of aberrant growth. As already
stated, Virchow traced their inception in areas of proliferating vascular con-
nective tissue. The progressive dilatation of vessels naturally results from ab-
sence of muscular and elastic tissue in the walls.

In the ovary Gottschalk describes a diffuse bilateral cavernous transfor-
mation. Orth observed a remarkable case of multiple congenital hemangi-
omas in both ovaries, skin, and other organs of a child.

Angioma of the brain occurs in two main forms, as (i) a more or less
diffuse varicosity of the vessels of the meninges, and (2) a true angioma, sim-
ple or cavernous, of the brain tissue. La Villette has collected 18 cases of
both types in various situations. Several cases have occurred in the region

228 N EOF LA STIC DISEASES

of the corpus striatum (Virchow, Luschka). They are probably of con-
genital origin, and in Hebold's case the intracranial was associated with cu-
taneous angiomas. They are of slow growth and usually produce only gen-
eral symptoms. Wergman's cavernous angioma of the left cerebellar
pedicle led to fatal hemorrhage. Orbison reported a racemose angioma of
cerebral pia invading the brain tissue and giving a long history of epi-
lepsy. Several cases of angioma in the substance of the pons are recorded by
LaFora and by Enders. One of LaFora's cases terminated after severe gen-
eral and focal symptoms lasting one month. The structure is that of sim-
ple or cavernous angioma.

Angioma arteriale racemosum consists of a dilatation and complex inter-
twining of many new formed and altered vessels of small caliber with sub-
sequent involvement of normal vessels (Deetz). The condition occurs in
infants or adults, and of 87 cases collected by Schuck 84 occurred on the
head, a few on the extremities. They usually arise in close connection with
the large carotid artery. The external appearance was likened by Virchow to
a pulsating mass of earthworms. Arising externally they extend over the
neck and scalp, erode the skull and penetrate the cranium, and in several
cases they have involved the cerebral and meningeal vessels. The walls of
the vessels show a variety of changes, as fatty degeneration and loss of
muscle- tissue of the media (Heine), hypertrophy of media (Lablee) hyper-
trophy of interna (Kretchmann), or hypertrophy of all coats. Emanuel
described leiomyomatous outgrowths of the media with degeneration, calcifi-
cation and formation of aneurisms. Deetz found uniform hypertrophy of
small arterioles and newgrowth of cellular capillaries. The exact position
of this process is difficult to determine but most authors .assume that it
arises from a congenital tissue abnormality and that it belongs in the class
of partial tumors.

LYMPHANGIOMA

Lymphangioma is a tumor composed of lymph-vessels.

It is therefore an organoid structure consisting of endothelial cells and
supporting connective tissue, both of which are involved in the neoplastic
process. Lymph-nodules or foci of round-cells are often present to complete
the parallel with a lymphatic structure. Lymphangioma has also been
associated with minute islands of lipoma, proliferating smooth muscle-cells
may be found in the septa, and Ritschl found an island of cartilage in an
intermuscular lymphangioma, observations which suggest an embryogenic
origin. New formed lymph-vessels are also present in many benign and ma-
lignant tumors, especially with endothelioma and sarcoma.

The clinical conditions which fall in the general class of lymphangioma in-
clude a variety of slowly growing, usually congenital, single or multiple tu-
mors of the skin, subcutaneous tissues, deep areolar tissues and muscles, of
the neck, trunk, lips, tongue, eye and orbit, and mediastinal and retroperi-
toneal regions. In the pathogenesis of these conditions many factors are
concerned and it is thus more difficult to distinguish between lymphangioma
and lymphangiectasis than between true and spurious hemangioma.

Ribbert's definition of lymphangioma as an isolated group of vessels
growing from their own resources and more or less disconnected from sur-
rounding channels can seldom be directly applied. In some typical examples
of lymphangioma the tumor has been found freely accessible to injections
through afferent and efferent vessels (Langhans).

Proliferating buds of endothelium forming new lymph-vessels have been
fully recognized in certain cases by Nasse, Schmidt, and Borst, but such

ANGIOMA 229

structures are usually missing. Size is not a reliable criterion since in some of
the large cystic growths the signs of a neoplasm are least distinct. More-
over, simple occlusion of large lymph paths may, although rarely, be fol-
lowed by extensive varicosities resembling lymphangioma. The appearance
of the stroma sometimes suggests a neoplastic growth but more often it is
fibrous or comparatively acellular. The general clinical features seem to
offer an important means of recognition of true lymphangioma, and many
would include in the class only such processes as show a congenital origin and
a progressive course, and absence of traumatic and inflammatory factors.
The histological structure of lymphangioma was first fully described by
Wegner who recognized three groups of cases, i. Lymphangioma simplex
consists of an anastomosing network of spaces and vessels of small and
medium caliber. The septa are either reduced to thin strands of acellular
connective tissue, or they are thicker and participate in the proliferation.
The endothelium is flat or cubical and rarely it may appear in multiple
layers or in the form of projecting buds (Freudweiler).

2. Lymphangioma cavernosum consists of a system of closed communi-
cating lymph-spaces supported by thin walls or thicker septa, lined by flat
endothelium and filled with fluid' or coagulated lymph occasionally mixed
with blood.

3. Lymphangioma cystoides consists of a congeries of large and small
cysts lined by flat endothelium and filled with lymph. Some of the cysts
may be closed and the main lymphatic vessels are usually occluded.

The great majority of lymphangiomas fall readily among these classes,
most of them being of the cavernous type. In not a few cases there is new-
growth of blood-vessels not communicating with the lymphatic system, and
forming a mixed hemolymphangioma (Nasse, Sutter, Novack).

In the development of lymphangioma several factors seem to be con-
cerned. Wegner believed that three modes of origin could be traced, (a)
passive dilatation with inflammatory hyperplasia of preexisting vessels,
lymphangiectasis, (6) neoplastic growth of vessels, and (c) heteroplastic for-
mation of lymph-vessels in granulation tissue.

(a) Lymph stasis doubtless influences the course of many lymphangiomas,
especially the large cystic type with occluded vessels, to a less extent the
saccular ectasise of the cavernous forms, but it has not been accepted as a
sufficient explanation of any of the characteristic varieties of lymphangioma.
Ribbert argues that any marked pressure would inhibit the growth of endo-
thelium, and it is clear that with free afferent and efferent vessels the stasis
must be slight. Ribbert assumes that lymphatic and other cystic tumors
develop as a result of a process of growth located in the walls which steadily
enlarges the circumference of the cysts and prevents the passive accumu-
lation of fluids. Secondary dilatation of new-formed vessels must be re-
garded as an important factor in cavernous and cystic lymphangiomas.
Intermittent attacks of inflammation influence the course and structure of
many lymphangiomas (Kuttner).

(b) The evidence of new formation of vessels is conclusive, for in many
cases have been observed hypertrophic and proliferating endothelium,
multiple layers of endothelium, and sprouts of endothelium growing out into
the connective tissue with subsequent canalization. Borst depicts the for-
mation of new lymph- vessels in a small fibromatous tumor in fat tissue where
lymph-vessels are normally scanty. In a type of cutaneous lymphangioma
the predominance of endothelium has led many to designate the process as
endothelioma and other types of endothelioma arise from lymphatic en-
dothelium. The occasional occurrence of definite fibroma and lipoma in

230

NEOPLASTIC DISEASES

lymphangiomas illustrates the organoid character of these tumors and
demonstrates the neoplastic growth of lymph-vessels.

(c). The heteroplastic formation of lymph- vessels in granulation tissue
has not been satisfactorily demonstrated.

In the origin of lymphangioma it must be assumed that there exists a
local predisposition resulting from an embryogenic disturbance similar to
that assumed for hemangioma. Of the nature of this disturbance nothing is
definitely known, but the congenital origin of most lymphangiomas is a strik-
ing feature in their etiology. A partial isolation of a segment of lymph-
vessels with imperfect development and retention of abnormal powers of
growth may be supposed to exist. The occurrence of cartilage in one re-
ported lymphangioma indicates that the isolation may be complete. I have
seen a circumscribed lymphangioma 2 cm. in diameter attached to the sper-

FIG. 63. — Structure of a congenital angiolymphoma occurring in skin of cheek of an infant.

matic cord. The vessels were lined by large cuboidal endothelium and sup-
ported by embryonal connective tissue. In a congenital flat tumor of the
subcutaneous tissue of the cheek I found many lymph-follicles and diffuse
lymphoid tissue in the septa of a cavernous lymphangioma. The structure
suggested an abortive attempt at the formation of a lymph-node.

The clinical forms of lymphangioma are numerous and difficult to classify.

Simple lymphangioma , consisting of moderately dilated and slightly
hyperplastic vessels in which a neoplastic element is either wanting or feebly
developed, occurs in many situations, chiefly in the skin. In elephantiasis
dilated lymph-vessels contribute largely to the increased bulk of the tissues.
In the lymph-scrotum of filariasis the swelling is referable to lymphangiec-
tasis and edema, and may be traced to occlusion of lymphatic trunks by
the parent worms. The process commonly involves the bladder with chy-

ANGIOMA

231

luria and the presence of filaria embryos in the urine. The tissues show only
inflammatory reaction and the process is not a tumor.

In the skin of face and neck congenital lymphangiectasis produces small
or large flat or wart-like prominences which after trauma may exude serous
fluid. They consist of dilated lymphatics of the derma. The endothelium
is slightly hyperplastic, but their chief neoplastic character is the occasional
relation to embryonal fissures and their congenital origin. In a case of Haug's
the tongue was involved and there was a congenital auricular fistula.

In lymphangioma cutis circumscripta, the skin of face, chest or extremities
is the seat of numerous small projecting translucent vesicopapules which on

FIG. 630. — Superficial diffuse lymphangioma of entire tongue, existing since infancy in

a boy of 19 years.

section prove to consist of many small cellular lymph- vessels. The endothe-
lium is hypertrophic and proliferating, and the channels are small and filled
with fluid or hyaline masses. There is extensive new formation of imperfect
lymph-vessels and the process is a true neoplasm (Fox, Hutchinson, Noyes,
Torok, Freudweiler, Waelsch).

Lymphangioma tuberosum multiplex was described by Kaposi as a small
superficial multiple tumor of cellular lymph- vessels. Beneke's case falls
in that histological group. The nature of other cases in dermatological
literature is not clear (Crocker, Perry, Kromayer).

In the eye lymphangiectasiae of congenital or inflammatory origin occur
in the conjunctiva. They may reach considerable dimensions and occasion-
ally there are evidences of considerable new formation of vessels (Steudener,
Bull, Wintersteiner, Sachs).

232, NEOPLASTIC DISEASES

Lymphangioma cavernosum occurs chiefly in the skin but also in the
intermuscular septa and in the mucous membranes. The dilated vessels
are filled with coagulable lymph often mixed with blood, and the contents may
be thrombosed, or hyaline, or extensively calcine. On analysis the aspirated
fluid shows a considerable content of blood-proteins and salts, many lympho-
cytes and exfoliated endothelial cells and usually cholesterin crystals. It lacks
the digestive ferments of pancreatic cysts (Sick, Bryck, Zeyneck). The septa
are thin and acellular or thicker and composed of proliferating connective
tissue, containing round-cells, lymph-nodules, and often much smooth muscle-
tissue. Newgrowth of small vessels is often associated with the larger ones.
The tumors are small and circumscribed or extend diffusely over considerable
areas.

In the skin elephantiasis lymphangiectatica may exhibit extensive dilata-
tion of old and new formed lymph- vessels.

The most frequent forms of cavernous lymphangioma occur in the lip,
cheek, and tongue and are designated as macrocheilia, macromelia, and
macroglossia. They are usually congenital and produce irregular and some-
times extensive enlargement of the tissues. The pharynx and larynx may
also be involved (Suchstorff, Nasse).

Chylangioma of the mesentery is a cavernous lymphangioma containing
milky fluid which arises from congenital or acquired obstruction to the lacteal
vessels (Kruse, Schmidt, Ritter). Multiple dilatations of the submucous
lymphatics of the intestine were observed by Krauss, and extensive grades
of this condition have been reported by Blatteis, Thalheimer, and Takano.

Cavernous lymphangioma occasionally occurs in the conjunctiva, eye-
lids, and orbit (Michel, Steudener, Sachs). Klien described a case occurring
in the vagina.

Extensive cavernous lymphangioma of the foot resembling elephantiasis,
multiple lymphangioma of the finger, hands and pleura, and hyperplasia of
many lymph-nodes, were associated in a remarkable case reported by Bryck.

Lymphangioma cysticum is a multilocular cystic tumor which occurs
chiefly in the neck and sacral region. They are usually of congenital origin
and exist at birth or shortly develop into tumors of considerable bulk and
wide extent.

Hygroma cysticum colli is a lymphangioma wThich usually arises in the
submaxillary region and ramifies upward toward the parotid and ear, inward
toward the median line, and downward to the supraclavicular fossa and even
into the pleura and mediastinum (Nasse, Suckstorff). One class of these
tumors occurs deep in the neck, reaches below the sternal notch and seems
to be connected with the thyroid (Otto). In one case which came to my
notice the cyst lay close to the trachea and reached from the sternal notch to
the inferior thyroid artery. Lymphangioma of the neck must be distinguished
from hydrocele colli, which is a simple dilatation in a branchial cleft,
lined by epithelium and walled by fibrous tissue containing lymphoid tissue
(Frobenius). The axilla and thoracic wall are occasionally the seat of cystic
lymphangioma (Nasse). Bilateral congenital cystic lymphangioma of the
back of the neck has been described by Frobenius.

Retro peritoneal and mesenteric lymphangioma occurs in children and adults
as a multilocular cavernous and cystic tumor, originating along the spinal
column and ramifying into the pelvis behind the kidney or colon, upward to
the liver, spleen and pancreas, and into the mesentery or omentum (Takano,
Lit.). The receptaculum chyli and thoracic duct have been found unaffected
by the process (Sick, Smoler, Schwarzenberger). Lion has reported a case
of lymph-cyst of the broad ligament. In a case of the writer's the broad

ANGIOMA

233

ligaments were chiefly involved with extensions throughout the pelvis and
along the lumbar spine.

The very early stages and exact origin of these tumors have not been
demonstrated, and as Hedinger points out, they require differential diagnosis
from a variety of other abdominal cysts. Their neoplastic nature seems
assured since the walls contain cellular connective tissue, often much smooth
muscle-tissue, and lymph-follicles. After partial removal the remaining
portion may rapidly increase in bulk. Along the edges of the growths,
Sick found proliferating areas of cavernous lymphangioma. He assumes that
they arise from misplaced and embryonal islands of connective tissue and
lymph-vessels. In the omentum and mesentery of newborn cats and pigs
Ranvier has demonstrated such misplaced islands of tissue.

FIG. 64. — Papillary growth in a cervical lymph-node which was the seat of chronic lymph-
stasis. Papillary fibro-endothelioma.

In the wall of the stomach and gastrohepatic ligament, Reimers and
Tilger have found small lymph-cysts which they referred to obstruction
of vessels following gastric ulcer.

Sacral hygroma is a cystic tumor developing in the region of the sacrum
and usually connected w'ith defects in the spinal canal. Some of them are
probably aberrant meningoceles. Borst found a large multilocular cystic
tumor in front of a defective sacrum and connected by a strand of tissue with
the spinal canal. Virchow described an external pedunculated hygroma
attached to the sacrum of a negro infant and containing a lymph-cyst and
portions of nervous tissue. Attached by a pedicle to the liver of 'a child

234 NEOPLASTIC DISEASES

of five years, Maresch found a large cavernous and cystic lymphangioma.
In the adrenal and in the uterine musculature, lymph-cysts have been de-
scribed by Sick.

In the ovary Kroemer finds lymphangioma of small dimensions not in-
frequent. Besides telangiectatic fibroma he describes two large cystic
lymphangiomas, in one of which the endothelial cells were prominent,
suggesting the designation fibro-endothelioma.

CHAPTER XVII
SARCOMA

General Characters. — Sarcoma is a malignant tumor composed of cells
of the connective-tissue type.

This definition is based on the morphology of the tumor-cells and on their
histogenesis. It accomplishes the main object of separating a large group
of malignant tumors from the carcinomas, but it overrides certain embryo-
logical considerations.

Thus it permits the inclusion of gliosarcomas which are of ectodermal
origin, and it accepts as sarcoma certain tumors, chiefly of endothelial origin,
while rejecting others. This position seems justified by the history of the
development of the conceptions of sarcoma, as ably sketched by Malherbe,
by certain anatomical and clinical features of the group, and by the peculiar
part played by the blood-vessels in the growth of many sarcomas. Never-
theless, it cannot be claimed that the effort to stretch the scope of the term
sarcoma over an extensive field of neoplasms has been entirely successful.
The diseases included in this group, such as angiosarcoma, lymphosarcoma,
and gliosarcoma, are of such varied origin and character that some writers
have urged the elimination of the term sarcoma. This radical reform has
not received approval since there are many common features among
sarcomas and the group as a whole is well-defined from carcinomas. Yet
future investigation will doubtless reveal many new and more precise facts
regarding the etiology, conditions of incidence, histogenesis, and clinical
course which will warrant the recognition of many sarcomas as specific
pathological entities.

The original conception of sarcoma as a tumor of fungating, soft or fleshy
character reflected truly the gross character of most sarcomas, but the
definition based on histogenesis is much more significant. Even this con-
ception of sarcoma we believe is destined to be replaced by etiological criteria.
Since there is often much difficulty in determining the origin of cellular
tumors the accepted scope of sarcomas has been subject to much revision.
In recent years, especially, many tumors once interpreted as sarcomas, have
been proven to be of epithelial origin. Further inroad has resulted from the
identification as endotheliomas, of many tumors once regarded as sarcoma,
but it appears unlikely that the separation between the latter groups will
be rendered complete.

In fact the finer analysis of the origin and composition of many sarcomas
reveals a prominent participation of endothelium in many tumors of distinct
mesoblastic characters. In such cases the characters of the tumor-cells
rather than their embryonal antecedents should determine the classification.
Even the spindle-cell sarcomas have not escaped suspicion, especially
in epithelial organs, since it is a fact too often ignored that squamous and
glandular epithelium may assume a fusiform shape during the vicissitudes of
tumor growth.

Gross Anatomy. — The majority of sarcomas are bulky, soft, and vascular.
In general, the bulky character results from the principle that sarcomas tend
to grow expansively upon a scaffolding of new blood-vessels rather than to

235

236 XEOPLASTIC DISEASES

infiltrate preexisting tissues as do carcinomas. The soft consistence reflects
the cellular structure of a rapidly growing tumor. The vascularity reveals
to the naked eye the prominence of blood-vessels as an essential part of the
growth.

Some specific varieties of sarcoma fail to display the usual features.
Fibrosarcoma is firm, resistant, and non-vascular; osteogenic sarcoma may
be as hard as ivory. In fact, there are so many variations in the appearance
of sarcoma that general statements are of little value and the gross characters
are best detailed in connection with specific tumors. As a rule the gross
appearance depends largely upon the tissue of origin, according to which
one recognizes fibrosarcoma, chondrosarcoma, osteosarcoma, liposarcoma,
myxosarcoma, angiosarcoma, myosarcoma, and lymphosarcoma. All adult
mesoblastic derivatives are represented in the tissues of origin. Gliosarcoma
occupies an especially peculiar position. While its cells of origin are derived
from neural epithelium, the form and function of the adult glia-cells, and
especially the characters of the tumors, do not encourage efforts to reform
current nomenclature in this group.

Sarcomas are usually single, but multiple tumors arise in bone-marrow,
nerve-trunks, and skin. Certain angiosarcomas are multiple or diffuse, and
some forms represent systemic diseases, as lymphosarcoma and myeloma.

Characters of Growth. — The growth of sarcomas is usually rapid and
locally destructive. The abundant blood-supply favors extremely active
cell-growth so that the tumors soon reach a large size, and their bulk is often
sharply increased by edema, hemorrhage, or mucoid degeneration. After
reaching a certain limit the excessive circulation fails and large areas of
necrosis form from infarction. The further growth of the tumor then
depends on its capacity to infiltrate or produce metastases.

Hence some sarcomas regress after extensive central necrosis and not a
few are remarkably susceptible to toxic agents or to absorbents such as .r-ray
or iodide of potash. Hemorrhage from the fragile vessels is prominent
in many vascular tumors. Into the extravasated blood-mass sarcoma-cells
are often observed to grow, replacing the clot.

Following necrosis, sarcomatous tissue is very susceptible to infection
and many cases terminate with local suppuration and gangrene or with
general sepsis. Accordingly, fever is often observed throughout the course
of malignant sarcomas, but in some instances it appears to result from specific
intoxication and not from infection.

Most sarcomas grow expansively, the central portions increasing with
the peripheral. Hence they are rather sharply marked off from the surround-
ing tissue although rarely presenting a capsule.

Infiltrative growth on the periphery fuses the tumor with the surround-
ing tissue so that it is difficult to extirpate and commonly recurs after opera-
tion. The more malignant growths infiltrate widely through fascial planes,
along vessels and nerves and directly through the soft tissues. Penetration
of the skin is followed by more rapid fungating growth with ulceration and
hemorrhage. Cellular bone-sarcomas rapidly destroy bony tissue and perfor-
ate joint cavities. To the attack of other sarcomas bone is resistant. I have
observed very wide infiltration of a spindle-cell periosteal sarcoma which
produced a large tumor of the ilium and spread beneath the periosteum over
the entire ilium, pubes, and upper third of the femur. The extensions of
lymphosarcoma and of myeloma are partly by infiltration and largely by
systemic development of new tumors.

Metastases are observed in the advanced stages of most sarcomas and
it is characteristic of the disease that with rare exceptions the embolic cells

'SARCOMA 237

travel through the blood-vessels. Except in lymphosarcoma, the occurrence
of metastases in lymph-nodes justifies the suspicion that the tumor is not a
sarcoma. The strong tendency of sarcoma-cells to grow upon a framework
of blood-vessels determines the early invasion of these vessels which occurs
even in sclerosing osteogenic sarcoma, while the expansive growth, as opposed
to the infiltration of preexisting tissues in carcinoma, explains the usual
failure to invade lymphatics. Sarcoma tissue itself is usually devoid of
lymphatics.

Cell-emboli thus pass readily into the vessels and lodge first in the lungs
which are the chief seat of sarcomatous metastases, and later they reach
liver, kidney, spleen and other organs and tissues.

General miliary sarcomatosis may result from discharge of very numerous
loose cells, but it is much less frequent than general carcinomatosis. Mechan-
ical pressure of actively growing sarcoma sometimes forces tumor-tissue
into the blood-vessels and thus leads to metastases when the infiltrating
power and capacity for independent growth of the cells appears to be limited.
Thus myxosarcoma of the thigh may be forced into the saphenous and iliac
veins and form a continuous mass filling vena cava, pulmonary veins, and
even reaching the heart. The same extensions of sarcoma of the kidney
have been observed.

Some sarcoma-cells seem comparatively resistant to any destructive
influence that may be exerted by the blood. They have frequently been
found in the peripheral blood. In the blood-vessels invaded by sarcoma
thrombosis is not as common as in carcinoma. Borst states that they
have a certain capacity to grow in the lumen without connection with the
vessel-wall. These considerations may tend to explain the frequency of
metastases by blood-vessels. The metastases of sarcoma often occur much
earlier than is generally conceived and this fact adds to the gravity of the
prognosis after surgical operation. In a considerable series of cases at the
Memorial Hospital the a:-ray photograph of the lungs has revealed pulmonary
nodules in apparently operable cases, especially of bone-sarcoma, and in not
a few which had just recovered from operation.

Structure. — Sarcomas are chiefly histioid tumors. With the exception
of mixed or teratoid growths, a definite arrangement of elements in organoid
form is missing. Yet considerable differentiation of tissues occurs in the
more mature types. Fibrosarcoma may present areas resembling cellular
connective tissue; bony trabeculae appear in many osteosarcomas; embryonal
fat tissue occurs in liposarcoma; while angiosarcoma produces many func-
tionating blood-vessels.

With increasing anaplasia the form and function of the originating cells
are gradually lost.

The controlling factor in the structure of sarcomas is found in the natural
tendencies of the cells of origin to reproduce the mother tissue. Many
authors have traced in the growth of sarcoma a repetition of the embryonal
development of the affected tissue.

In many cases, the origin of the tumor is readily determined by the
presence of cellular connective tissue, cartilage, bone or fat.

In other cases the tumor is highly cellular and reveals few traces of the
original form or function of its cells, and in the most anaplastic types the
cells are round and completely undifferentiated.

According to cell form, sarcomas may be divided into spindle-cell,
round-cell and giant-cell groups, but these terms convey little information,
and, unless the tissue or origin can be stated, no significant diagnosis has
been reached. Since any one of the three above types of structure may

238

N EOF LA STIC DISEASES

arise in sarcomas from each mesoblastic tissue, it is desirable to avoid terms
referring solely to the morphology of the cells.

According to histogenesis sarcomas may be classified as fibroblastic,
angiosarcoma, chondrosarcoma, osteosarcoma, liposarcoma, myosarcoma,
myxosarcoma, lymphosarcoma, and gliosarcoma. In typical cases the
structure of each of these forms is specific.

In general the structure of sarcomas presents an imperfect development
of the tissue of origin. The cells are usully larger and always more numerous.
Very large spindle-cells belong chiefly to malignant fibroblastic, angioblastic,
and myxosarcomas. Quite small spindle-cells also appear in tumors of these
same origins. Giant-cells of various types appear in many sarcomas,
especially in the tumors of bone and smopth muscle. In muscle they result
chiefly from hypertrophy of tumor-cells; in bone-tumors they have been
interpreted as giant osteoclasts; in bone-marrow tumors they are likened to
the myeloplacques ; in many cases they evidently form by cell fusion in

FIG. 65. — Large spindle-cell fibroblastic sarcoma.

poorly nourished areas; in the epulis they represent fused endothelium sur-
rounding foreign material; while amitotic nuclear division is responsible
for many.

The origin and significance of the different forms of giant-cells is best
considered in connection with specific tumors, since in many respects they
are peculiar in each tumor and form an important means of diagnosis.
Wakabayashi found the same groups of chromosomes and lack of mitoses in
seven types of sarcoma as he observed in tuberculosis and syphilis. Howard,
studying the morphology of many giant-cells, observed in the behavior of
the nuclei many resemblances to protozoan nuclei.

Round-cells appear in lymphosarcoma, gliosarcoma, and myelosarcoma,
but it is doubtful if true round-cell tumors arise from any other mesoblastic
tissues. While very cellular and anaplastic growths composed of indifferent
spheroidal cells arise from many tissues, perfectly fixed portions of these
tumors regularly show the cells to be spindle or polyhedral, and the effort
should be made to detect these features so as to exclude the tumor from the
group of true round-cell growths.

SARCOMA 239

Such distinctions are, however, rarely attempted and the term round-cell
sarcoma is in very' general use and enjoys recognition from practically all
writers. Malherbe, however, separates sharply between round-cell sarcomas
which he regards as exclusively lymphoid, and true fibroblastic tumors.
Virchow stated that a round-cell tumor could safely be identified as sarcoma
only when a definite intercellular stroma was demonstrated. Borst describes
the cells of small round-cell sarcomas as identical with the round-cells infil-
trating granulation tissue, but the source of these cells he left undetermined.
Highly malignant small round-cell tumors arise in the intermuscular septa,
periosteum, submucous stroma, meninges, skin, kidney, testicle, and liver
(Borst), and are said to represent the highest degree of sarcomatous degenera-
tion (Rindfleisch) . Yet it has never been shown and appears unlikely that
any fixed connective-tissue cells in such numerous situations give origin to
Such tumors.

From my own observations I have been forced to conclude that with rare
exceptions such round-cell growths are either lymphosarcomas or small-
cell carcinomas. They usually invade lymph-nodes.

It is chiefly among the sarcomas of bone that small round-cell tumors
appear which suggest an origin from periosteal fibroblasts, but here the
proximity of bone-marrow provides a possible origin from lymphoid
cells.

Much the same uncertainties surround the origin of most of the so-called
large round-cell sarcomas. These tumors may, as a rule, be divided among
endotheliomas, tumors of lymphoid cells, carcinomas, and sarcomas of which
the cells are not strictly round.

The round-cell tumors of the testis and thyroid are among the epithelial
growths commonly misinterpreted as large round-cell and alveolar sarcoma.

The nuclei of sarcoma-cells exhibit the widest variations in size, form,
chromatin content, nucleolar elements, and methods of division; all of which
features reflect rapid and lawless growth and the accompanying degenerative
processes. All the abnormalities observed in carcinoma-cells are duplicated
or even exaggerated in sarcoma. In pronounced grade they are specific
of a malignant tumor process but not of sarcoma. Favre and Regaud
find the same mitochondria granules in sarcoma-cells as in carcinoma.

Degenerative changes in the cells of sarcoma occur chiefly in areas of
necrosis from infarction. In actively growing, well-nourished zones the
cell cytoplasm is usually less subject to fatty and hydropic degeneration
than in carcinoma. Yet under appropriate conditions the cells undergo
the usual forms of cytoplasmic decay. The most common change is a
mucoid transformation of cells and stroma which affects nearly all forms of
sarcoma, especially those arising from connective tissue. Extensive deposits
of blood-pigment may lead to confusion with melanoma. Calcine deposits
are comparatively rare, except in osteogenic tumors. Glycogen is found
in the cells of many rapidly growing sarcomas (Brault).

The arrangement of the cells reflects the structure of the mother tissue
and often gives a clue to the origin, yet in cellular growths all traces of the
originating tissue may be lost. Prominent in many sarcomas is the tendency
of the cells to grow about blood-vessels simulating the type of angiosarcoma
or perithelioma. The specific structure of these latter tumors may be all
but duplicated by tumors which have no angioblastic relations whatever.
On the growing edges of infiltrating sarcomas the cells are commonly gathered
about the small blood-vessels. A true alveolar arrangement is rarely if
ever assumed by sarcomas. While it cannot be asserted that the small
spheroidal or polyhedral sarcoma-cells never appear in groups surrounded by

240 N EOF LA STIC DISEASES

stroma, the history of most alveolar sarcomas has terminated in their identi-
fication as carcinomas or endotheliomas.

The stroma of sarcomas is derived from remnants of preexisting tissue,
from blood-vessels appropriated for the nutrition of the tumor or new formed
as an integral part of the neoplasm, and from the specific intercellular sub-
stance derived from the tumor-cells. In relatively adult growths an inter-
cellular stroma is regularly laid down by the cells, and in tumors of bone,
cartilage, mucoid tissue and glia-tissue it may form an easily recognized
element. Yet in very cellular tumors the attempt to demonstrate a stroma
commonly fails and it would appear that the diagnostic significance of this
element in sarcomas has been overstated. W. C. White found a fine inter-
cellular reticulum very constant in sarcomas but absent in carcinomas. He
identifies the reticulum of lymphosarcoma with white fibrous tissue. Seelig,
in specimens digested by pancreatin, found a rather abundant fine reticulum
in many sarcomas but failed to note any constant differences in the reticulum
of lymphosarcoma from that of other round-cell sarcomas. Bielschowsky's
stain is particularly effective in demonstrating a reticulum in sarcoma
as well as in carcinoma.

The blood-vessels form the most important part of the stroma. They
are of various forms and sources. Following the analogy with granulation
tissue the blood-vessels may represent elongations of those of the originating
tissue about which the tumor-cells grow. Such vessels may be venous,
arterial or capillary, and their walls are composed of adult normal cells. In
the course of their growth they may become varicose or sinusoidal and the
walls thin and fragile. Some of the well-formed vessels are probably appro-
priated directly from the invaded tissue. As the tumor develops, the
adventitia of the vessels is lost in the stroma of the neoplasm. Eventually,
nothing but a swollen endothelial cell separates blood-current from tumor-
tissue. Malherbe describes the apparent sarcomatous transformation of the
muscle-cells of vessel-walls and points out the diagnostic importance of the
swollen condition of the cells in the vessel-walls of sarcoma. Many blood-
spaces and channels appear to be formed by modified tumor-cells but such
structures are extremely fragile and leave the tumor-tissue subject to inter-
stitial hemorrhage.

In a large group of angiosarcomas and of peritheliomas the tumor-cells
exhibit true angioblastic properties and the tumors are composed essentially
of a congeries of very cellular blood-vessels.

The continued growth of most sarcomas is closely dependent upon the
capacity of the cells to excite the development of blood-vessels.

Where the vascular channels fail, growth ceases, and when they become
occluded anemic necrosis promptly follows. Yet some very cellular actively
growing small spindle-cell sarcomas contain few vessels.

Lymph circulation in sarcomas is very deficient and according to Ziegler
lymph-vessels cannot be demonstrated. Yet in some varieties clefts and
canals appear which probably represent lymph pockets or channels, and some
cutaneous sarcomas have abundant lymph-vessels (Unna). Nerve-trunks
invaded by sarcoma undergo pressure-atrophy.

In neurosarcomas fragments of myelin sheaths and axis-cylinders may
long persist. Definite new formation of nerve-fibers in sarcoma has not been
demonstrated.

Etiology. — Of the specific etiology of sarcoma little is definitely known.
These tumors demonstrate the very great proliferative capacity of meso-
blastic cells released from the restraints to growth. This capacity may
reasonably be estimated as even greater than with most epithelial tissues.

SARCOMA 241

It is commonly assumed that normal adult cells are incapable of such
great proliferation as occurs in sarcoma, and the further assumption is
then necessitated that sarcomas as a rule grow from isolated, or superfluous,
or embryonal cell groups. Thus when trauma is followed by an extremely
malignant bone-sarcoma, the violent explosion of growth capacity seems to
require some element which is not attributable to normal cells regenerating
after contusion. The rarity of any definite observations of the beginnings
of such sarcomas is a strong defense of this hypothesis. Moreover there are
many instances in which sarcomas are known to arise from isolated or em-
bryonal cell groups, especially in the mixed tumors of teratoid type.

On the other hand it may be urged that the regenerative capacities of
mesoblastic cells are very great, especially in youth when most sarcomas
occur. It must be admitted that the existence of isolated cell groups as the
source of many sarcomas has not been proven.

Sarcoma has been observed to follow #-ray injury in rats, and in mice
the continued growth of carcinoma is said to have excited sarcomatous pro-
liferation of the tumor-stroma. Finally, increasing observations of very
early sarcomas and of presarcomatous lesions of inflammatory origin favor
the view that sarcomas often arise from previously normal adult cells.

It is clear that no general rule can be applied in this field and that the
evidence must be worked out separately in each form of sarcoma.

Presarcomatous Lesions. — The occurrence of atypical productive
inflammatory lesions leading to sarcoma must be regarded as fully in accord
with established views regarding the nature of sarcoma. Many sarcomas
show such marked histological resemblances to inflammatory processes
that pathologists have long been inclined to accept in a certain sense the
inflammatory or even the parasitic origin of certain sarcomas. The lympho-
sarcomas especially stand in this position and Borst, among others, antici-
pates the ultimate identificaion of this group of neoplasms with the infectious
granulomas. In such an event the sarcoma must be regarded as an indirect
result of the parasite, much as some carcinomas are an indirect sequel of
chronic irritation. Syphilis and tuberculosis are the most prominent infec-
tions which lead to sarcoma.

Relation of Tuberculosis and Syphilis toLymphosarcoma. — Clinical observa-
tions have long indicated that tuberculous lymphadenitis may pass rapidly
or after several recurrences into lymphosarcoma. Ricker in a case termin-
ating after 14 years found typical tuberculosis associated with lymphosarcoma
of neck, lungs, adrenals and spinal cord. Miiller saw general sarcomatosis
from a primary tumor of the breast, miliary tubercles being nearly coexten-
sive with widespread sarcomatous tumors. The rather frequent discovery
of tubercle bacilli in lesions supposed to be pure lymphosarcoma suggests
that a very slight difference separates some of such tumors from the immedi-
ate or distant presence of tubercle bacilli or their toxins. I have followed
a case of cervical tumors originally tuberculous, recurring four times in six
years and terminating with the picture of endothelioma of lymph-nodes.
In this study it was shown that an infectious granuloma may cause prolifera-
tion of the reticulum cells, producing large-cell lymphosarcoma, or of the
sinus endothelium producing endothelioma of lymph-nodes, and it was
also shown that exactly similar tumors of lymph-nodes occur in the axilla
without any histological evidence of granuloma. Various diphtheroid bac-
teria may be isolated from such tumors.

The transformation of Hodgkin's granuloma into sarcoma has been
described by various authors, but I have found evidence that most of these

242

NEOPLASTIC DISEASES

tumors arise from the thymus where again they are implicated with
granuloma.

The difficulty of distinguishing from sarcoma certain late syphilitic
lesions in bone and muscle is mentioned by many authors, especially by
v. Hansemann. The clinical diagnosis of syphilis is rendered difficult by
the recurrence of the lesions after operation, by their multiplicity, and by
the resistance to syphilitic treatment, while the structure presents very
marked cellular overgrowth of round-cells or spindle-cells. Yet the syph-
ilitic process tends toward necrosis and cicatrization rather than progressive
growth. There are many indications that true sarcoma develops from such
lesions, but satisfactory proof is lacking.

FIG. 66.— Structure of rapidly forming callus developing in muscle-tissue two weeks"after
fracture of clavicle. Note resemblance to osteogenic sarcoma.

In the healing of fractures and of wounds of the periosteum the histolog-
ical picture shows very active growth of bone, giant-cells and connective-
cells, and regenerating capillaries, and may distinctly resemble sarcoma.
The actual transition into sarcoma has not been traced.

Traumatic myositis ossifkans appears to occupy a position intermediate
between inflammatory and neoplastic processes (Berndt). The clinical
history of established cases is that of a self-limiting productive inflamma-
tion, but the histology of the early lesions may be difficult to distinguish
from bone-sarcoma. It appears that the division of cases is accidental,
some of the lesions progressing as myositis, others going on as traumatic
sarcoma. I have observed the two conditions combined. Central giant-cell

SARCOMA 243

sarcoma of bone has often been interpreted as a form of productive inflamma-
tion, but its various phases show every gradation from the benign to a
malignant process. Kolisko finds that osteitis fibrosa may be followed
by progressive changes leading to giant-cell sarcoma of moderate malignancy.

Many clinical observations point to the development of sarcoma from
granulation tissue, and the histological study of granulation tissue and of
organizing blood-clots occasionally reveals pictures which closely approach
the structure of sarcoma. Heukelom has traced in considerable detail the
gradual transformation of the cells of granulation tissue into sarcoma-
cells. Occasionally one finds small tumors following trauma and containing
much blood-pigment, of which the structure is distinctly sarcomatous.

Against the hypothesis of the origin of sarcoma from previously normal
cells stands the opinion of Birch-Hirschfeld, Borst and others that sarcomas
do not develop from previously normal cells but from embryonal cell groups.
This view must be regarded as an hypothesis without adequate proof.
Ackermann was unable to find any evidence of the origin of a series of sar-
comas from embryonal cells.

It seems highly probable that sarcomas, like carcinomas, arise through
exaggerated inflammatory and regenerative overgrowth of tissue-cells.
While in many cases the cells of origin are adult, theoretical considerations
suggest that in some instances they are embryonal.

In the former group only would specific presarcomatous stages be
expected.

The clinical transformation from benign into malignant mesoblastic
tumors has repeatedly been observed, but the exact nature of the changes is
somewhat uncertain. There is no doubt that in a small proportion of cases
of fibroma, uterine myoma, neurofibroma, and lymphangioma, a long stand-
ing and quiescent tumor eventually displays rapid growth and the structure
proves highly cellular and malignant. In rare instances there is every
indication that the slowly growing cells have taken on greatly increased
powers of growth. In other cases it has been assumed that the malignant
process arises de now in some element of the tumors, as the blood-vessels.
For the assumption that the sarcoma develops from embryonal cell groups
included in the benign tumors there seems to be very insufficient basis.

CHAPTER XVIII
CLINICAL TYPES OF SARCOMA

Spindle-cell Sarcoma; Fibroblastic Sarcoma.— This common tumor
represents the purest form of fibroblastic neoplasm. It is of widespread
occurrence, developing in nearly all situations where supporting connective
tissue is found. The chief locations are in the subcutaneous and submucous
tissues, the fasciae and muscles, periosteum, and in the parenchymatous
organs.

In the gross these tumors are usually single, but occasionally multiple.
The form is rounded or lobulated and the borders are not sharply marked.
The consistence is hard in the fibrous and small cell-growths, softer and more
elastic with the large cell-tumors. The hard tumors are opaque and non-
vascular, the soft ones are vascular, succulent, reddish and variously altered
by secondary changes. The minute markings are as a rule not distinctive.
In size one encounters very small nodules in the earliest stages and bulky
fungating and necrosing growths in the later periods. In the skin they form
multiple, nodular or globular growths which may become polypoid.

The rate of growth varying with the structure may be very slow or very
rapid. Cessation of growth is rare but cutaneous tumors may be sponta-
neously extruded. Extremely rapid and bulky tumors are observed espe-
cially after injuries. Being poorly circumscribed local recurrence frequently
follows removal even with the comparatively benign forms. Metastases in
lungs, liver, and other organs frequently occur with large cell-growths, and
rarely, as in Walter's case, one is surprised to find secondary growths from
apparently benign small spindle-cell sarcoma.

The structure falls into two main classes which differ also in their clinical
features: (i) small, and (2) large spindle-cell sarcoma.

The small cell-tumors are slowly growing, relatively benign neoplasms
which approach the structure of fibrosarcoma on the one hand and on the
other may approximate the type of large cell-tumors. Their rate of growth,
density and malignancy, usually accord with these distinctions. The large
cell-tumors show more active growth, are softer, more vascular, readily
suffer from necrosis, ulceration and hemorrhage, and often recur locally and
produce metastases.

The spindle-cells of either type resemble fusiform fibroblasts. They are
much smaller than normal fibroblasts and more densely packed in the small
cell-growths, but reach very large dimensions and are loosely arranged in
the large cell-type. The cytoplasm is granular, opaque and acidophile,
the nuclei vesicular and provided with one or more small nucleoli.

In the compact tumors cell borders are distinguished with difficulty and
nuclei occupy most of the field but when the texture is looser the cells exhibit
elongated processes and an intercellular stroma becomes visible. This
stroma when well developed is composed of fibroglia fibrils demonstrable
by Van Gieson's or better by Mallory's stain. It may become abundant
or be reduced to a trace or be altogether absent. Much of it radiates from
the blood-vessels. Its diagnostic importance is not great. Besides the
specific stroma of the tumor, remnants of invaded tissue often appear and
these with the blood-vessels often determine the arrangement of the cells.

244

CLINICAL TYPES OF SARCOMA 245

The cells may run diffusely, but as a rule they lie in broad bundles or
narrower columns following blood-vessels or inclosed in connective-tissue
septa, or coursing in various directions so that longitudinal, cross, and oblique
sections appear in the same field. Virchow and others have employed many
terms to designate these structural details as sarcoma lamellosum, fascicula-
tum, trabeculare, radiare. As a rule these features do not give any clue to
the histogenesis.

The spindle-cell sarcoma tends to infiltrate surrounding tissues, the
cells pushing their way between fat-cells, vessels, or gland structures, all
of which suffer atrophy. The walls of vessels may be infiltrated, penetrated
and destroyed, and since the vessels are an easy prey metastases by these
channels are common (Goldmann, Hedinger). Bone is penetrated by
way of the Haversian canals, and readily absorbed.

The blood-vessels of spindle-cell sarcoma increase with the larger size
of the cells and the more rapid growth. They present a variety of structural
types. Scanty but well-formed vessels predominate in small cell-tumors
but in others the vessels may be very numerous and the walls are composed
of single layers of endothelial cells supported by little or no adventitia. In
several forms the vascular paths consist of a system of sinuses walled only
by tumor-cells. Thus hemorrhage is common and metastases by way of
blood-vessels is facilitated. While in many cases the vessels appear not
to belong to the neoplastic process, as they become more abundant the
cells usually appear hyper trophic and their nuclei hyperchromatic. The
indications of lymph-paths are usually wanting, but Unna describes abundant
dilated lymph-spaces in certain cutaneous sarcomas. In defective lymph-
paths v. Heukelom saw a factor in the pathogenesis of sarcoma, but Lubarsch
properly interprets the absence of lymph-channels when it exists as a result
and not the cause of the sarcomatous process.

Secondary changes in spindle-cell sarcoma are not prominent. Fibrosis
may appear in slowly growing small cell-tumors and an arrest of growth may
rarely be establishe'd. Wide fibrous areas sometimes appear in large cell-
tumors as a local result of occlusion of vessels. More often hemorrhage
and necrosis follow rupture or thrombosis of vessels, and pseudomelanosis
frequently recalls old extravasations of blood. Chronic edema affects old
and large tumors in which venous stasis occurs, and a pseudomyxomatous
change may overtake small foci or the whole tumor. Edema, fatty degenera-
tion and simple necrosis combine to produce cysts with serous or blood-
stained contents.

In many soft vascular tumors the cells are polymorphous, small and large
spindle, polyhedral and round-cells appearing in foci or throughout. Such
growths are often called round-cell sarcoma but a true round-cell sarcoma of
fibroblastic origin probably does not occur. Likewise polynuclear cells
may form and reach considerable dimensions but the term giant-cell sarcoma
is better limited to other classes of tumors.

Types of nuclear division are extensively illustrated, especially in the
large cell-tumors. They occur in the elongated spindle-cells and especially
in large round-cells mingled with them. Increasing numbers of round-cells
result from multiplication of dividing cells and constitute a sign of malig-
nancy. Many of the anomalies of cell-division in tumors appear in the
fibroblastic sarcomas (Stroebe).

The diagnosis of spindle-cell sarcoma seldom presents difficulty but there
are some notable exceptions to this rule and the proper erminology is still
a matter of discussion. Typical structures occurring in ordinary situations as
skin, bone, etc., are readily identified. When cell-fibrils become prominen

246 NEOPLASTIC DISEASES

and are of adult type the tumor is relatively benign and deserves the designa-
tion fibro sarcoma. The numerous small cells and abundant fibrils serve
to distinguish most fibrosarcomas from cellular fibromas which show more
resemblance to large spindle-cell sarcoma. From myosarcoma the fibro-
blastic tumors may be distinguished by their location, the large vesicular
nuclei, and lack of acidophile quality of the cytoplasm. Yet the myogenous
origin of certain spindle-cell sarcomas has often been suggested and is well
worthy of consideration (testis, kidney). Very vascular tumors may be
called telangiectatic or angiosarcoma, but the latter term has repeatedly
been condemned as wrongly inferring an origin from blood-vessels. The
malignant (sarcomatous) angiomas have quite a different structure and
origin. From typical perithelioma the large spindle-cell sarcoma can some-
times be distinguished with difficulty, but the perivascular units of radiating
cells and the characteristic large giant-cells of the former growth are usually
unmistakable.

Large spindle-cell sarcoma may be closely simulated by various tumors
whose existence must be specially noted. Malignant epithelial tumors of
the thyroid are very prone to assume the spindle-cell type, as do also the
embryonal forms of the so-called hypernephroma. Metastatic melanoma
may appear as a spindle-cell or large round-cell unpigmented tumor. Not
a few epidermoid carcinomas present spindle-cells throughout most of their
substance.

Diffuse endothelioma may exactly reproduce the structure of fibro-
blastic sarcoma, but the location of the former growths, the appearance of
typical endothelial characters in small areas, the arrangement of the cells,
and their minute structure usually but not always permit a positive separa-
tion of these closely allied types.

Histogenesis. — In the origin of spindle-cell sarcoma the adventitial cells
of the blood-vessels appear to take a prominent part. The early stages of
these tumors have many times been traced to foci of vascular proliferating
connective tissue which has been identified on doubtful evidence with granu-
lation tissue. Some of these tumors appear to follow trauma, and the
processes which result from solution of continuity, extravasation and absorp-
tion of blood, often bear considerable resemblance to sarcoma. In organizing
blood-clots there may be very active growth of vessels about and into the
clot and it may be supposed that an exaggerated growth of these structures
leads in certain cases to sarcoma. Likewise in some established and sponta-
neous tumors the cells appear to be derived from proliferating adventitial
fibroblasts. Such appearances are rather frequent and occasionally con-
vincing, and Babes and Ackermann have expressed the opinion that fibro-
blastic sarcomas in general originate from blood-vessels. Lubarsch also
described spindle-cell sarcomas in young subjects which on close analysis
reveal themselves as obliterating cellular angiomas.

The part played by endothelial cells in the genesis of sarcoma has been
variously estimated but in the pure spindle-cell tumors they are not promi-
nent. Many endotheliomas, however, closely resemble this type of sarcoma
and since it is desirable to adhere to the fibroblastic origin of spindle-cell
sarcoma the endothelial tumors must be excluded from this group as long
as endothelial characters are retained.

Smooth muscle-tissue may also give origin to tumors of spindle-cells,
as in myosarcoma uteri, but these tumors also must be separately classified.
The intermuscular fasciae and the peri- and endomysium give rise to fibro-
blastic sarcoma. Those occurring in the muscles of the thigh produce
bulky tumors with a notable tendency toward mucoid degeneration. It

CLINICAL TYPES OF SARCOMA 247

appears probable that in certain situations (e.g., testis) spindle-cell sarcoma
represents a one-sided development of teratoma, but to what extent this
principle applies elsewhere remains to be determined.

Sarcoma of the Skin.— The skin is the primary seat of a variety of sarcomas
or sarcomatoid processes, the exact nature and position of which have not
been determined.

Some of these are of spontaneous origin, extend by displacement of
normal tissues, grow progressively, produce metastases and cachexia, exhibit
the definite histology of a malignant tumor usually composed of spindle-
cells, and belong clearly in the group of sarcomas. Others, while producing
single or multiple tumor-like growths, progress by infiltrating the tissues,
may often regress or disappear, do not produce metastases although appearing
in numerous foci, and they present in their earliest stages or throughout the
histology of an inflammatory lesion which, however, may sometimes assume
a more or less distinct neoplastic character. These conditions are often
called sarcoids of the skin.

Of the latter group many types have been described (Pollard, Lit.),
of which some have been finally disposed of among infectious granulomas.
Such are: (i) mycosis fungoides, types of which are often mistaken for sarcoid
(Paltauf); (2) multiple benign sarcoid of Boeck, which proves to be a form
of tuberculosis; (3) various cases of benign sarcoid which consist of diffuse
lymphocytic infiltrations, and which, while sometimes reaching considerable
dimensions, show a distinct tendency toward regression (Spiegler, Joseph,
Pollard). Numerous other peculiar cases have failed to receive a final
interpretation.

The chief general significance of the study of these cases lies in the evi-
dence which they offer that various inflammatory conditions may closely
approach the true sarcomatous process. Spontaneous regression is perhaps
not a sufficient ground, as Fano claims, for the exclusion of such processes
from the group of tumors, since other true sarcomas may occasionally regress,
but the entire clinical and histological picture justifies the current view that
these processes are pseudo-neoplasms. Not clearly separable from the
regressing sarcoids, but distinguished from them by its capacity to develop
genuine malignant tumor characters is the multiple hemorrhagic sarcoma of
Kaposi.

1 Multiple Hemorrhagic Sarcoma (Kaposi). — This interesting malady,
first fully described by Kaposi in 1872, has attracted much interest from
dermatologists. Recently the data have been fully analyzed by Mariani.

Observed chiefly in southern Europe, in elderly subjects, it exhibits
a definite relation to certain predisposing factors, as general or local vascular
lesions, sclerosis, ectasise, hemorrhagic diathesis, edema, and to trauma and
alcoholism. A prodromal stage is marked by local cyanosis, edema and
slight inflammation, or by definite vascular ectasiae (De Amicis). In the
stage of tumor growth multiple soft bluish nodules or flat infiltrations form in
the derma of the outer surface of hands, feet, cheeks, nose and elsewhere.
They are often painful, inflamed, and may ulcerate, involving deeper tissues
and even eroding bones. The nodules may be very numerous, Babes observ-
ing 450 in one patient. Hemorrhage often occurs leaving pigmentation
prominent in some cases. The disease progresses from the extremities
upward, some areas showing a tendency to heal, especially under arsenic.
The lesions may be symmetrical. In the stage of cachexia the cutaneous
lesions may become numerous or diffuse and in several fatal cases secondary
nodules appeared in the pharynx, gastro-intestinal tract and liver, kidney,
pancreas, lungs and serous membranes (Phillipsohn,* Mariani, Lit.). Most

248 NEOPLASTIC DISEASES

of the cases are eventually fatal from hemorrhage, diarrhea, fever and
cachexia.

The histological structure exhibits in the early stages chiefly new and
dilated lymph- and blood-vessels and infiltration by lymphocytes, plasma-
cells, mast-cells, and edema, and the lesion resembles that of an infectious
granuloma. According to W. Pick the early lesion is indistinguishable
from elephantiasis lymphangiectatica. Proliferation of endothelium and
perivascular spindle- and round-cells may appear early and become so
prominent as to lead to the diagnosis of angiosarcoma, etc. In the later
stages spindle-cells may predominate and the lesion is indistinguishable

FIG. 67. — Multiple hemorrhagic sarcoma. Kaposi. (After W. Pick, A.D., 87.)

from spindle-cell fibroblastic sarcoma (Pick). In all stages vascular ectasiae,
hemorrhage and pigmentation are constant or frequent.

Regarding the nature of this disease opinions are naturally at variance,
but the conclusion seems well founded that we have here to do with an
infectious granuloma of unknown origin, which in its later stages in pre-
disposed subjects and under suitable conditions may take on genuine neo-
plastic properties. Justus seems to have carried the agent through five
generations of rabbits with the production of typical lesions. The secondary
growths in the viscera are probably not metastases but extensions to new
originating foci.

Beginning in local lesions in the extremities in which an infectious agent

CLINICAL TYPES OF SARCOMA

249

is probably concerned and aided by the various predisposing factors, trie
entire vascular system seems to be overtaken by degeneration with over-
growth of vasoformative cells leading in many instances to true tumor
formation. In the histogenesis the numerous discussions have dealt with
all the data regarding the interrelations of endothelium, perithelium, fibro-
blasts, plasma-cells, and polyblasts, but the final tumor product is a spindle-
cell sarcoma, which on account of its early history and tendency toward
regression has often been called sarcoid.

Spindle-cell Sarcoma of Skin. — These tumors appear as single large
growths which tend to become pedunculated or as multiple small nodules
widely distributed. Appearing in the derma or subcutaneous tissue they
form circumscribed nodules or masses which vary widely in color. ^consist-

FIG. 68. — Multiple hemorrhagic sarcoma. Kaposi. Intestinal lesion.

A.D., 98.)

(After Mariana,

ence, as well as in number and position. Some are hard, opaque and fibrous,
others soft, reddish, vascular and edematous. Both the single and multiple
tumors are usually of slow growth and relatively benign, but either type may
develop greater malignancy and terminate with metastases, and cachexia
(Unna). As a rule these tumors show a limited capacity for growth and
while recurring locally are not directly fatal. Fibrosis (Linser), peduncu-
lation, and spontaneous extrusion may occur. Ulceration and necrosis are
rare. They appear at almost any age and Maldovan and Fernet describe
congenital cases.

The structure is in many instances that of the simplest form of small
or large spindle-cell tumor, but many variations from this type are encoun-

250 NEOPLASTIC DISEASES

tered. Blood-vessels may be numerous and the tumor-cells may appear
to be derived from their adventitial cells. Varying in this direction spindle-
cell sarcoma of the skin approaches angiosarcoma and perithelioma from
which types they are not always sharply separable. In one group endothelial
proliferation appears to be prominent and yields many rounded and poly-
hedral cells (Johnston). Chronic edema may lead to secondary myxoma-
tous characters. Unna describes a rich supply of lymph-spaces in some
tumors.

The arrangement of cells also varies greatly. They may be closely
packed, of small size, with little stroma, and quite diffusely arranged. An
interfascicular form is yielded by cells whose axis is determined by the course
of blood-vessels (Unna). The cells may form whorls or intertwining bundles

FIG. 69. — Structure of multiple hemorrhagic sarcoma. (After Mariani.)

which have suggested an origin from nerve- trunks. The cells penetrate sur-
rounding tissues and develop new outlying nodules, or they may remain well
circumscribed. In the central portion of all true sarcomas of the skin Unna
finds elastic fibrils missing.

The histogenesis of cutaneous spindle-cell sarcoma is a complex question,
and it has not been possible to clearly define the subgroups probably exist-
ing in this class according to their exact origin. Yet the fibroblastic nature
of the typical form seems reasonably certain. Many have concluded that
the adventitial cells of blood-vessels and lymph- vessels are the chief seats of
origin. In certain cases I have been impressed with the evident relation
of the tumor-cells to numerous abortive blood-vessels which seemed to be-
come lost in the tumor-tissue. Yet Unna believes that the importance of
blood-vessels in the origin of these growths has been overestimated, espe-

CLINICAL TYPES OF SARCOMA

251

cially by Babes. The connective tissue about cutaneous glands rarely seems
to^be specially concerned. That an endothelial element is present in some
cases is highly probable, especially in tumors with rounded, polyhedral or
giant-cells. In cases of multiple symmetrical tumors with cells in inter-
twining bundles an origin from nerve-sheaths and an endothelial element are
indicated. The occurrence of congenital cases indicates that misplaced or
superfluous cell groups, and not normal tissues, are occasional or frequent
points of origin. Finally it is clear that some tumors closely resembling
fibroblastic sarcoma belong in the group of nevomelanomas, and that the
highly malignant cutaneous sarcomas as in Pini's case, must be regarded with
suspicion from this standpoint.

In the etiology, various forms of trauma not infrequently precede the
solitary sarcoma (Lowenstein). Virchow (II, 245) cites many cases of

FIG. 70. — A giant-cell tumor of tendon sheath, probably of endothelial origin.

sarcoma arising in scar tissue which had been subjected to long irritation.
For the multiple tumors a tissue predisposition and the various inflammatory
and nutritional changes illustrated in the sarcoids may be held responsible.

Giant-cell Sarcoma of Tendon-sheaths and Aponeuroses. — The specific
structure and benign clinical course of a group of giant-cell sarcomas of
tendon sheaths of the hand and feet have long been recognized. They
have been fully described, especially by French observers under the terms
myeloma or xanthosarcoma (Gross, Paquet, Reverdin, Heurteaux, Spiess,
Lit.).

The tumors arise chiefly in tendon sheaths and aponeuroses of hands and
feet, and reach moderate dimensions after a period of i to 20 years. Sudden
increase in size may rouse a suspicion of malignancy, but they seldom reach
the size of an egg. They are well encapsulated, firm, opaque or yellowish
and markedly lobulated, and are readily shelled out by operation. They
never yield metastases and rarelv recur after removal.

252 N EOF LAST 1C DISEASES

The structure presents four main features, (i) Groups of spindle- or
polyhedral cells surrounded by dense connective tissue. Some of^the
tumors are exclusively of this type. Although the tumor may be quite
cellular and free from giant-cells it still maintains its benign character. (2)
Groups of large cells containing much doubly refractive lipoid material.
These are the so-called xanthoma-cells. They may be so abundant as to

FIG. 71. — Myxosarcoma of fascia of thigh.

duplicate the appearance of xanthoma of the skin, and their origin is referred
to proliferating fibroblasts or endothelium. (3) Giant-cells of very large
size up to 125 m. are commonly present in abundance, and present very
numerous small vesicular nuclei. The cytoplasm is granular, acidophile,
and often contains much lipoid material. They belong to the class of foreign
body giant-cells. (4) Pigment of the type of hemosiderin frequently collects
in the tumor-cells.

Etiological factors are very indefinite but the structure and benign char-

CLINICAL TYPES OF SARCOMA 253

acter of the process suggests that the tumors arise from a local inflamma-
tory process connected with trauma and some peculiar disturbance of local
lipoid metabolism. Fleissig denies that they have any neoplastic quality
and regards them as a form of granulation tissue, yet similar arguments
apply almost equally well to many other sarcomas. They have often been
classed with xanthoma.

Sarcoma of Muscles. — Primary sarcoma of the muscles arises from the
connective tissue and vessels of the perimysium and endomysium and usually
takes the form of fibrosarcoma or myxosarcoma with small or large spindle-
cells, and often with a marked prominence of capillary or larger blood-
vessels. Occasionally they are described as round-cell sarcoma (Chambe,
Pasteau, Kuttner).

They occur chiefly in young adults, the rapidity of growth varies with
the structure but is often rapid, they reach a large size if undisturbed, recur
locally after operation, and the cellular forms produce metastases. Chambe
has collected 39 cases illustrating many features. Many cases were fatal.
Virchow observed that in the muscle fasciae slowly growing fibrosarcoma or
spindle-cell sarcoma predominate, while at tendon insertions many round-
cell and malignant tumors appear. A characteristic fibrosarcoma arises
from the sheath of the rectus abdominis (Bodenstein, Lit.).

The histogenesis has been traced in certain cases to the interstitial tissue
(Birch-Hirschfeld), and the remarkable proliferative tendency of this
tissue renders such an origin probable. The muscle-cells usually atrophy,
but Sokalow, Guitton and others reported the transformation of muscle-
cells into sarcoma-cells. About many tumors of muscle there is a pronounced
reactive myositis with various alterations in the form of the cells (W.
Schaffer).

That sarcoma of muscle may be derived from groups of embryonal and
undifferentiated muscle-cells has often been suggested (Borst). It seems
probable that with myxosarcomas and malignant growths approaching the
round-cell type the origin is from misplaced cell groups connected with bone
formation. In a series of bulky sarcomas of the thigh I have observed
gradations in structure from myxosarcoma to chondrosarcoma. In an early
sarcoma of muscle, I found very many small blood-vessels which seemed to
be the source of the spindle-cells of the tumors. Peabody's study of Peters'
cases suggested a vascular origin. Sokalow traced some tumors to the sarco-
lemma, but Cornil and Ranvier, Malherbe, and most authors assume that
they arise from the inter fib rillar connective tissue.

Periosteal sarcomas of many types commonly invade the muscles and
some may appear largely intramuscular.

Sarcoma of Esophagus. — Sarcoma of the esophagus is a rare condition.
Howard (1902) analyzed 12 cases. Herxheimer, 1908, refers to 18 cases,
two of which were combined carcinoma and sarcoma. Hacker, 1909, gave
a complete analysis of the subject with reference to 21 cases. They occurred
usually in males, in the upper or lower segment, and in subjects from 4 to
70 years of age, and were rapidly fatal. They appear either as an ulcerative
process or as a polypoid tumor. The former usually contain round- or poly-
hedral cells, the latter, spindle-cells. Stephan describes a peculiar lympho-
sarcoma in an infant. In Eucken's case there were many giant-cells. With
the round-cell growths metastases are early and widespread (Shaw, Stark,
Rolleston). The spindle-cell tumors were usually free from metastases
(Targett, Ogle, Livingood, Herxheimer).

It seems probable that two entirely different tumors have been included
in this group. The round-cell growths strongly resemble embryonal carci-

254 NEOPLAST1C DISEASES

noma in gross appearance, and Stark suspected that his two cases might be
carcinomatous. One case of this type with bulky metastases in the liver
strongly suggested to me a carcinomatous origin (Norris). The spindle-
cell tumors are probably genuine sarcomas, but little effort has been made
to determine their origin. Howard regarded his spindle-cell tumor as a
myosarcoma. Wolfensberger and Glinsky have observed mixed tumors of
the esophagus composed of striated muscle-, spindle-, and giant-cells. Herx-
heimer describes combined sarcoma and epithelioma arising apparently
from the submucosa and the epithelial lining. Metastases were wanting.
Baur describes a melanotic sarcoma of esophagus.

Sarcoma of Stomach. — The reported cases of sarcoma of the stomach
constitute about i per cent, of all gastric tumors. On analysis the cases fall
into three distinct groups: (i) Spindle-cell myosarcoma; (2) lymphosarcoma,
and (3) miscellaneous round-cell or alveolar sarcomas, the nature of which is
uncertain. Of all these 150 cases have been collected by Ziesche and
Davidsohn.

i. The spindle-cell my osar comas constitute a well-defined group. They
form solid or cystic growths, single or multiple, which project from the wall
of the stomach into the peritoneum, or remain interstitial, or protrude into
the cavity of the organ where they suffer necrosis and ulceration. Very
early small growths have been observed, while Brodowski's tumor grew to the
size of a child's head between the mesenteric layers. Cantwell's case weighed
12 pounds and Baldy's nearly filled the abdomen. Most of these tumors
arise from the curvatures, rarely from the pylorus (Manges, Schlesinger).

The external pedunculated tumors may draw the stomach out into a
funnel form; the interstitial tumors may cause dilatation; and Ewald found
the organ reduced to a narrow canal surrounded by multiple or diffuse masses
of fibrosarcoma. Ulceration and hemorrhage frequently occur. The
large tumors are often cystic, and the bulky metastases which commonly
form in the liver are often cystic and may transform this organ into a series
of large cystic tumors (Hosch, Lit.). The course of gastric myosarcoma
is relatively slow in the typical cases (three and one-half years) but with
greater anaplasia of the cells the growth is often quite rapid.

The structure varies between considerable limits. In some cases the
type approaches that of a cellular myoma and the recognition of a myogenous
origin is readily accomplished. Or the cells are of large spindle-form and
the designation as a myosarcoma depends on the attitude of the observer.
Such a case is that of Hoesch-Kaufmann which appears to be identical in
structure with others described as large spindle-cell sarcoma. There is
little doubt also that some or many of the so-called large round-cell sarcomas
are of muscular origin. In some cases careful examination has revealed
typical myosarcoma in one portion of the tumor, indifferent spindle-cells
in other portions, and elsewhere only round-cells (Moser). The arrange-
ment of the cells in intertwining bundles is often a characteristic feature.
The grouping of cells about blood-vessels has sometimes suggested that the
tumor arose from the walls of the vessels as in myoma uteri (Kaufmann,
Howard), or it has led to the diagnosis of angiosarcoma, or lymphangiosar-
coma (Steudel). The gross appearance of many of these tumors of doubtful
nature is very similar to that of definite myosarcoma.

In the etiology of myosarcoma a congenital anomaly must be sought
for the stomach as for the uterus. Of the nature of this embryogenic dis-
turbance there are scant indications. That isolated islands of muscular
tissue occur in the stomach is shown by Alsleben's report of an adenomyoma

CLINICAL TYPES OF SARCOMA 255

in the pyloric mucosa, while the congenital occurrence of myosarcoma is
probably demonstrated by Finlayson's case.

2. Lymphomatous tumors of the stomach occur (i) as a part of the leu-
kemic process; (2) in gastro-intestinal pseudoleukemia; (3) as a part of gen-
eral lymphosarcoma, and (4) in the form of localized lymphosarcoma. They
are considered in detail under these headings.

3. Miscellaneous Sarcomas of Stomach. — In not a few gastric sarcomas
the structure has appeared not to fall into any of common groups and the
tumor has been variously described as alveolar or mixed-cell, or angiosarcoma,
or myxosarcoma. None of these histological features deserves special
recognition as a separate variety of gastric tumor.

Dreyer described a pyloric tumor composed of spindle-cells and carcinoma
occupying a large ulcerated area at the pylorus. The metastases were
carcinomatous. Leube also observed mixed carcinoma and sarcoma. Such
observations suggest the conclusion that carcinoma of the stomach may
give histological appearances resembling sarcoma. Cammidge has men-
tioned four cases of this type and concludes that many so-called sarcomas
of the stomach are really carcinomas (Wilson) . This criticism appears to be
justified and the writer would urge great caution in interpreting as sarcoma
any tumor associated with an ulcer and of which the gross appearance
strongly suggests carcinoma. That sarcoma of the stomach may follow
ulcer appears possible (Moser, Kehr), but this relation has not been satis-
factorily proven. Eighteen cases of metastatic sarcoma of the stomach,
chiefly lymphoid and melanotic, have been collected by Ziesche and
Davidsohn. They are not uncommon.

Sarcoma of Intestine. — The small and large intestines and the rectum
are subject to the same types of sarcoma as the stomach. Baltzer called
attention to the surgical aspects of this group of tumors in a report of 14 cases.
Rademacher (1908) collected 140 cases. Of rectal sarcomas Key found
55 reports to which he added three. The majority of these cases were
studied exclusively from the clinical standpoint, which emphasizes the
symptoms of an abdominal tumor causing intestinal obstruction. The
nature of the growths is seldom clearly stated but the great majority appear
to be lymphomatous, while a considerable proportion are fibroblastic.

1. Spindle-cell sarcoma arises chiefly from the muscular coat, and pro-
duces a large, solid or cystic growth lying external to an intact mucosa. A
rather well-defined group is the myxosarcoma affecting chiefly the cecum
and appendix and said to arise from the submucosa. It may contain large
cysts. The subserous tissue is said to give origin to certain angiosarcomas.
A congenital angiosarcoma of ileum is described by Stern, and a subserous
angiosarcoma of the splenic flexure by Baltzer. I have examined a large
spindle-cell vascular sarcoma of the omentum.

2. Miscellaneous sarcomas of intestine constitute a small group of ill-
defined and imperfectly described varieties. An interesting case is that of
Lehmann who designated as interfascicular endothelioma a diffuse thicken-
ing of the entire intestine with secondary growths in liver. Pigmented
sarcomas occur in the rectum and ileum (Sandner, Treves), but the source
of ^ the pigment is not clear and intestinal metastases of melanoma of the
skin are common. I have studied one slightly pigmented primary sub-
mucous melanoma arising around the opening of the appendix in a child
(cf. Melanoma).

3. Lymphomatous tumors of the intestine are considered under that
heading^ They arise chiefly in ileum, colon and rectum. Rarely they
develop in the appendix (Warren, Carwardine).

256 N EOF LA STIC DISEASES

Sarcoma of Ovary. — Primary sarcoma is a comparatively rare tumor
constituting about 5 per cent, of all ovarian neoplasms (Kroemer). Yet in
this small group many histological varieties are represented, concerning the
histogenesis of which little is known. The process of organization of blood-
clot in the corpus luteum and of regression of this structure offers conditions
very favorable to the development of sarcoma, and it is probable that this
source of myxosarcoma, perithelioma, etc., has not been given due atten-
tion. Other sarcomas, especially of the embryonal type have been traced to
a teratoid origin.

1. Spindle-cell sarcoma is a well-defined type which is closely related
to fibroma and probably also to ovarian myoma. It appears as a diffuse
process affecting the whole ovary and producing either a solid tumor of
moderate dimensions or a large growth containing many cysts. The surface
is nodular or lobulated and section reveals a smooth opaque texture, or many
dilated vessels, or cysts which are more irregular in size and form than in
cystic adenoma. Areas of edema and.mucoid degeneration may be present
and hemorrhage or infarction may follow torsion.

The structure presents spindle-cells of moderate dimensions mingled
usually with spheroidal cells. Trabeculae of adult connective tissue separate
the tumor into lobules, while between the cells there is little demonstrable
stroma. The cells may grow diffusely but more often they are definitely
connected with small blood-vessels which are either thin-walled and telan-
giectatic or compressed or occluded by hyaline degeneration. The main
feature of some tumors is the abundance of hyaline vessels between which lie
scanty spindle-cells. In the cystic tumors dilatation of lymph-vessels,
edema and liquefaction necrosis, seem responsible for the irregular cavities
which contain serous or bloody fluid and are lined by a ragged layer of sar-
comatous tissue supported by connective tissue. Such growths may be
interpreted as cystic lymphangiosarcomas. The spindle-cell tumors are
of slow growth and relatively benign.

The origin of the spindle-cell tumors must be referred to the ovarian
stroma but to which elements is uncertain. The perivascular arrangement
of the cells suggests an origin from the walls of vessels but not an endothelial
character. The perithelial tissue has been suggested as a possible source
but without definite basis, since the tumors are usually diffuse. Smooth
muscle-cells have been observed in round-cell and spindle-cell sarcoma
and it appears probable that some of these tumors are of myogenic origin
(Basso, Gangolphe, Kroemer).

2. Round-cell sarcoma of the ovary is an ill-defined and rare form of
malignant tumor which occurs chiefly in young subjects or children and
proves rapidly fatal. The tumors are single or bilateral, reach a considerable
size, are usually solid or contain softened or necrotic areas. They are soft,
edematous, infiltrated with blood, and exhibit numerous necrotic foci. The
structure is of small round-cells lying diffusely or grouped about thin vessels.
In some cases the cells are of larger size and exhibit an alveolar arrangement
(alveolar sarcoma). Or spindle-cells, small round-cells, large spheroidal
cells and giant-cells may be variously combined.

In none of these cases does the structure offer any clue to the histogenesis
and this group of tumors therefore invites subdivision according to the
histogenetic principle. It seems probable that some of the tumors with in-
different round-cells are to be interpreted as one-sided developments of
teratoma, but to which forms this view may apply it is difficult to decide.
One form of large round-cell sarcoma of the ovary closely resembles a similar

CLINICAL TYPES OF SARCOMA 257

tumor of the testis and is probably of teratomatous nature. It is very
prone to necrosis.

It also seems probable that some so-called alveolar sarcomas are really
of epithelial origin arising from the cells of the granular layer of the follicles,
since these cells in adenomatous tumors readily assume a small round form
and diffuse arrangement. That the theca cells of the ovarian follicles give
rise to certain sarcomas is claimed by Pinto but this origin still lacks definite
proof.

The relationship of cells to blood- and lymph-vessels has often led to the
designation of such tumors as angiosarcoma and perithelioma. In favor of
this view is the frequency of angiomas in the ovary and of sarcomas in which
the blood-vessel is the prime unit, yet most of these tumors are composed of
spindle-cells.

Against the origin from vessels is the well-known tendency of all tumor-
cells to thrive best in the proximity to blood-vessels, giving spurious angio-
sarcoma. Nevertheless Kroemer recognizes a special group of ovarian
angiosarcoma of blood and lymph-vascular origin. They are difficult to
distinguish from the group of perithelioma (q.v.). In this field also one
encounters evidences of the close relationship of endothelioma and sarcoma.
The existence of a true ovarian endothelioma is elsewhere discussed.

A form of plexiform sarcoma is described by Kroemer. It consists of
anastomosing columns of syncytial and giant-cells which he derives from the
perivascular cells about lymph-vessels, a lymphangiosarcoma. The endothe-
lial cells of the vessels proliferated slightly in places but tended to disappear
from the field. This nice histological analysis still leaves untouched more
important questions of histogenesis.

Finally among the polymorphous cell ovarian sarcomas there remains
a rather well-defined type.

Myxo sarcoma. — Areas of secondary myxomatous change are frequently
seen in other forms of ovarian sarcoma. They occur about the blood-vessels
and lymph-vessels, especially of fibrosarcoma and sometimes become so
prominent as to call for the designation of myxosarcoma. Yet such cases
are rare. Segalowitz found only one largely myxomatous tumor among 300
from the ovary, and Kroemer states that a pure myxosarcoma of the ovary
does not exist. An interesting observation is that of Walker who records
three fatal myxosarcomas in sisters.

Myxomatous areas occur especially with chondrosarcoma as in the case
of Gibb which was probably of teratoid origin, and myxomatous changes
in the stroma of ovaries invaded by epithelial tumors is so common as to
lead Glockner to regard it as a specific reaction of ovarian tissue. A specific
variety of myxomatous tumor of the ovary has been described by Krunken-
burg with Marchand's endorsement, under the term fibrosarcoma mucocellu-
lare carcinomatodes (see section, Carcinoma of Ovary).

Chondrosarcoma occurs in the ovary as a one-sided development of a
mixed tumor or of a teratoma, or as a metaplastic growth derived from the
ovarian stroma.

The former class is illustrated by tumors in which islands of cartilage
are associated with dermoids, or with other derivatives of the ectoderm or
entoderm. The cartilaginous elements may predominate and a character-
istic case of this sort is that of Reis in which a large chondromatous tumor
after extirpation was followed by a rapidly growing carcinoma. A similar
origin probably applies to Gibb's myxochondrosarcoma occurring in a child
of two and one-half years. Donati observed very large giant-cells in a
tumor containing cartilage and much round- and spindle-cell tissue. Here

258 N EOF LAST 1C DISEASES

it seems impossible to decide whether the origin was teratomatous or
metaplastic.

Some authors assume that ovarian and other chondromas of the female
genital organs arise from inclusion of the Miillerian or Wolman ducts (Wilms),
and Kehrer states that such tumors contain areas of embryonal round-cell
mesodermal tissue which differentiate into various tissues.

That cartilage arises by metaplasia from the ovarian stroma was strongly
suggested by the old observation of Kiwisch who found cartilaginous plates
in the outer layers of a bilateral ovarian fibroma. Buet also described
cartilaginous metaplasia in a nbrochondroosteoma of the ovary. These
processes were diffuse involving the entire ovary. The most notable evidence
of metaplastic development of cartilage in the ovary is furnished by the case
of Jung.

In a multipara of 48 years with cervical endothelioma (epithelioma?) a myomatous
uterus was removed with one-half of one ovary which was very slightly enlarged. This
ovary was found to contain several islands of young and some ossifying cartilage embedded
in edematous connective or in spindle-cell sarcomatoid tissue. There was a prompt recur-
rence of a pelvic tumor at the site of the ovary containing chiefly chondrosarcoma with
areas of spindle, round, and large polyhedral cells. Meyer interprets this case as a teratoma,
Kehrer as a mixed growth of Wilms type, and Jung and Kroemer as a metaplastic chon-
drosarcoma. The diffuse distribution of multiple islands of cartilage in edematous con-
nective tissue of the ovary seems to favor a metaplastic origin.

Sarcoma of Uterus. — Sarcoma of the uterus occurs in two rather distinct
forms which it is desirable to separate because of their anatomical position,
histogenesis, and clinical features. These are (i) mural sarcoma, and (2)
sarcoma of the mucosa (Virchow).

It was early recognized that certain apparently benign uterine tumors
recurred after operation and these were described by English observers as
recurrent fibroids (Hutchinson, Callender). In 1864 Virchow described a
group of uterine sarcomas and these tumors have since been fully discussed
by Gusserow, 1870, Tertillon 1890, Gessner 1899, Piquand 1905, and lately by
Meyer, 1908.

i. Mural Sarcoma. — This tumor occurs chiefly in the body, less often in
the cervix (12 per cent. Gessner). It may appear as a primary sarcoma, or
develop secondarily in myoma. In either case the growths present many of
the features of uterine myoma. Thus they are often encapsulated, more
frequently diffuse, and their position is subserous, interstitial, or submucous.
The cervical and submucous tumors are usually polypoid and the interstitial
growths may early break into the mucosa and thus become indistinguishable
from originally submucous tumors. A rare type encircles the tubal orifice
(Meyer). All varieties may be single or multiple. Multiple sarcomatous
fibromyomas have been described by v. Kahlden, Gessner, and Busse. The
single tumors may reach a very large size, and Terrillon has recorded a
weight of 20 kilos. The submucous tumors and especially the cervical
growths may be extensively polypoid or even papillary.

On section the uterine sarcomas are soft and opaque as compared with
myoma and are subject to liquefaction necrosis, and hemorrhage. Fatty
degeneration,, thrombosis of vessels and infarction, with extensive softening
may produce large cysts in which suppuration may occur. While the mucosa
is usually intact, many of the tumors which project into the cavity become
ulcerated and extensively excavated. Overdevelopment of blood-vessels
or lymph-vessels is observed and Meyer describes a markedly lobulated
tumor in which the lobules were separated by large lymph-sinuses. The
more circumscribed tumors have the general outline of fibromyomas but
diffuse forms infiltrate the wall, the mucosa, and the neighboring structures.

CLINICAL TYPES OF SARCOMA 259

Metastases appear late with encapsulated interstitial tumors but when
the parametrium is invaded secondary growths often appear in the regional
areas and in the lungs as well as in many other tissues and organs (Lubman).
Yet Gessner observed regional metastases with circumscribed tumors. The
uterine veins and lymphatics have been found thrombosed by tumor-masses
without metastases. The ovaries may be extensively invaded through the
vessels or by implantation.

The gross anatomical features suggest the following somewhat serviceable
classification:

1. Circumscribed primary sarcoma chiefly subserous or interstitial.

2. Diffuse sarcomas chiefly submucous or infiltrating the wall and para-
metrium, with metastases, and subject to hemorrhage and necrosis.

3. Polypoid sarcomas of body or cervix.

FIG. 72 — Polypoid sarcoma of cervix uteri, in a subject of 52 years. (After ± McCann.)

4. Extra-uterine single or multiple myosarcoma.

5. Secondary sarcoma in myoma.

Structure. — The structure of uterine sarcoma is extremely varied. Many
authors have described them as myosarcoma, spindle-cell, round-cell, mixed-
cell, and giant-cell growths and other subvarieties. Yet there is strong reason
to believe that the entire group with rare exceptions, is of myogenic origin.
It is well-known that the malignancy varies with the cell type, reaching its
acme in round-cell and giant-cell structures, but it has repeatedly been shown
that in the same tumor the structure of different portions may exhibit several
cell types and that different tumors illustrate all transition phases of smooth
muscle-cells to round-cells and giant-cells. Even in well-formed fibromyomas
areas of round-cell sarcoma may occur (Meyer, Moraller, v. Franque).
In a case of large polypoid submucous sarcoma, I found areas of adult myoma,
very cellular lobules resembling the recurrent myoma, indifferent spindle-
cell sarcoma, numerous areas of round-cells (very short spindles), and in
edematous portions alveolar sarcoma with many large polyhedral cells.
Moraller observed a notable perivascular grouping of round-cells. Meyer
concludes that the round-cell sarcoma of cervix is often regarded as endothe-

260

NEOPLAST1C DISEASES

lioma. In fact it is evident that in this field too much importance has been
attached to variations in cell forms and too little to histogenesis and gross
anatomy.

From the prognostic standpoint, how-
ever, considerable significance attaches to
the cell type and somewhat characteristic
clinical varieties of uterine sarcoma are often
associated with the predominance of cells
showing different grades of anaplasia.

(a) Recurrent myoma is a term that may
well designate a tumor occurring chiefly in
the cervix, which recurs after a difficult ex-
tirpation and which contains rather long,
loose spindle-cells and scanty imperfectly
formed long giant-cells. In a case of this
type the structure remained uniform after
three recurrences, while the pelvis and vagi-
nal wall were slowly infiltrated. A charac-
teristic recurrent myoma of the broad liga-
ment occurs in the form of multiple nodules
composed of well-formed muscle-cells with
marked vasoformative tendencies. The cells
are short spindles with long nuclei and strongly
acidophile cytoplasm. The arrangement of
the cells is quite orderly, the vessels well
formed, and giant-cells, hemorrhage, degen-
eration, necrosis, and metastases are wanting.

(b) Large spindle-cells with granular cyto-
plasm, large vesicular nuclei, and occasional
giant-cells compose the bulk of many tumors
which invade parametrium, broad ligament
and mucosa, with ulceration, necrosis, and
cachexia. In some cases the giant-cells are
very numerous and of enormous dimensions.

(c) Predominance of round-cells usually marks rapidly growing tumors
which are locally destructive, produce cachexia from necrosis and hemorrhage,

FIG. 73. — Recurring myoma of
cervix uteri.

FIG. 74. — Section of a recurrent myosarcoma of vagina and cervix uteri.

and early yield local and distant metastases (Meyer). Yet many metastases
contain chiefly spindle-cells. Heinrich found both spindle-cells and round-

CLINICAL TYPES OF SARCOMA

261

cells in tubal metastases of spindle-cell tumors, and both original and metas-
tatic tumors contained all transitions from muscle-cells to spindle-cells,
giant-cells, and round-cells in the cases of Busse and Masty.

Histogenesis and Etiology. — While many efforts have been made to incul-
pate the connective tissue of the uterus in the genesis of sarcoma there is
no sufficient evidence to show that these tumors include any of fibroblastic
origin.

On the other hand the wide variation in form of neoplastic smooth muscle-
cells demonstrated in these and other myosarcomas leaves little room for
doubt that the entire group is essentially of myogenic origin. Yet there
remains the possibility that the group of cells
giving rise to the tumor contains besides
muscle-cells a portion of the specific stroma-
cells of the uterine mucosa. Such isolated
complex groups of cells have been shown to
give rise to adenomyoma, but the adenosar-
comas which doubtless originate from such
cell groups have quite a different structure
from myosarcoma and contain gland alveoli
(v. Winckel, Amann).

In certain sarcomas areas of small round-
cells traverse the main spindle-cell tumor in
broad but sharply circumscribed bands and
some have derived these bands from the stroma
of the mucosa. Yet the adult stroma is
probably not connected with the origin of
any of these tumors and similar round-cells
are observed in encapsulated intramural
growths.

Regarding the nature of the embryogenic
disturbance giving origin to sarcoma, one
must refer to the same data which serve for
uterine myoma. (For the sarcomatous trans-
formation of myoma see myoma uteri.)

2. Sarcoma of Uterine Mucosa.- — -Two
main anatomical forms of this condition are
commonly recognized, viz., (i) diffuse, and
(2) polypoid. The latter represents a natural
tendency of growth of the former, and there
is no essential distinction between them.

Arising from fundus or Cervix the diffuse cell groups surround minute vessels.

forms are usually widespread, Piquand find-
ing the entire mucosa involved in 33 of 54 reported cases, while a portion
or even the whole of the tubal mucosa may be affected (Griffith, Simp-
son). In advanced cases polypoid outgrowths frequently form. From a
broad base bulky tumors may develop over which the uterus is stretched
with thinning or hypertrophy of the wall (Beckmann, Terillon). Occlusion
of the uterine canal may lead to retention of serous, bloody, or purulent
fluids. In one case Terillon withdrew 1 5 liters of bloody fluid. A thin uterine
wall may suffer inversion (Williams). The original mucosa may remain
intact but is gradually altered by the growth of the tumor, by interstitial
endometritis, or by erosion and replacement by granulation tissue.

The tumor is at first sharply separated from the muscularis but soon
invasion of the wall occurs and extension follows to the parametrium,

FIG.
uterus.

75. — Myosarcoma of
A rare type. The small

262 N EOF LA STIC DISEASES

peritoneum and vagina. Metastases are observed in the regional nodes,
lungs, and elsewhere (Gessner).

Secondary changes are common in both forms of sarcoma of the endo-
metrium. The superficial portions early become eroded, infected, and ne-
crotic. Hemorrhages, edema, myxomatous softening, wide areas of caseation,
and fibrinous exudate combine to give a varied appearance.

The polypoid form is most pronounced in the cervix where it is not readily
distinguished from polypoid mural sarcoma and certain malignant teratoid
growths. The teratoid tumors include the malignant myxosarcoma of
Spiegelberg which is the most important cervical sarcoma and is to be sharply
distinguished from the present group. Many reported polypoid sarcomas
of the cervix refer to cellular polyps chiefly of inflammatory origin and it
appears doubtful if the cervical mucosa is the seat of any true sarcomas apart
from the two above types.

The structure of endometrial sarcoma is quite varied. Ruge describes
four varieties: \i) Large round- and spindle-cells; (2) decidua-like cells;
(3) giant-cells with small round-cells and spindle-cells, and (4) small round-
cells. It is probable that all these forms represent variations of one original
cell type. Thus Meyer found round-cells in the superficial layers, spindle-
cells in the deeper portions of a polypoid tumor. He interprets the decidual
cells as transitory effects of the menstrual influence, and the giant-cells as
regressive forms. In my own cases the chief features have been the diffuse
arrangement of large and small rounded cells with hyperchromatic nuclei.
The long spindles, parallel intertwining columns, and vasoformative tenden-
cies of myosarcoma are wanting. The liability to necrosis is much more
pronounced.

The diffuse distribution of many endometrial sarcomas is strong evidence
that the tumor arises from the stroma-cells. Some have traced the earliest
stages to the periacinar stroma. Wolgren describes as " fibromatosis uteri"
a tumor-like thickening of the endometrium due to overgrowth of stroma-
cells most marked about cystic glands, and Fellander places in an intermediate
group between inflammatory and neoplastic processes his case of benign
" elephantiasis flbrosarcomatosa " in which many giant-cells were mingled
with short spindles. The occurrence of such intermediate forms of hyperplasia
renders it probable that highly malignant tumors also arise from the stroma-
cells. That some of the supposed sarcomas of the mucosa are advanced
stages of mural myosarcoma is nevertheless probable. Ruge states that
sarcoma follows periacinar interstitial endometritis and that the tumor
process first affects groups of glands about which the stroma-cells increase
in size and number.

For the endometrium a special factor in the genesis of sarcoma which
should not be overlooked is the influence of gestation. Yet the varieties of
sarcoma are well represented in children and virgins. Highly malignant
lymphosarcomas are said to have existed in rare cases, but their exact
nature is uncertain (Wilischamin, Wagner, Gow). Melanosarcomas result
from imbibition of blood. Alveolar and angiosarcomas illustrate occasional
secondary structural features.

Carcino sarcoma of Uterus. — In a series of cases carcinoma and sarcoma
have been found in the same uterus and the interpretation of these cases has
given rise to much discussion (Gessner, Meyer, Herxheimer, H. Albrecht).

i. Simultaneous occurrence of two separate tumors has been observed in
ten cases and constitutes the most frequent and least notable form of the
combination. Usually a polypoid sarcoma is associated with diffuse adeno-
carcinoma of the body (Niebergall).

CLINICAL TYPES OF SARCOMA 263

2. Two tumors arise separately but later one invades the other (Nebesky,
Schaller).

3. At the point where a submucous or mural sarcoma meets the glandular
layer carcinoma develops secondarily. This event seems to be not infrequent
and is illustrated in Albrecht's case where carcinoma developed in the mucosa
of a uterus inverted by a sarcomatous polyp. It may indicate a stimulating
influence of sarcoma-cells upon epithelium or, more probably, the ordinary
effects of the hyperemia and irritation to which the mucosa becomes exposed.
I have seen it in connection with a benign submucous fibromyoma, and near
a calcine myoma.

4. The glands included in sarcomatous polyps or in inflammatory polyps
or in adenomyoma may become carcinomatous. In Gebhard's case the
glands surrounded by round-cell sarcoma of the mucosa appeared to become
carcinomatous. Amann's case has usually been interpreted as an adeno-
sarcoma in which the glands became carcinomatous and appeared alone in
the recurrences. Ballin assumed a simultaneous process in both stroma and
glands.

5. The sarcomatous transformation of the stroma of a cervical carcinoma
was assumed to have occurred in a case of Lindemann's, but the gross appear-
ance of his specimen strongly suggests an ordinary cervical carcinoma with
vesical fistula and with marked inflammatory cell changes.

6. Spurious cases are undoubtedly recorded in which atypical proliferation
of glands was interpreted as carcinoma (Klein), or endothelial proliferation
was so mistaken (Riederer), or in which carcinoma, becoming diffuse and its
cells assuming a spindle form, bore a certain resemblance to sarcoma.

There is little doubt that many so-called carcinosarcomas result from
the atypical growth of epithelial cells. Gessner refers all such tumors to
this origin, pointing out that their metastases are usually carcinomatous.
The exudation and inflammation accompanying tumors of the endometrium
greatly favor atypical cell-growth the scope of which is, I believe, under-
estimated. I have studied several tumors which appeared to exhibit sarco-
matous and carcinomatous structure but have regarded them as unfavorable
material for accurate observations on histogenesis. R. Meyer holds that
sarcomatous transformation of the stroma of a carcinoma has not yet been
demonstrated.

CHAPTER XIX
SARCOMAS OF BONE AND BONE -MARROW

The malignant tumors of bone constitute one of the most important
departments of oncology. Their very frequent occurrence, local destructive
tendencies resulting in loss of limbs, rapid extension with loss of life, and
the difficulties in establishing the prognosis render them a complex surgical
problem. Arising from cells whose natural function is to produce the most
stable of tissues, these tumors rank with the most rapidly growing of neo-
plasms. Although often most clearly connected with a traumatic origin
the mode of action of the trauma remains highly obscure, and while the
neoplastic nature is usually most obvious, the general etiology of some of the
growths reveals complex relations with normal growth of bone and physio-
logical regeneration and with nutritional, inflammatory, and infectious
processes.

Finally the histological structure of this group of tumors while often
highly characteristic is subject to wide variations so that many problems
of histogenesis remain unsolved.

Historical. — Although Astley Cooper recognized a distinction between
periosteal and medullary tumors of bone, the older clinicians separated
imperfectly between primary sarcoma, secondary carcinoma, and chronic
inflammations of bone. Boyer first employed the term osteosarcoma and
applied it to certain malignant bone- tumors. The microscopical distinc-
tions between sarcoma and carcinoma of bone were established by Lebert
in 1845. Virchow very fully described the morphology of these tumors
but did not separate them sharply from cancer. In 1849 Robin described
two types of marrow-cells which he believed gave origin to bone-tumors.
One of these, the myeloplacque, was described as a large giant-cell with 6 to 10
nuclei each with nucleoli and found chiefly in young mammals in the spongy
tisssue and between the marrow and the inner wall of the bone. These cells
appeared abundantly in some tumors. The other type of cells, the medullo-
celles, were large round-cells with single nuclei and often made up the major-
ity of marrow-cells. They also were found in tumors. It is clear that
Robin did not fully distinguish bone-forming from blood-forming cells in
the marrow. Kolliker identified the myeloplacques with osteoclasts and
the medullocelles with osteoblasts.

In 1853 Paget also recognized a variety of tumors containing large giant-
cells which he identified with the giant-cells of marrow, and Gray described
these cells as forming a well-defined layer where the marrow comes in contact
with the bone in subjects under 20 years of age. In 1860 Nelaton contributed
an important monograph in which he emphasized the importance of
Robin's cell groups and sharply distinguished between the malignant
tumeur a medullocelles and the benign tumeur a myeloplacques. In 1879
Gross reviewed the history and morphology of giant-cell sarcoma, empha-
sizing against Billroth's opinion, the benign prognostic importance of the
giant-cell structure and showing in four fatal cases that this tumor might
become malignant.

Gross' description of the origin, structure, clinical characters and treat-
ment of bone-sarcoma stands to-day as the classic contribution on this subject.

264

SARCOMAS OF BONE AND BONE-MARROW 265

Robin's derivation of the giant-cells from bone-forming cells of the marrow
did not receive complete endorsement. Rindfleisch, Virchow, Wyss,
Ziegler, and Hulke derived the giant-cells from hypertrophied bone-cells
liberated during the absorption of bone (Gross). Wegner in Germany and
Malassez and Monod in France and many later writers have claimed that
these cells are vasoformative in nature and of endothelial origin. Many
observers have shown that they are present in many forms of inflammation
of bone (Rustizky, Fehr, Barrie).

In recent years, studies in this field have dealt with the origin of the
giant-cells, the relation of giant-cell sarcoma to inflammation, and the general
etiology, prognosis, and treatment of these tumors.

Classification/ — Tumors occurring primarily in bone include those arising
from bone-cells or osteogenic tissue and those arising from bone-marrow.
Bone-cells give origin to tumors which retain more or less of the function
of bone production and are properly called osteogenic, while the marrow-
cells give origin to a very different class of tumors which are called myelomas.
Malignant tumors of bone-cells, although differing markedly in many features,
are essentially one and the same disease which may be designated as
osteogenic sarcoma. The anatomical varieties of osteogenic sarcoma result
from exaggeration of bone production as in sclerosing osteogenic sarcoma,
or overgrowth of blood-vessels as in the telangiectatic type, or from the
predominance of fibrocellular tissue as in the so-called periosteal sarcoma.
Many osteogenic sarcomas combine all three of these features. The location
of the growth is of minor importance, and yet periosteal tumors are usually
fibrocellular, telangiectatic tumors either originate in the medullary por-
tion of the shaft or soon involve the marrow cavity, and sclerosing sarcoma
fills the marrow cavity with dense bone. The attempt to classify these
tumors as periosteal or medullary is therefore unsatisfactory, since most of
them involve marrow cavity, shaft, and periosteum.

The benign giant-cell sarcoma of epulis type is not osteogenic but is
essentially connected with the absorption of bone and usually of cancellous
bone. Its position is usually medullary. Its structure may arise as a
secondary process in osteogenic sarcoma.

A peculiar and somewhat rare tumor of bone presents the structure of
angio-endothelioma. It is not osteogenic, although it may arise from the
blood-vessels of bone, or, more probably from the vessels of the marrow.
It is described as an endothelioma.

The myelomas, although destroying bone, have no relation to osteogenic
sarcoma.

The entire group of primary sarcomatous tumors of bone and bone-marrow
may best be classified as follows:

Primary sarcomatous tumors occurring in bone.

1. Osteogenic sarcoma.

a. Fibrocellular, chiefly periosteal.

b. Telangiectatic involving marrow cavity, shaft, and periosteum.

c. Sclerosing, affecting marrow cavity, shaft, and periosteum.

2. Benign giant-cell sarcoma of epulis type.

3. Myeloma, arising from bone-marrow cells.

4. Endothelioma, or angio-endothelioma, arising from blood-vessels
of bone or marrow. (Described under endothelioma.)

Osteogenic Sarcoma. — (a) Periosteal Sarcoma. — The ends of the long
bones, femur, tibia, and humerus are the chief seats, but the small bones of
hands, feet and skull and many other portions of the skeleton are involved.
The main gross feature of the periosteal sarcoma is the production of a tumor

266

NEOPLASTIC DISEASES

arising in the inner layers of the periosteum, extending along and inclosing
the shaft, with a sharply marked border, causing a relatively bulky rounded
fusiform or lobulated tumor lying outside the shaft which long remains intact.
This position favors a bulky growth so that periosteal sarcomas commonly
reach a large size, some of them attaining very large dimensions after a
long period. The integrity of the shaft is usual but not constant, for the
more cellular growths early penetrate and destroy the compact bone and

FIG. 76. — Periosteal sarcoma completely traversing shaft as a telangiectatic structure.

lead to spontaneous fractures. Even thus the extramedullary tumor is usually
more bulky than with corresponding central telangiectatic sarcoma.

According to the consistence periosteal sarcomas are (i) soft, cellular,
and highly malignant, or (2) firm and fibrous, or (3) irregularly ossified. En-
capsulation by the periosteum is maintained for periods varying with the
character of the growth but the more malignant tumors invade not only the
shaft but the surrounding muscles, fasciae, vessels, and eventually the skin.

SARCOMAS OF BONE AND BONE-MARROW

267

Tendon insertions offer considerable resistance to progress of the growth.
The general appearance of these tumors supports the view that the peri-
osteum is not passively displaced by an underlying growth, but, as Marullaz
finds, that the periosteum contributes to the growth and undergoes sarco-
matous transformation. A thin, bony capsule may be laid down^by the
periosteum.

FIG. 77.— Periosteal sarcoma, combined with diffuse central sclerosing sarcoma.

Incision reveals a solid tumor mass in which the shaft is fused with ossi-
fying tumors or eroded by cellular growths. An expansion of the shaft
as noted with benign central giant-cell sarcoma is missing. Fatty and mucoid
degenerations, hemorrhage, and necrosis may greatly alter the appearance.
Maceration by removing the soft parts may leave bony trabeculae radiating
out from the shaft, or a globular mass resembling an exostosis, or isolated
bony areas may be removed entirely. Many of the large tumors, especially
of the spindle-cell variety, contain cysts filled with serous fluid, or semifluid

268

NEOPLASTIC DISEASES

detritus, or blood. Although sometimes quite vascular periosteal sarcomas
do not pulsate.

All the histological varieties of bone-sarcoma originate in the periosteum,
but the spindle-cell type is most frequent. Giant-cells are absent in many
cases, and always less numerous than in benign central sarcomas, being
found usually in areas of dissolving bone. The tendency to calcification and
ossification is very prominent. In one group, in which' the cells are usually

large and polyhedral, the matrix is
chiefly cartilaginous. Some of the
most malignant bone-tumors are of
this type, and at times the large
polyhedral cells grow diffusely while
the cartilaginous matrix is missing
or reduced to hyaline traces.

(b) Telangiectatic Bone-sarcoma.
— A considerable proportion of bone-
sarcomas present an extensive de-
velopment of blood-vessels sup-
ported by more or less cellular
osteogenic tumor-tissue, they early
destroy the shaft, penetrate the
marrow cavity for a short distance,
and rupturing the periosteum extend
widely through fasciae and muscle.
The exact origin of these tumors is
not satisfactorily located but they
seem to arise from the blood-vessels
and bony tissue of the shafts of long
bones. They are sometimes called
central osteogenic sarcoma, but the
majority of central tumors are not
of this type. They are often con-
fused with benign giant-cell sar-
coma, which is a central medullary
tumor, but is not osteogenic nor
malignant. The structure of this
telangiectatic sarcoma is occasion-
ally seen over an entire tumor, but
more often it is associated with
other structural types, so that it is
best interpreted as an exaggeration
of the blood-vessel element in osteo-
genic bone-sarcoma.

The absorption of bone occurs

rapidly and the line of absorption while ragged is rather sharp, suggesting
that the growth has originated in the marrow, but the same type of absorp-
tion occurs in vascular portions of tumors which are chiefly periosteal.
Spontaneous fracture quickly results in many cases and may be the first
symptom of the disease to be detected.

Telangiectatic sarcomas of bone are osteogenic but the production of
bone and even of tumor-tissue may be slight. The more solid portions of
such tumors usually present irregularly ossified or only calcified strands,
plates, or spicules of imperfectly formed bone. In some cases the periosteum

FIG. 78. — T elangiectatic, periosteal,
spindle and giant-cell sarcoma of femur.
Perforation of shaft.

SARCOMAS OF BONE AND BONE-MARROW

269

is displaced outward and succeeds in laying down a thin shell of bone which
crepitates on pressure.

In the malignant bone aneurism, the vessels are widely dilated into
irregular sinuses and the tumor-tissue is correspondingly reduced, or limited
to an irregular layer disposed along the periphery. Formation of bony
or osteoid tissue is also reduced and may be missing. The tumors may pul-
sate and yield a bruit.

The head of the humerus, upper end of tibia, and lower end of femur are
the chief seats of malignant bone aneurisms. As a rule the tumor proves
highly malignant and recurs locally or in the lungs after amputation.

The relation of the malignant bone aneurism to cavernous angioma,
benign giant-cell sarcoma, and simple blood-cysts of bone, has been much

FIG. 79. — Malignant central osteogenic sarcoma of lower end of femur.

discussed. The opinion expressed by Nelaton, Volkmann, Lucke, and
Gross, that the great majority of bone aneurisms are forms of sarcoma has
been supported by recent observers (Gaylord, Nakayama, Bloodgood).

It is not always easy but yet highly important to distinguish between
malignant bone aneurism and very vascular forms of benign giant-cell
sarcoma. The malignant disease is almost never found until it has destroyed
much of the shaft of the bone, whereas the benign process long spares the
shaft and expands so slowly that the periosteum is able to lay down a firm
bone capsule about the expanding tumor. The great majority of simple bone-
cysts are not connected with tumors.

270 N EOF LA STIC DISEASES

(c) Sclerosing Osteogenic Sarcoma. — The production of much dense solid
bone occurs in portions of many bone-sarcomas but occasionally it forms the
bulk of the tumor or is exclusively present, and since it is associated with a
prolonged clinical course, there are both anatomical and clinical grounds
for recognizing it as a specific form of osteogenic sarcoma. These tumors
were once the subject of much debate (cf. Gross), being regarded by many
authors as bone cancers, until Volkmann and Virchow established their
true nature and termed them sclerosing osteoid sarcoma.

In typical cases a large portion of the end of a long bone is converted into
a solid mass of dense almost ivory-like bone, which obliterates marrow cavity
and shaft and produces a fusiform swelling of considerable dimensions.
Blood-vessels are very scanty except about the periphery or over a small
area of the tumor, yet metastases form in a high proportion of cases, so that
this slowly advancing tumor has long been known to be fully as malignant
as the others. They show comparatively little tendency to invade surround-
ing soft parts.

Areas of sclerosing sarcoma occur frequently with periosteal growths
in which they show all grades of bone formation up to the very dense ivory-
like type.

Capsular and Parosteal Sarcoma.- — Osteogenic tumors not infrequently
involve the capsules of joints or appear in the soft tissues about joints or
along the shafts of bones. This group of cases is important not only for
their clinical interest but also for their bearing on the origin of bony tumors
and of certain neoplasms not always recognized as related to bone. The
capsule of the knee-joint is the chief seat of capsular sarcoma and here the
tumors illustrate most of the clinical and histological features of bone-sarcoma
(Rydygier, Lit.). They are distinguished chiefly by the failure to involve
the joint-cavity or the bone, and their malignancy is distinctly less than
that of corresponding tumors of periosteum or medulla. Yet malignant
cases occur which are rapidly fatal after resection or amputation. Some
produce a fusiform swelling of the joint and being accompanied by fever the
case resembles tuberculosis (Garre). Or a localized tumor appears at one
point in the capsule (Marsh).

Pedunculated giant- and spindle-cell sarcomas have been described by
Weir and by Dowd. The structural variations cover most of the scope of
bone-sarcoma with corresponding prognosis.

Capsular sarcomas of the ankle exhibit much the same characters as in
the knee (Moser, Lit.). The tendon-sheaths are a common seat of sarcoma
which usually takes the form of a giant-cell tumor 'of slight malignancy.
The deep fasciae may be the seat of sarcomas of various osteogenic varieties
which have no definite connection with the periosteum and the true nature
of which may therefore be overlooked. They include giant-, spindle- and
round-cell types, and may belong in the group of chondrosarcoma or its
derivative myxochondrosarcoma.

Along the cranial sutures, base of skull, pharynx, nares, vertebrae and
pelvis, occur many tumors of pronounced osteogenic character which belong
in this group, and not a few in which the derivation from bone is only vaguely
indicated by the structure.

The course of osteogenic sarcoma varies greatly and accords in general
with the histological structure. As a rule they are malignant tumors appear-
ing before the 3oth year, recurring after incision or amputation and producing
pain, fever, metastases, and cachexia. Coley reports four bone-sarcomas
occurring in subjects aged 17 months to 9 years, and Goebel has collected
cases of congenital bone-tumors. The spindle-cell tumors grow rather

SARCOMAS OF BONE AND BONE-MARROW 271

slowly but nevertheless tend to recur and cause death by local growth and
internal metastasis. Jackson recorded an unusual case in which a small
growth on the under side of the knee increased very slowly for 32 years when
after trauma it grew rapidly and produced a large medullary tumor. The
highly osteoid tumors may also pursue a very chronic course, as with cases
of Paget and Holmes which proved fatal with metastases after 21 and 25
years.

Metastases are frequent with osteogenic periosteal sarcoma, in the ad-
vanced stages of all types and very early with soft and cellular varieties.
A period of months or years may intervene between the appearance of the
primary and the secondary tumors or there may be almost simultaneous
involvement of several bones (LeDentu, Zahn, Poncet). That these tumors
are not myelomas is attested by Poncet's case. The lungs are chiefly in-
volved by emboli through the blood-vessels and other widely distant organs
may be reached by the same route. Neighboring or distant lymph-nodes are
also occasionally invaded through lymphatics but swollen lymph-nodes
usually prove to be purely inflammatory. The occurrence of pulmonary
tumors secondary to periosteal sarcomas was noted by Virchow but the
frequency and extent of such metastatic tumors has lately been emphasized
by LeCount (Lit.).

These tumors appear as multiple nodules, or as superficial pleural growths
or as bulky pleural or pulmonary tumors. Extensive diffuse pleural growths
are reported by Virchow, Pitts, LeCount and others, and pedunculated
pleural tumors by Virchow and Cocks and Wilks. Massive intrapulmonary
growths have been observed by Birch-Hirschfeld, Kuster, Allin, Meakin and
others. In structure the tumors have been soft and cellular or cartilaginous
and bony, or encased in a bony shell. In a remarkable case described by
Bosch, the pulmonary metastases of an osteoid sarcoma of the femur ex-
hibited lamellar structure as in the long bones, and enclosed groups of cells
resembling lymphoid marrow. Pleural effusion may be absent and pulmon-
ary symptoms may be slight, but bloody effusions, dyspnea and hemoptysis
frequently occur and suggest tuberculosis.

In a few cases extensive intravascular growths have been observed.
Hektoen found bony masses from a tibial sarcoma, which nearly filled the
right ventricle and produced secondary growths in the lungs. Feistmantel
found cylindrical bone masses in one lung and large nodules in the opposite
lung which probably resulted from metastases in the pulmonary artery from
a femoral sarcoma. Pulmonary metastases appear to have occurred while
the primary tumors, of foot and wrist, were quite small in the cases of Pitts
and of West. Usually they appear a few months after operation on the
primary growth, while in Jenckel's case death from a pulmonary growth
occurred 15 years after amputation of the femur.

That metastases are often produced by the trauma of operation is in-
dicated by McAuliffe's observation of tumor-cell emboli in many organs
after death from resection of a sacral sarcoma.

Benign Giant-cell Sarcoma (Epulis Type). — This peculiar condition was
first fully described as a benign process in bone by Nelaton, who emphasized
the reddish jelly-like appearance of the tumor-tissue, noted its capacity to
absorb bone and widen the marrow cavity, and fully established its benign
course and the wisdom of conservative treatment. All of these features
have been full recognized by most later observers but not by all, so that many
limbs have been needlessly sacrificed because of the failure to distinguish be-
tween this benign process and the malignant central telangiectatic sarcoma.

The disease appears at the ends of the long bones, but it very frequently

272 NEOPLASTIC DISEASES

arises in the maxillae after the extraction of teeth so that it is often called
the epulis type of sarcoma. It has frequently appeared as a multiple tumor,
and one of the most remarkable of these cases is that of Martland in which
tumors appeared in widely distant parts of the body over a long period
without showing any evidence of local malignancy.

Very similar tumors occur in the capsules of the joint, and along the
tendon sheaths and bursae.

In the long bones the tumors produce reddish jelly-like tumor masses
resembling granulation tissue and replacing the cancellous portions of the
bone. They may also slowly absorb the shaft while the periosteum lays
down an advancing shell of new bone. 'Eventually this shell may become
thin and allow passage of the tumor-tissue but there is seldom any tendency
toward invasion of soft parts. Likewise the cartilaginous surfaces of the
joint may be reached and absorbed and the joint surfaces may collapse, from
simple absorption but without infiltration (Gross, Stimson).

There is considerable variation in the rate of growth and bone absorption
by benign giant-cell sarcoma. As the spindle-cells of the stroma become
more active and abundant, the giant-cells diminish, the tumor shows less
resemblance to granulation tissue, but becomes firmer and like spindle-cell
sarcoma. Such growths recur locally and may destroy bone and infiltrate
the soft tissues, but I have never known them to yield metastases. They
regularly fail to produce bone.

The earliest stages of this disease have been traced to the walls of small
cysts forming in osteitis fibrosa cystica. Here the process may be interpreted
as a form of bone absorption, or as some prefer, rarefying osteitis or osteomye-
litis, with the formation of cysts.

In some cases the process appears to subside, leaving cysts with smooth
lining and serous contents. In most cases it is progressive and acquires the
characters of a mild tumor process, and rarely it develops greater momentum,
actively destroys bone and exhibits certain clinically malignant tendencies.

Structure of Bone Sarcoma. — There are three main histological varie-
ties of bone-sarcoma: (i) spindle-cell, (2) giant-cell, and (3) round-cell tumors
and in each of these classes there are marked variations which are of
importance in prognosis. Since all these tumors arise from bone-forming
cells the varying morphology may be interpreted as the expression of different
grades of anaplasia. To some extent also it probably represents the varying
etiology, and the complex pictures resulting from bone absorption and imper-
fect bone production. Inflammation, degeneration and necrosis also leave
pronounced effects in many cases.

i. Spindle-cell tumors are most frequent and this is the usual form of
periosteal growths. The cells have a short spindle form, or they appear
large and almost polyhedral, and in very malignant processes they are small
and appear almost round although never assuming lymphoid characters.
They present many variations in size and chromatin content of the nuclei
which are of much importance in prognosis. Intercellular substance varies
from a scant trace in soft malignant growths to the great abundance of
osteoid or bony tissue in the osteoid sarcomas.

The slowly growing sarcomas are poor in vessels but the malignant cellular
forms may be very vascular. The walls of the larger vessels are often infil-
trated with round-cells, occasionally they appear sarcomatous, and rarely
they have been found distended with tumor-tissue (Bristowe).

In vascular tumors a close relation of the tumor-cells to the blood-vessel
is common and occasionally the structure of perithelioma is simulated. A
pseudo-alveolar structure is sometimes observed.

SARCOMAS OF BONE AND BONE-MARROW

273

A distinguishing character of the spindle-cell periosteal tumor is the
production of bone or cartilage. The bone appears in short trabeculae dis-
tributed throughout the growth, or more often in the form of osteoid tissue
which may compose the bulk of the tumor. In the osteoid tumors the cells
are reduced in number and appear partly or completely inclosed in lamellae
of hyaline partly ossified material. Areas of cartilage are often mingled
with the osteoid tissue and many phases appear of the transformation of
cartilage and osteoid tissue into bone. Most tumors, however, fail to carry
the development of bone to a completion. The most advanced bone pro-
duction is seen in the stalactite tumors which resist maceration, and in the
diffuse ivory-like growths. When osteoid sarcoma invades the muscles the
histological picture may resemble myositis ossificans. When bone is ab-
sorbed by the progress of the sarcoma, the solid trabeculae first exhibit inter-

FIG. 80. — Periosteal sarcoma. Vein lined with tumor cells. This structure explains the
ready metastases of these tumors.

fibrillary clefts from advancing decalcification, then canals are formed by
advancing blood-vessels or groups of tumor-cells, or giant-cells form in
Howship's lacunae, producing the lacunar resorption. Likewise when an
osteoid sarcoma suffers resorption its structure changes and all the above
processes may be observed. In all cases where bone, normal or neoplastic,
is being absorbed the giant-cells tend to assume the foreign body type of
benign sarcoma.

2. Giant-cell Sarcoma. — When giant-cells predominate or form a promi-
nent feature of bone-sarcoma the tumor is called a giant-cell sarcoma. This
term has been applied chiefly to sarcomas of the epulis type, central or
periosteal, in which characteristic giant-cells are abundant or form the bulk
of the tumor, and it would be advisable to restrict the term to this relatively

274

N EOF LA STIC DISEASES

benign tumor. Similar cells are sometimes seen in portions of malignant
tumors. These cells are of large size, the cytoplasm is opaque and acido-
phile, and the nuclei are numerous, separate, oval and usually grouped in
the center of the cell. They often contain vacuoles, fatty detritus, homo-
geneous material, red blood-cells, and occasionally spicules of bone. They
have the general characters of foreign body giant-cells (Fig. 82).

The bulk of these growths is composed of loosely packed spindle-cells,
surrounding many vessels, capillaries, and sinuses. There is much variation
in the vascularity of these tumors and in the number, size, and nuclear chro-
ma tin of the spindle-cells, and there is
a corresponding difference in their
powers of growth.

Periosteal sarcoma may contain
giant-cells of the above type, espe-
cially where the tumor comes in contact
with absorbing bone, but both peri-
osteal and central sarcomas may exhibit
giant-cells of distinctly different type
and significance. These cells may be
large or small, the cytoplasm stains
poorly, the nuclei are large and vesi-
cular and composed of many lobes which
may become detached. As a rule
these cells belong to malignant tumors.
While the two types of giant-cells are
usually distinct, it must be admitted
that transitional forms seem to occur,
especially when malignant tumors un-
dergo regressive changes, erode bone or
become inflamed (Fig. 83).

The existence of different types of giant-
cells in bone-sarcoma has been recognized by
several observers. Poncet describes true and
false myeloplacques. The former are as large
as 3 to 4 ordinary tumor-cells and contain 5 to 6
nuclei; the latter are as large as 4 to 5 ordinary
cells and contain 12 to 20 nuclei, and corre-
spond to the common giant-cell of the epulis.
Borst states that the giant-cells of medullary
sarcoma are more delicate than those of peri-
osteal origin, in which the cytoplasm is more
compact, often free from granules, and more

sharply defined, and the cell processes are longer than in medullary tumors. ' Mallory dis-
tinguishes between true tumor giant-cells and the foreign body giant-cells of osteogenic
and other sarcomas. The tumor giant-cells differ from other tumor-cells chiefly in size
and number of nuclei which may multiply by mitosis. They produce specific fibrils.
The foreign body giant-cells are of endothelial origin, and correspond in type to those of
the epulis.

The origin of the giant-cells of the epulis type has been the subject of much discussion.
Virchow and Rindfleisch believed that they were hypertrophied bone-cells set free by the
absorption of the bone matrix and that they are identical with the osteoblasts of Kolliker.
Robin and Nelaton, in describing the giant-cell sarcoma of bone (tumeur a myeloplaxes),
accepted the identity of the giant-cells with Kolliker's osteoblasts. This view is favored
by the very frequent presence of giant-cells in many lesions of bone and has been widely
accepted. The direct transformation of bone cells into giant- cells of sarcoma has been
traced by Wyss, Ziegler and others, but it is not clear that the giant-cells observed in
the malignant tumors of those authors were identified with those of the epulis. Ziegler
found that giant-cells are by no means constant in the absorption of bone and suspected
that osteoclasts might have a variable origin.

FIG. 81. — Malignant chondrosarcoma of
femur.

SARCOMAS OF BONE AND BONE- MARROW

275

Wegner, Malassez, and many later observers have been led to conclude that the giant-
cells of the epulis are derived from modified endothelium or angioblastic cells, and Malassez
classified this tumor with the angioblastic sarcomas. Very similar results were reached
by Ritter who traced the cells in Howship's lacunae to proliferating endothelium and he
further concluded that these cells may take on the function of bone-cells. Borst recognizes
the multiple origin of the giant-cells of sarcomas, but clings to the view that in the epulis
they stand as evidence of the bony origin of the tumor matrix. Mallory holds that the
giant-cells of epulis are transformed wandering endothelial leukocytes and do not belong
to the tumor process.

Thus, both in morphology and in origin it is necessary to recognize two
types of giant-cells in bone-sarcoma. One occurs chiefly in the benign
epulis, is chiefly of endothelial origin, and belongs among the foreign body

' ? - \

FIG. 82. — Benign giant-cell sarcoma of head of tibia. Epulis type of medullary sarcoma.
Giant-cells forming about blood masses and lipoid material.

giant-cells, although participating in the tumor process. The other occurs
chiefly in malignant periosteal tumors and is derived from tumor-cells.

The giant-cells of bone-sarcoma are therefore contributed both by the
bone-cells and by proliferating angioblastic cells. Apparently the growing
endothelium feels the influence of the mother tissue and may take on some
of the form and function of bone-cells, giving the specific structure of the
benign epulis which is rarely observed except in connection with bone.

On account of their chiefly angioblastic origin and benign course many
have suggested that bone-tumors of the epulis type should be excluded from
the class of sarcomas or even of true tumors. Yet these cases show many
features of neoplasms, not a few are moderately malignant, and many transi-
tional forms up to highly malignant tumors are observed.

276

N EOF LA STIC DISEASES

3. Round-cell Sarcoma of Bone. — In many very malignant bone- tumors
the cells are of small size and assume a short spindle or rounded form. Since
these tumors are not of lymphoid origin and since traces of the spindle
form are nearly always present it is of doubtful wisdom to employ for them
term "round-cell." Moreover, there is a true round-cell tumor of the bones
which is of lymphoid character, the multiple myeloma, and which should be
sharply distinguished from osteogenic sarcoma. Yet in rare cases of perios-
teal sarcoma groups of lymphoid cells may be found which seem to represent
abortive efforts toward the production of bone-marrow. At present it is
impossible to state to what extent cells of this character enter into the struc-
ture of the common bone-sarcomas.

M* »"V"

FIG. 83. — -Periosteal sarcoma.

Malignant giant-cell structure.

These tumors are the most anaplastic actively growing and malignant
of bone neoplasms. They rapidly destroy the bone, periosteum and marrow
cavity, infiltrate joints, and surrounding tissues, recur promptly after opera-
tion and produce early metastases.

In the common small cell tumor the cells are of short spindle form, or
on cross-section round or polyhedral. Multinucleated cells are often pres-
ent. Mucinous and fatty degeneration, hemorrhage, and necrosis are
frequent in this variety.

Prognosis of Bone-sarcoma. — The widest extremes are represented in
the prognosis of different sarcomas of bone, and it becomes a matter of first
importance to determine the prognosis in the light of all the data, clinical
and pathological.

The age of the patient, the duration of the disease, its rate of progress,
the particular bone affected, the completeness of the operation, and above all

SARCOMAS OF BONE AND BONE-MARROW 277

the structure and essential malignancy of the tumor, must all be considered.
Subjects under 20 years withstand the progress of malignant tumors poorly.

The duration of the disease must be considered from several standpoints.
A tumor which grows very slowly is for that reason probably less malignant,
yet there are numerous records of long existing tumors suddenly assuming
active growth after trauma (Jackson). Certain slowly growing but malig-
nant osteoid tumors appear not formidable in themselves but early produce
metastases (Le Count). The local damage to tissues occurring in the
advanced stages of otherwise comparatively benign tumors is an impor-
tant element in prognosis, chiefly because it complicates the operation, but
also because it favors invasion of veins and metastasis. Kramer states
that encapsulation is the most important factor in the prognosis of most
bone-sarcomas.

The rapidity of growth is a very reliable clinical sign of malignancy and
should always control the deductions drawn from histological structure.
Rapidly growing tumors are nearly always malignant and eventually fatal.
A highly anaplastic, small spindle-cell, traumatic sarcoma of patella sub-
mitted to me by Dr. John Rogers proved fatal six weeks after the trauma,
with very extensive local recurrence and metastases. Many would have
described this growth as of round-cell structure.

Yet the essential capacity for growth cannot always be estimated clin-
ically, encapsulation restrains growth, and it is possible for a tumor to change
its rate of growth. A central tumor which long remains confined by the
periosteum usually has a limited growth capacity, for very malignant tumors
early perforate the shaft. Yet in one of Bloodgood's fatal cases symptoms
had existed for 25 years.

It is an established rule that periosteal growths are much more malignant
than central tumors but this rule has little practical value. Gross found the
average duration of life with round-cell, spindle-cell and osteoid periosteal
tumors with operation at 18, 20, and 92.7 months respectively. While
amputation in the early stages of spindle-cell or osteoid sarcoma of
the extremities may be followed by complete recovery, the prognosis of any
variety of periosteal sarcoma located in or near the trunk is very grave. The
great majority of cases which seem to recover after operation eventually
suffer from local recurrence or internal metastasis. Gross concluded that
practically all cases of round-cell or spindle-cell periosteal sarcoma eventually
die of the disease, while with osteoid sarcoma 65.62 per cent, of the cases
prove fatal. More recent statistics show slightly better results and some
dependence of the outcome upon the particular bone affected.

Kocher collected 48 cases of sarcoma of long bones which were regarded
as cured. Of these the radius was the seat of the growth in 4, ulna i, humerus
10, femur 23, tibia 12. Coley collected 57 cases of apparent cures, 30 of
the "myelogenous" type, 15 periosteal, 12 undetermined. Butlin collected
18 cases of periosteal sarcoma of humerus which survived operation, but
only one remained well after three years. Of 68 cases of periosteal sarcoma
of femur only one doubtful case remained well three years. Yet McCosh
had three recoveries of spindle-cell sarcoma of the femur among seven cases.
Bloodgood reports 26 medullary giant-cell sarcomas all living; 18 inoperable
malignant sarcomas; 34 high amputations without a single cure; and 6
permanent cures (periosteal osteosarcoma, 3, myxochondrosarcoma, 2,
fibrosarcoma, i).

Rheinhardt reported 7 permanent cures (8 to 12 years) out of 54 cases,
including 4 round-cell tumors, of tibia 2, and humerus, 2. Coley collected
62 cases of sarcoma of clavicle of which 6 recovered but in many the result

278 N EOF LA STIC DISEASES

was not known. Nancrede could find no cases of recovery from sarcoma
of the scapula. The interscapulothoracic amputation, while comparatively
effective for benign tumors of the humerus, appears to have succeeded in
curing only one advanced malignant tumor of the humerus (Berger's case)
(Jeanbreau, Riche).

From a general survey it appears that recovery has occasionally followed
operation for almost every variety of sarcoma of the long bones, but in none
of the statistical reports of Nasse, Reinhardt, Koeber, Butlin, Coley, has
adequate attention been given to the dependence of prognosis upon the
location, origin, and structural type of the tumor.

Although Billroth asserted that the histological structure is of no aid
in prognosis this opinion cannot apply to the more malignant tumors, most of
which prove fatal and among which recovery is determined by the location
and stage of growth of the tumor. Contrary to the above opinion histo-
logical studies have established the benign nature of the central giant-cell
sarcoma, the greater malignancy of other types of giant-cell tumors, and the
very unfavorable prognosis of the small spindle-round-cell growths. The
chief source of difficulty and confusion in this field has arisen from the as-
sumption that the tumors fall into a few sharply defined categories, as giant-,
spindle-, and round-cell, whereas there are different grades of potential
malignancy in each of these groups. When this factor is considered I
believe it will be found in bone-sarcoma as with other groups of tumors that
there is a definite relation between prognosis and structure.

1. The benign nature of central giant-cell sarcoma of the epulis type
was early pointed out by Nelaton, later by Gross, Haberer, and others,
and is now generally recognized. Bloodgood finds that practically all of
these tumors respond to conservative operations, and that considerable
invasion of the soft parts is no bar to conservative treatment. This treat-
ment consists of curettage, or resection, followed by application to the wound
of pure carbolic acid, and alcohol, or chloride of zinc. Implantation of
bone is employed when necessary. Among 26 cases curetted, Bloodgood
records five recurrences all of which were cured by a second curettage or
by resection or by amputation. Kramer and Hinds report successful
curettage when both condyles of the femur were involved. Most of these
tumors respond well to radium.

It was early shown that certain giant-cell sarcomas of bone are very
malignant (Ziegler, Wyss, Gross), and this fact has stood against the general
recognition of the benign nature of the epulis type. Yet the giant-cells
of the malignant tumor are quite different in appearance from those of the
epulis and present single multilobed hyperchromatic nuclei while the chief
spindle-cells of the tumor also show the features of malignancy, mitoses
and hyperchromatic nuclei. Gross found that the malignant giant-cell
sarcomas exhibit calcine deposits and bony trabeculae, but these features
are wanting in the sarcomas of the epulis type.

2. The telangiectatic sarcoma and the bone aneurism usually contain
many giant-cells but the prognosis of these tumors varies extremely, some
proving highly malignant. Here I have several times observed that
the character of the giant-cells is not a safe guide but that in the malig-
nant cases the chief or spindle-cells present unmistakable features of malig-
nancy. My experience leads me to conclude that telangiectatic bone-
sarcoma tends to prove malignant when it occurs near the trunk, when
round- or spindle-cells with hyperchromatic nuclei predominate over giant-
cells, and when perforation and destruction of the shaft occur early. In the

SARCOMAS OF BONE AND BONE-MARROW

279

malignant cases reported by Nakayama and Bloodgood the scanty tumor-
tissue was composed chiefly of round- and spindle-cell tissue.

3. A source of error arises when one portion of the tumor differs from
another. When ulceration and necrosis occur the superficial portions of
the tumor may lose their original structure and giant-cells assume the
benign foreign-body type. I have made an erroneous prognosis of benign
sarcoma from the fungating tissue about a sinus leading to a malignant,
sclerosing, central and periosteal tumor.

4. With spindle-cell growths considerable differences in structure and
malignancy exist which are constantly revealed by the minute characters

rs»w 1 -* r&"±-

£,;«>

-.' mz rfXr**£
••$:$ :f •##***"*

i^i***** , ^n ,n* *«" ^t*«

FIG. 84. — Malignant telangiectatic central sarcoma of head of humerus in a child.
Malignant bone aneurism. The giant-cells are of the epulis type, but the malignancy is
indicated by the spindle-cells with very hyperchromatic nuclei.

of the cells. Comparatively adult types of spindle-cells with much fibrous
or osteoid tissue belong to the slowly growing tumors which, however,
recur locally and in advanced stages metastasize. Here the prognosis depends
upon the location, extent, and complications of the tumor. At the other
extreme stand the very malignant rapidly growing small spindle-cell tumors,
often called round-cell sarcoma, for which a fatal prognosis must be given
at all stages. Tumors of large polyhedral or rounded cells occur in bone
which in general exhibit marked malignancy. The exact grade may be
estimated by the minute characters of the cells, especially by the activity of

280

N EOF LAST 1C DISEASES

cell division and by nuclear hyperchromatism. Fibrosarcoma and cellular
chondromas are comparatively benign. Myxochondrosarcoma is also
as a rule not very malignant, and if as is often the case such tumors are
parosteal and encapsulated, the condition invites conservative treatment.

5. It should be emphasized that the histological structure indicates only
the potential malignancy of a tumor, or its rate and capacity of growth.
This factor is only one of many which determine the actual course of the
tumor, which forms the clinical conception of malignancy. In the field
of bone-sarcoma when the clinical course does not accord with the structural
characters the discrepancy should be attributed to lack of information
regarding the gross and clinical features of the case.

Etiology. — The etiology of bone-sarcoma is highly obscure. While
trauma must be accepted as a very common exciting factor, little is known

L^y^-ftR*

FIG. 85. — Central sarcoma of bone. (Epulis type.) This particular tumor is more cellu-
lar than usual, and is not entirely benign.

about the growth or structure of bone which can explain the mode of action of
the Irauma. A study of the healing process in fractures is yet very sug-
gestive of the mode of origin of traumatic sarcoma. In the average specimen
of callus the proliferative activity of fibroblasts, osteoblasts, and endothelium
is quite remarkable and often presents a picture which is difficult to separate
from sarcoma. Especially in certain foci the cells may be quite as abundant
as in sarcoma, but their arrangement is more orderly and the nuclei are not
hyperchromatic. The organization of considerable masses of blood provides
conditions favorable for very free growth of atypical cells. Some organizing
blood-clots after fracture, I have found quite difficult to separate from
sarcoma. Formation of progressive traumatic angiomas which gradually

SARCOMAS OF BONE AND BOX E-M ARROW 281

extend beneath the periosteum, often inclosed by a shell of new bone, may
apparently precede the late development of traumatic sarcoma.

As a rule the trauma is moderately severe and may result in fracture or
splintering, or in local hemorrhage, and the tumor seems to represent an
exaggeration and perversion of the healing process. Klebs describes a very
early medullary sarcoma in which the adventitial cells of the blood-vessels
seemed to be chiefly concerned. There is some evidence that the presence of
blood exerts a peculiar stimulating influence on the regeneration of bone.
Both these factors are present in the healing of fractures and other traumatic
conditions.

All varieties of sarcoma have been attributed to trauma, but it is evident
that the injury is only one of several essential factors, since many or most
cases fail to give a history of trauma, many tumors arise in bones protected
from injury, and occasionally bone-sarcomas are multiple. The traumatic

FIG. 86. — Structure of malignant chondrosarcoma of bone.

origin applies chiefly to periosteal sarcoma. The fact that central sarcomas
arise usually near the epiphyseal line indicates that disorders in the growth
of bone at this point are involved in their origin. Borst reports a remarkable
case of periosteal ossifying sarcoma which contained islands of lymphoid
cells and hematoblasts, and he suggests that the tumor arose in part from an
aberrant portion of marrow-tissue. For the common epulis of the alveolar
border injury to the periosteum and bone from extraction of teeth is usually
responsible.

The origin of parosteal sarcoma must be referred to misplaced islands
of bone-forming tissue. An imperfect differentiation of tissues neighboring
to bone such as has been assumed to exist in myositis ossificans may also
be included as an etiological factor. The observed facts do not seem to

282 N EOF LA STIC DISEASES

require the theory of a metaplastic development of any recognized type of
bone-sarcoma.

Simple chronic inflammation of various types may be concerned with
some of the capsular sarcomas. Syphilis and tuberculosis may be suggested
as probable factors in certain of the round-cell and diffuse sarcomas but
the grounds for such an assumption are quite indefinite. The Wassermann
reaction has been present in some of my cases of extensive bone-sarcoma.

The idea that trauma or any other factor may lead to the development of
sarcoma at the ends of long bones which are previously entirely normal is,
I think, without satisfactory foundation. There is, however, abundant
evidence that developmental disturbances, chiefly at the epiphyseal lines,
form an essential factor. The routine examination of the ends of bones in
infants shows not a few irregularities in growth resulting in the displacement

FIG. 87. — Excessive callus developing in two weeks about a comminuted fracture of inner
end of clavicle. Clinically resembling sarcoma.

of islands of 'cartilage in marrow cavity or periosteum. These irregularities
I find especially frequent after rickets. Many osteogenic sarcomas are
sharply separated from the marrow cavity by a septum of bony or osteoid
tissue, indicating that the tissue of origin was also separated. After rickets
definite masses of imperfectly ossified cartilage are often found in the marrow
cavity. It is reasonable to assume that mild forms of bone dyscrasiae exist
which are not recognized clinically but which are capable of causing abnor-
malities in the formation of the ends of the bones with a tissue predisposition
to tumor growth.

The elements of tissue predisposition and constitutional tendency become
most apparent in connection with the disease osteitis fibrosa.

Osteitis Fibrosa. — This interesting malady, first fully described in 1891,
has important bearing on the etiology and significance of giant-cell sarcoma of
bone of the epulis type (Haberer, Bloodgood, Lit.). It occurs chiefly in chil-
dren and has been termed osteodystrophia juvenilis (Monckberg, Tietze,

SARCOMAS OF BONE AND BONE-MARROW 283

Konig). It also occurs in elderly subjects where its relation to osteomalacia is
apparent. It pursues a long course but often ends fatally from cachexia or
intercurrent disease. It is characterized by defective calcification of the
bones which leads to thickening, weakening and deformity of one or many
bones of the limbs, jaws, skull or trunk. The bone tissue is replaced by cel-
lular fibrous tissue which may invade the marrow cavity replacing the red
marrow. From this stage the disease takes one of two courses, the cellular
tissue softening and producing multiple bone cysts lined by fibrous tissue and
filled with clear fluid, or in the walls of the cysts or with cyst formation giant-
cell sarcoma develops. There has been much controversy regarding the rela-
tion of the different stages of this process, some holding that the cysts always
follow the sarcomatous process, others finding that the sarcoma develops in
the cysts. Both events seem to occur. A history of trauir a and the presence
of hemorrhage and pigmentation in the walls of cysts seem to show that the
presence of blood coagulum influences the development both of cysts and of
sarcoma. In some cases fibrous cysts are chiefly observed (Monckberg,
Heinecker) in others cystic sarcomas (Haberer) or again solid sarcomas
(Rehn). The long duration, nine years (Rehn) and relatively benign quality
of the sarcomatous process are notable features. Arising in the course of a
nutritional disturbance of bone and being associated with inflammatory
changes Rehn concludes that the entire process is inflammatory. Cystic
softening of the- tumors, transformation into fibrous tissue, and spontaneous
disappearance have several times been observed. Lubarsch points out that
very similar processes giving rise to a diagnosis of sarcoma occur at the points
of fractures in cases of osteitis fibrosa and he inclines to the opinion that the
process is not a true sarcoma (Gaugele).

A remarkable case reported by Martland of multiple giant-cell sarcomas
involving many of the bones of the body probably belongs in this category
and illustrates a universal tissue predisposition to the disease. Knaggs and
Gruner describe an atypical case of fibrous osteitis affecting femur, tibia, and
fibula, and ending in malignant sarcoma.

Kolisko identifies osteitis fibrosa with Paget's osteitis deformans and finds
that in both the transformation of bone-marrow into fibrous tissue may be
followed by regressive changes leading to bone cysts or to progressive changes
giving rise to giant-cell sarcoma of slight malignancy.

MULTIPLE MYELOMA.

Multiple myeloma is a specific malignant tumor of the bone-marrow
arising probably from a single cell type, and characterized chiefly by multiple
foci of origin, a uniform and specific structure composed of plasma-cells or
their derivatives, rare metastases, albumosuria, and a fatal termination.
This orthodox definition of the classic picture of the disease is, however,
subject to extensive modifications as will appear in the context.

The disease was first described by Mclntyre in 1850 under the term "mol-
lities ossium," and has been variously interpreted by subsequent observers,
as senile osteomalacia (Marchand); myelogenous pseudoleukemia (Zahn);
primary multiple sarcoma of bone-marrow (Buch). The general clinical
characters were early recognized, Mclntyre reporting the presence of Bence-
Jones albumose in the urine, while the tendency of the disease to limit itself
to the bone-marrow and the resemblance to an infectious granuloma, have
been repeatedly noted. Rusticky (1873) seems to have first recognized the
disease as a specific affection of the bone-marrow and employed the term
myeloma. Kahler (1889) demonstrated the nearly constant occurrence of
the albuminuria and the peculiar nature of the protein involved. The

284 NEOPLAST1C DISEASES

identity of the tumor-cells in many cases with plasma-cells was pointed out by
Wright in 1900. The etiology, pathogenesis, origin of the albumosuria, and
the relation to other tumors and pathological processes in bone-marrow still
remain obscure.

Gross Anatomy. — The ribs and sternum are the chief original seats of the
tumors, while the vertebras, skull, femur, pelvis, and humerus, are less fre-
quently involved and in the order named. In three cases the ilium appears
to have been the primary seat (Hoffmann). The tumors form small nodules,

FIG. 88. — Diffuse myeloma of the humerus.

multiple and as large as a bean, or bulky growths as large as an orange,
associated with many smaller tumors. Twenty-eight separate tumors have
been observed in the skull (Winkler), and the diffusion of the process is often
widespread, involving many bones and revealing a certain systemic quality
which, however, is nearly always much less marked than that of leukemia.
Yet the process occasionally appears in diffuse form and circumscribed

SARCOMAS OF BOXE AXD BONE-MARROW 285

tumors are missing (Winkler, Jochmann, Schumm, Abrickassoff, Hirschfeld,

Lit.).

The tumors are soft or firm, translucent or opaque, and whitish, gray, or
deep red according to vascularity. Hemorrhage, infarction, blood cysts, and
necrotic areas may be present. The bone tissue suffers active absorption
and the shafts become very thin, or multiple perforations result, or fractures
occur. After passing the periosteum the surrounding tissues are diffusely
invaded.

Many cases terminate without metastases in the organs but distant second-
ary growths have been found in liver, spleen, kidney, lung and ovary, while in
certain very malignant cases that probably belong in this category nearly
every organ in the body may be involved.

The clinical course of multiple myeloma is that of a progressive malignant
tumor with gradual and often very extensive invasion of the bone-marrow,
pronounced lesions in the other organs, a somewhat specific cachexia, and an
invariably fatal termination. These same general clinical features are
observed in all types of myeloma, in so-called myelosarcoma, and in endothe-
lioma of bone, and were closely simulated by a case of chondrosarcoma
reported by Seegelken.

The disease arises chiefly in males, in the 4th and 5th decades (24 to 69
years) and continues a few months or several years. The tumors are usually
first detected from the pain they produce from erosion of periosteum, pres-
sure on adjacent nerves, and from general toxemia, and continuous or parox-
ysmal pain usually persists. Recurring fever has been observed but the
temperature is usually subnormal. Fractures and extensive deformities of
the skeleton mark the later stages. Prolonged cases may resemble osteo-
malacia (Marchand). Anemia may become very severe and exhibit perni-
cious features (Grawitz), but in many cases the blood shows no pronounced
changes. Rarely there is an increase of myelocytes in the blood, in one case
up to 21.8 per cent. (Saltykow, Sternberg). In the blood of Aschoff's case
Schridde found plasma-cells. Albumosuria has been noted first in the nth
week or 5th year of the disease. Its occurrence may be continuous or periodic,
and the quantity of albumose may be scanty or large, up to 6.9 per cent.
It has been found in less than half the cases, and occurs in myxedema, leu-
kemia, carcinoma of bone, etc.

Neither the exact nature, position, nor origin of the urinary protein are
fully understood. It bears some relation to a severe but non-specific nephri-
tis which commonly marks the disease, and other proteins may occur in the
urine. The peculiar qualities of this protein have been fully studied by Mag-
nus-Levy, Jochmann and Schumm and others. It precipitates at 55°C., the
precipitate becomes most abundant at 65°, and gradually dissolves at 85° and
reappears on cooling. Williams finds that its physical properties may change
from day to day, that it contains a carbohydrate radicle, no phosphorus, and
falls in the group of mucins. According to Geis the albumose is derived
from the elastin of bone tissue absorbed by the tumors.

The spleen is often moderately enlarged, at times partly in compensation
for the loss of bone-marrow, or from the general toxemia, and from metas-
tases. The lymph-nodes are rarely hyperplastic (Weber, Scheele, Ewald).
Extensive amyloid degeneration of the muscles of thorax and intestine was
observed by Hueter. The termination of the disease is marked by anemia,
emaciation, diarrhea, dyspnea, paralysis, and coma.

Structure. — While in some cases the cells of myeloma exhibit the features
of plasma-cells, large or small, with single or multiple nuclei, yet in the entire
scope of tumors which probably belong in this class the cells vary widely

286

NEOPLASTIC DISEASES

in size and character. In some cases the entire tumor is composed of loosely
packed typical plasma-cells, 8 to i2ju in diameter, round, oval, or polygonal,
and with opaque, amphophile, non-granular cytoplasm. The single or mul-
tiple nuclei are relatively small, eccentric, or protruding from the cytoplasm,
surrounded by a clear zone, and presenting blocks of chromatin arranged
along the nuclear membrane. Mitotic figures are observed in many cases
but are less numerous when the cells are typical plasma-cells. Certain cyto-
plasmic bodies have been interpreted as centrosomes (Christian). The
clear zone about the nucleus has been described as a vacuolated secretory
product. In rare cases the round-cells are mingled with spindle-cells which
probably result from pressure (Wieland).

In a second group of cases the cells are larger, giant-cells with multilobed
nuclei appear, multiple and vesicular nuclei are more prominent, nucleoli are

FIG. 89. — Structure of a diffuse lymphocytic myeloma involving whole shaft of humerus.

(Same tumor as in Fig. 88.)

large and acidophile, the resemblance to plasma-cells is not striking, the
tumors are more malignant and metastases occur. Here one finds a structure
which recalls lymphosarcoma with large cells.

In this group are rare cases of very malignant large cell sarcoma of the
bone-marrow with universal involvement of this tissue and very extensive
growths in lymph-nodes, spleen and other organs, and in which the cells are
uniformly round, large, granular, and with single or multiple vesicular and
hyperchromatic nuclei. An extreme case of this group has been fully
described by Norris. It seems probable that these tumors are a very malig-
nant form of neoplasm derived from bone-marrow. The relation to myeloma
is especially indicated by the fact that the tumors in certain regions may
exhibit a structure closely resembling ordinary myeloma.

The arrangement of the cells in myeloma is diffuse but there is often a

SARCOMAS OF BOXE AND BONE-MARROW

287

scanty stroma separating groups of cells. Occasionally the cells are embed-
ded in a hyaline acidophilic material, and in malignant forms the tumors
are very edematous. As the tumor progresses the other elements of the
marrow disappear, but on the edges tumor and marrow-cells are intermingled.
Bone trabeculae undergo simple absorption or in the case of compact bone
osteoblasts are found in lacunae. The tumor never produces bone. An
inflammatory reaction with exudate of lymphocytes and plasma-cells may
mark the advance in bone-marrow, periosteum, or other tissues. Some of
the tumors are oversupplied with small blood-vessels, and in Rusticky's case
a frontal tumor pulsated. The larger vessels possess well-formed walls but

FIG. 90. — Structure of plasma-cell type of multiple myeloma.

many small sinuses occur without definite walls, as in bone-marrow. Hemor-
rhage is frequent in the central growths and leads to softening, forms blood
cysts, and leaves pigmentation. Extensive areas of necrosis occur and here
the cells undergo the usual forms of degeneration. Similar degenerative
changes overtake single cells in well-nourished tumors and have been used by
Hoffmann as a basis of classification of cell types. Extensive fibrosis seems
to be the natural termination of the process in many areas of typical
myeloma.

Histogenesis. — The origin of the cells of multiple myeloma has been the
subject of much discussion which necessarily invades the extensive fields of
literature on the relations of bone-marrow cells and on the origin of plasma-
cells (Hirschfeld, Lit.). That the tumor-cells in one group of cases represent

288 N EOF LA STIC DISEASES

various forms of plasma-cells is strongly attested by the comparison made by
Christian. In one group of cases the identity with plasma-cells is so striking
as to suggest that those writers who doubt this identity have never seen such
a case. Assuming that the plasma-cells are derived from adventitial cells
of the vessels the myeloma must be derived from the supporting tissue of the
blood-vessels of the marrow and not from blood-forming cells. Although the
earliest stages of formation of myeloma from adventitial cells have not been
traced, this theory of origin accords with certain important clinical features of
the disease such as its relatively benign character, and partial resemblance to
a granuloma and serves to maintain the complete separation of the malady
from leukemia. It also serves to explain in some degree the capacity of the
tumor to destroy bone tissue. The origin from adventitial cells nearly
related to endothelium is further supported by the occurrence of multiple
perforating tumors of bone clinically resembling myeloma but composed of
cells with striking endothelial characters. Such cases have been recorded by
Kahler, and Marckwald, and observed once by the writer, and in fact if soli-
tary marrow tumors are included they are not infrequent.

In another group of cases the cells lack close resemblance to plasma-cells
and their form and arrangement strongly suggest an origin from the blood-
forming cells of the marrow. Both the red- and the white-cell progenitors
have been included in the scope of this origin. Sternberg, Lubarsch, Herz
and Charles were able to demonstrate a few neutrophile granules in the cells
of their cases and this evidence is believed by some to demonstrate an origin
from the granular leukocyte series (Leukocytoma). Since these granules
are demonstrated with difficulty in tissues from leukemia and since they may
well be absent in neoplastic cells; many, after careful study, admit the absence
of granules, but still claim the identity of the tumor-cells with immature
myelocytes, basing their conclusion on the other features of the cells (Menne,
Lit.).

Against this view stands especially the fact that other tumor-like processes
affecting myelocytes, as in leukemia, pursue a wholly different course from
myeloma. The so-called myelocytomas being as a rule more active than the
plasmomas, it may be urged that a greater degree of anaplasia may transform
olasma-cells into cells resembling myelocytes.

Opinions regarding the scope of the disease, multiple myeloma, have been
based not only on the histological structure of the tumors but also upon the
clinical features. Many observers would adhere narrowly to certain general
clinical characters which they assume to be essential and would eliminate
from the group all cases which do not present these features. Thus Winkler
insists upon the strict limitation of the process to the bone-marrow, the
absence of metastases, the importance of albuminuria, and the perfectly
uniform size and character of the cells. Yet it is clear as Lubarsch pointed
out that the occurrence of metastases is more or less accidental, that albu-
mosuria may be absent, and the size and form of the cells may vary con-
siderably, in cases which in general strongly impress themselves as essentially
the same disease.

On structure chiefly, Kaufmann separates from multiple myeloma a group
of malignant lymphosarcomas of bone-marrow. In these the cells are
larger than plasma-cells, giant-cells occur, a reticular matrix is present, and
metastases occur. They correspond to the writer's group of more malignant
myelomas. Yet the cases of Wieland to which Kaufmann refers present the
main characteristics of malignant myeloma and it is clear that many authors
have accepted such cases as true myeloma, so that the grounds for their
separation seem inadequate. Both are multiple primary tumors of bone-

SARCOMAS OF BONE AND BONE-MARROW 289

marrow, perforating the compact tissue, sparing lymph-nodes, producing
albumosuria, and following the same general clinical course, while varia-
tions in the cells seem to indicate only different grades of anaplasia.

A distinctly different condition from myeloma appears to have existed in
the case described by Hammer in which severe recurrent fever, invasion of
lymph-nodes, metastatic growths in the dura, and extensive thickening of
many bones without albumosuria were associated with diffuse lymphoid
hyperplasia without circumscribed tumors of the bone-marrow. Such a
picture suggests a true pseudoleukemic process and differs essentially from
multiple myeloma. Very similar cases of myelogenous pseudoleukemia have
been described by Baumgarten and by Rubinstein. Hodgkin's granuloma
affects the bone-marrow but its structure is specific and quite different from
that of multiple myeloma.

An erythroblastic origin of certain cases of myeloma is indicated by the
observation of Ribbert who found hemoglobin in the cells of his case. Norris
has also encountered such a case. In a recent case of multiple perforating
bone-tumors with enlarged regional lymph-nodes, I found most of the cells
smaller than lymphocytes with pyknotic nuclei and strongly acidophile
homogeneous cytoplasm.

Finally in certain cases the tumor-cells seemed to the observers to lack the
specific features of any of the adult marrow-cells and either to belong to the
lymphocyte class or to represent an indifferent blood metrocyte. It is nota-
ble that certain of these cases have been very rapid and malignant forms of
myeloma (Scheele, Herxheimer, Jellinek, Vignard, Norris).

Thus if one classifies myeloma according to the views of different observers
concerning the origin of the tumor-cells the following groups appear: (i)
Plasmocytoma, (2) erythroblastoma, (3) myelocytoma, adult and embryonal,
(4) lymphocytoma. Whether such varied interests are actually represented
in the scope of multiple myeloma or whether we have to deal with varying
grades of anaplasia in a single cell or origin remains to be determined. At
present the data seem to favor the former alternative.

Regarding the etiology of multiple myeloma little can be said. It is a
disease of middle ages, occurring chiefly in males (19-7), of the middle classes.
Multiple tumors can hardly be closely connected with trauma, yet three cases
were referred to injury (Marchand, Ewald, Winkler), and Winkler discusses
at length its mode of action. Grawitz observed a case which followed
typhoid fever. Stokvis found two cases in brothers. An infectious origin
has frequently been suggested from the clinical features, the general signifi-
cance of plasma-cells, and the relatively slow course of many cases. As a
late and indirect sequel of an infectious process acting in subjects with
tissue predisposition the disease is perhaps well conceived. Yet several cases
have indicated a dependence on nutritional disorders of the bone itself
which in other subjects leads to osteitis or osteomalacia.

CHAPTER XX
ENDOTHELIOMA

The term endothelioma is applied to an extensive group of tumors which
are believed to be derived from the lining cells of blood-vessels, lymph-
vessels and spaces, subdural spaces, and serous cavities.

The scope of endothelioma has suffered wide fluctuations because of the
uncertainty surrounding the embryological relations of different classes of
endothelial cells, the peculiar position occupied by these cells as intermediate
between epithelium and fibroblasts, and the difficulty of determining the origin
of many tumors supposed to belong in this class. Thus some authors find
the group extremely numerous and complex, while others insisting upon
more rigid data describe a very restricted class of tumors as endothelioma.

Origin and Functions of Endothelial Cells. — The embryological relations
of the flat internal lining cells of the body deserve first consideration in the
study of endothelioma both for the sake of accurate classification and for
the bearing on many peculiarities of these tumors.

Although our knowledge in this field is still incomplete two main facts
seem to be sufficiently attested: (i) The lining cells of the great body cavities,
pleura, pericardium, and peritoneum arise from cells lining the ccelomic
cavity which forms early by the splitting of two layers of mesoderm; (2)
the lining cells of the blood- and lymph-vessels, as well as the subdural
membranes are derived from mesenchymal cells and are very closely related
to connective tissue.

Through the researches of Huxley, Balfour, Lancaster and the Hertwigs,
it has been shown that the mesoderm owes its origin in vertebrates to a
separation of cells derived from both ectoderm and endoderm near the
primitive groove. The definite layer thus produced splits into two lamellae
uniting with the ectoderm on the one hand to form the somatopleura, and
with the endoderm to form the splanchnopleura, and inclosing the ccelomic
cavity between them. In addition to the processes which gives rise to a
definite middle germ layer, an entirely different process gives origin to the
sustentative tissues of the body which spread out into the various ramifica-
tions of the main germ layers. O. and R. Her twig ' (i 88 1) and others have
shown that the sustentative tissues are derived from the middle germ layer
by the splitting off of many ameboid cells which spread out between the
epithelial germ layers and form the mesenchyme. From this embryonal
tissue it is now generally agreed that the connective tissues and the lining
cells of the vessels, blood-cells, lymphoid organs, .the smooth involuntary
muscles, heart muscle, and in some cases the striated muscles are derived.
Concerning the exact mode of origin of the blood and vessels, opinions are
still at variance but the data are becoming more definite. According to
Ziegler the fundaments of the blood- and lymph-vessels are derived from the
interstitial spaces of the primitive body cavity which persists as lacunas
and interstices in the advancing mesenchyme and become confluent in that
tissue. A very similar process is described by others who assume that the
first vessels arise from mesenchymal cells, which arrange themselves in

290

EN DO THELIOMA 291

rows and become canalized, forming the vessels. Finally there are those
who assume an entirely different origin for connective tissues and vascular
endothelium, attributing the former to migrating cells from the mesoderm
and the latter to cells of the endoderm which are constricted off as an inde-
pendent tissue and give origin to the whole vascular system (Uskow,
Gegenbauer, Ruckert). Thus, embryological data do not warrant funda-
mental distinctions between the various cells now commonly grouped 'as
endothelium since all are of mesodermal origin. Although the ccelomic
lining cells which give origin to the serous endothelium maintain a lining
character throughout, that fact does not warrant their identification with-
any forms of epithelium such as is derived from ectoderm or endoderm.

The vascular endothelium being of mesenchymal origin is closely related
to the connective tissues and this fact may serve to explain the resemblance
of certain endotheliomas to connective- tissue tumors, while the difference
in the embryological history of serous and vascular endothelium seems to
find some expression in the morphology of tumors derived from these two
types of cells. Tumors of the serous cells show certain carcinomatous
rather than sarcomatous tendencies. From the embryologic standpoint
one might assume a certain relation between endothelioma and tumors of
lymphoid or smooth muscle-tissue, but observation does not indicate that
this relation is important. In the field of endothelioma as elsewhere the
adult characters of the cells seem to be of more importance than their embryo-
logical history.

The physiology of endothelial cells establishes their position as inter-
mediate between epithelium and connective tissue. They enjoy certain
functions recalling those of epithelium but less specialized. In the formation
of lymph Heidenhain and Hamburger have shown that the lymphatic
endothelium exerts a secretory action. The secretion of a mucinous lubricant
is a constant property of serous endothelium. Thoma attributed to a secre-
tory process the appearance of blood fluids in the closed cell layers of the
area vasculosa of the chick. Metabolic functions are evidenced by the
occurrence of fat droplets in the normal endothelium of the pleura (Thoma).
Phagocytosis by vascular and serous endothelium is often extremely active;
especially in the spleen and liver.

Considerable light has been thrown on the origin of endothelium and
blood-cells by Stockard's study of fundulus embryos without a circulation.
Here the serous endothelium secretes large amounts of fluid distending the
pericardium until it deforms the embryo. Vascular endothelium forms
locally throughout the mesenchyme from wandering mesenchymal cells.
Similar wandering mesenchymal cells also produce chromatophores. The
vascular endothelium never produces red or white blood-cells. The red
blood-cells arise from a specialized portion of mesenchyme or intermediate
cell mass, derived from the posterior region of the embryo. Some of these
cells wander out on the yolk-sac producing the blood islands of Pander.
Leukocyte production is largely limited to mesenchymal cells in the anterior
portion of the embryo but later occurs throughout the mesenchyme, always
from extravascular mesenchymal cells and not from endothelial cells.

According to these data vascular endothelium, leukocytes, and red
blood-cells are separate cell series derived from different mesenchymal
anlagen. Closely related to them in origin is a series of wandering
chromatophores.

This study is in accord with others which indicate that lymphocytes
are not derived from the reticulum cells of lymph-nodes. The results are
probably not irreconcilable with the opinions of Councilman, Mallory and

292

NEOPLASTIC DISEASES

others that lymphatic endothelium is a source of some large mononuclear
cells of the blood.

The general pathology of endothelium most clearly illustrates the dual
tendencies of these cells, revealing on the one hand the assumption of epithe-
lial qualities and on the other the possession of certain potencies of con-
nective-tissue cells. In the course of inflammation of serous surfaces endo-
thelial cells multiply readily, and form giant-cells and concentric endothelial
pearls. In granulation tissue they become ameboid and phagocytic. Pial
tubercles may be composed exclusively of aggregations of proliferating
endothelial cells. Birch-Hirschfeld found serous endothelium closely related
to fibroblasts observing that they participated largely in chronic thickenings

FIG. 91. — Angio-endothelioma arising in a thrombosed vein.

of the peritoneum. In artificial adhesions of serous membranes, Graser
and Roloff traced the change of serous cells into fibroblasts while fibroblasts
in turn produced serous endothelium on new surfaces. Borst saw serous
cells assume star and spindle shapes, and Lubarsch and Marchand have
described the formation of intercellular substance and fibrils from these cells.
Yet Ribbert, Ziegler and others do not accept these observations as proving
the transformation of serous cells into genuine fibroblasts, and it seems
highly probable that the new tissues produced by proliferating endothelium
have not the permanence of true connective tissue but early undergo
hyalinosis and atrophy.

Vascular endothelium also proliferates readily in inflammation and forms
collections of cells which may resemble the groups of endothelioma or
carcinoma. In endarteritis the endothelial cells may contribute largely

ENDOTHELIOMA 293

to the new tissue, especially in syphilis. In tuberculous endarteritis very
extensive newgrowth of endothelium is observed in the intima. In the
organization of thrombi the endothelial cells are very active, wandering out
into the blood clot, acting as phagocytes, replacing the thrombus with
strands of spindle or masses of flat cells, and conducting new capillaries.
The subsequent cicatrization of the organized thrombus illustrates the
usual fate of new tissues produced by proliferating endothelium. Many
authors have described the alveolar structures produced by the reversion
to the cubical type by endothelium of tissue spaces in chronic inflammation.
In many cases of chronic inflammation of serous membranes groups of
endothelial cells become incarcerated by adhesions and transformed into
cubical or cylindrical cells producing structures resembling gland alveoli
(Ribbert, Renngli, Meyer, Menetrier). In most tissues the endothelial
cells are the chief source of the epithelioid elements in miliary tubercles.

In lymph-nodes some remarkable grades of endothelial proliferation
are observed. In chronic lymphadenitis, probably of tuberculous origin,
several types of large cell hyperplasia occur, some of which closely resemble
or actually merge into neoplasms. In scrofulous lymphadenitis the entire
node may be replaced by masses of poorly staining endothelium. In chronic
congestion of the spleen the sinuses may appear lined by cubical endothelium.
These and many other details, which have been extensively discussed by
Borst, illustrate the behavior of endothelial cells under abnormal conditions
and they may serve as a standard of comparison in the interpretation of neo-
plastic processes in these cells.

History of Endothelioma. — The history of endothelioma has passed
through many stages. Arising from a well-characterized cell type these
tumors are of such wide distribution and exhibit so many of the varied
qualities and relations of the originating cells that much change and conflict
of opinion have always existed regarding their scope and classification.

Koster first clearly maintained the opinion that the endothelium of
lymph spaces and vessels gave origin to many tumors, which, however,
he regarded as carcinomas. His demonstration that endothelium may
give rise to tumors closely resembling carcinoma strengthened the old doctrine
of Virchow that all cancers arise from the matrix of connective tissue.
When Thiersch and Waldeyer established the epithelial origin of carcinoma
and Carmalt showed that cancer-cells could be washed out of the invaded
lymph-vessels, leaving the endothelial cells intact, the way was opened for
the recognition of a special group of tumors derived from endothelium.
Waldeyer 's authority encouraged the interpretation of certain tumors in
various organs as of endothelial origin.

In 1869 Golgi introduced the term endothelioma, applying it especially
to psammoma of the dura mater, which has always stood as a standard
type of the growth. The use of this term became established slowly, many
authors classifying endothelial tumors with sarcoma. Thus Waldeyer
described the perivascular growths as angiosarcoma, and Kolaczek in an
extensive study classified all the tumors of the endothelium of blood- and
lymph-vessels as angiosarcoma. The mixed tumors of the salivary glands
previously regarded as carcinomas were placed by Kaufmann among sarcomas
until Wartmann in 1879 first maintained that the polyhedral cells of these
growths are derived from endothelium. Yet the endothelial origin of
salivary gland tumors has never been universally accepted and while Ribbert
and many others have firmly maintained their epithelial nature, Kaufmann,
Borst and others accept in part the endothelial theory.

As early as 1866 Lucke described a pulsating tumor following a fracture

294 N EOF LA STIC DISEASES

of the forearm, the adenoid structure of which he referred to a growth from
indifferent cells of the connective tissue. Kocher (1868) and Billroth (1869)
derived somewhat similar tumors of bone from the walls of blood-vessels.
Tillmanns (1873) and Joppe trace these tumors to the endothelial or peri-
thelial cells. Schweninger (1876) clearly traced the development of an
adenoid bone tumor to the endothelial cells of blood- and lymph vessels and
lymph spaces.

In the orbit Pagenstecher first described a tumor removed by Knapp,
which by exclusion he was compelled to refer to proliferating endothelium
of lymph spaces, and this view was endorsed by Knapp (1872) in the descrip-
tion of later cases. Yet it now appears probable that most of these tumors
were derivatives of the lachrymal gland and that endothelioma of the orbit
arises chiefly from the optic nerve sheath.

In 1879 a group of ovarian endotheliomas was brought forward by
Marchand, although Leopold had previously regarded certain large solid
tumors of the ovary as of endothelial origin. In 1870 Wagner recognized
the endothelial origin of certain pleural tumors and his view was strongly
supported by Neelsen's study. In 1867 Massey and in 1879 Hubl described
endothelial tumors of the peritoneal serosa.

In the skin Kaposi described under the term lymphangioma tuberosum
a tumor which Jarisch later grouped among the hemangio- endotheliomas,
but it has long been known that this tumor is derived from the epithelial
structures of the skin.

The lymph-nodes were drawn into the sources of endothelioma by Zahn
in 1874 under the title of sarcoma epithelioides, while in 1881, Hoffmann
and Schottelius described a similar tumor as endothelioma. Most of these
tumors appear to have been classed as carcinomas, angiosarcomas and
alveolar sarcomas. The writer in 1914 finds that tumors derived from the
endothelium and reticulum cells of lymph-nodes form separate well-defined
and rather frequent groups of tumors.

In the stomach Hansemann maintained that many of the so-called
scirrhus cancers are derived from endothelial cells of the lymph spaces,
a view which Borst accepts. Yet this interpretation is open to question
and the existence of a true endothelioma of the gastro-intestinal tract
remains unproven if not improbable. Likewise the existence of an
endothelioma of the cervix uteri is claimed by Amann, Hurdon,
Kirschgessner, and denied Sperber, R. Meyer, and others.

In the kidney a group of vascular tumors became generally recognized
as probable endotheliomas. The common angiosarcoma of this organ was
interpreted by de Paoli as a derivative of perithelial cells, but the exact
nature of these tumors and their common origin has not yet been determined.
Most of them are probably derived from adrenal rests or represent renal
adenomas. In 1896 Hansemann claimed to have traced the origin of a
vascular renal tumor to the lining endothelium of a small and originally
angiomatous growth, but it has remained practically impossible to separate
from the numerous renal tumors any which may safely be referred to this
origin.

From time to time specific terms have been introduced to designate
structural types of endothelioma or of tumors so interpreted. In 1856
Billroth described under the term cylindroma a tumor composed of glassy
translucent cylinders of hyaline connective tissue between which ran a
network of tumor-cells. This structure, which is regarded by some authors
as a form of interfascicular endothelioma, is still often designated as
cylindroma.

ENDOTHELIOMA 295

v. Ohlen in 1893 pointed out that many authors had been recognizing
a second form of cylindroma arising by degeneration of groups of cells in
endothelial masses and the formation of cylinders of mucinous material.
This structure likewise often received the designation of cylindroma but it is
doubtful if it is ever produced by endothelioma.

For many years the term angiosarcoma was loosely applied to certain
endotheliomas. This term was first employed by Waldeyer and Kolaczek
to designate all tumors originating from blood- and lymph-vessels and thus
it came to include those developing from endothelial cells lining the vessels.
With the recognition that Eberth's perithelial cells, described originally for
the cerebral vessels, exist also in many other organs, as testicle, adrenal,
breast, and salivary glands (Arnold, Paltauf, Luschka, v. Brunn), and
that tumors probably arise from these cells, a specific variety of angiosarcoma
was admitted under the term "perithelioma." This term was especially
recommended by Hildebrandt. It has remained firmly established in the
nomenclature but its relation to endothelioma has not yet been finally
determined. According to Borrmann, perithelial cells are modified endo-
thelial cells of adventitial lymph spaces. Many vessels possess not merely
lymph spaces and perithelium but also a definite plexus of lymph-vessels from
which Borrmann believes tumors arise. He would therefore distinguish
between perithelioma and peri-endothelioma, the cells of the former radiating
from, those of the latter encircling the vessel. In any case perithelioma
exhibits sarcomatous, not endotheliomatous characters, and in the writer's
opinion this tumor should be grouped with the sarcomas (Barth, Hippel).
Thus the old class of angiosarcomas is to-day resolved into perithelioma,
periendothelioma, and the various forms of endotheliomas arising from
blood- and lymph-vessels. The present tendency is to limit the term angio-
sarcoma to cellular angiomas in which the unit is the vessel and not the
endothelial cell.

The scope of the group of endothelioma as commonly accepted, especially
in Germany, reached its acme with the appearance of Volkmann's study in
which he endeavored to establish the endothelial origin of the mixed tumors
of the salivary glands. In 1897 Borst reviewed in great detail the behavior
of endothelial cells under physiological and pathological conditipns with a
result favorable on the whole to the probable wide extent of endothelial
tumors. In France the tendency to recognize endothelioma as of frequent
occurrence was much less pronounced (Malassez, Berget, Collet). In recent
years a rigid critique has emphasized the fact that comparatively few of the
recognized groups are supported by satisfactory data. In 1899 Hinsberg
actively contested the endothelial origin of the salivary tumors and he
has been supported by Ribbert, Marchand, and others, so that the fibro-
epithelial nature of this group has become generally accepted. Lubarsch
also has demolished the diagnosis of endothelioma in several types of tumors,
including Mulert's multiple endothelioma of scalp, a so-called endothelioma
of the orbit which he derived from the lachrymal gland, and a cylidromatous
epithelioma of the nasal mucosa. Ribbert does not accept the endothelial
origin of various cutaneous growths, cylindromas, and tumors of parotid.
The so-called renal endothelioma he thinks is of epithelial origin, while the
endothelial origin of bone-tumors, as in Sternberg's case, is not proven.
No tumor of perithelial cells, he believes, has yet been demostrated.

Thus while the existence of certain distinct classes and many well-defined
forms of endothelioma was early demonstrated, the attempt to enlarge the
scope to this group of tumors by assuming an endothelial origin for many
growths of uncertain nature has met with only partial success. The studies

296 NEOPLASTIC DISEASES

of recent years have served chiefly to emphasize the difficulty of separating
true endothelioma from many typical sarcomas, lymphosarcomas, carcinomas,
and certain embryonal tumors.

In this dilemma one may follow Ribbert's plan of discriminating rigidly
against the tendency to discover endothelial qualities in many tumors
of uncertain origin. In that case the discussion of endothelioma becomes
comparatively brief. Or one may accept Borst's conception that the scope
of endothelioma is probably very wide and one may thus give full expression
to the views of many who favor the endothelial origin of a very wide variety
of tumors whose exact nature has not been determined. While fully admit-
ting the deficiencies of present knowledge my own experience in this field
inclines me to pursue the latter course.

Classification and Nomenclature.- — Various plans of classification of
endotheliomas have been suggested. Hansemann at one time recommended
the elimination of the term endothelioma and the designation of these
tumors as endothelial sarcoma, carcinoma, adenoma, etc. Ackermann
classified the tumors according to their origin as intravascular, lymphangio-
matous, and interfascicular (from lymph spaces). Many recognize peri-
thelioma as a separate variety derived from blood-vessels.

Borrmann has constructed an ideal histogenetic scheme including
hemangio-endothelioma, lymphangio-endothelioma, capillary endothelioma,
perithelioma, and peri-endothelioma. Of capillary endothelioma, with pro-
liferating capillaries filled with endothelial cells he finds only three recorded
cases (Langhans, Limacher (Case II), Borrmann). Peri-endothelioma
refers to a growth of cells of perivascular lymph-vessels concentrically about
the vessel-wall. In a case described by Perthes he detects a combination
of perithelioma and peri-endothelioma. However desirable such histogenetic
distinctions may be, the practical difficulty of unraveling them has stood
in the way of general adoption of this scheme. Borrmann's capillary endo-
thelioma is generally, and I think, better designated as an angioma.

The writer agrees with Borst that the most serviceable grouping of
endotheliomas is based on their morphology and he has long employed the
following plan:

Histological Types of Endothelioma.— i. Interfascicular.— The cells
grow in thin layers between strands of connective tissue. When these
strands are swollen and hyaline the tumor may be designated a,s cylindroma.

2. Alveolar. — The cells grow in small or large groups, as in adenoma.
When appearing in long sections the groups may be tubular. When mucin-
ous degeneration occurs in these cell groups a variety of cylindroma is
produced, but the use of this term for such structures leads to confusion
and is inadvisable.

3. Plexiform.- — The cells grow in convoluted columns often surrounding
vascular paths. Papillary projections may arise from these columns sug-
gesting the term papillary endothelioma. This structure is represented
by several tumors of doubtful origin.

4. Perivascular. • — The cells surround definite vascular paths usually
in concentric fashion, as in the dura mater. Psammoma or sand tumor,
applies to this growth when the units are calcified. Osteo-endothelioma
forms rarely in the same manner (Perthes).

5. Diffuse. — The cells grow diffusely or without definite arrangement
in uniform relations.

6. Miscellaneous changes in the stroma, progressive and regressive, are
readily indicated by appropriate terms as osteo, myxo, fibro, cysto, etc.

Perithelioma, whatever its origin, is a highly characteristic structure

ENDOTHELIOMA 297

which exhibits the qualities of sarcoma or carcinoma, with which groups
it should be classed.

Origin and Growth.— The exact origin of endotheliomas must be referred
in general to the various endothelial cells, but the earliest stages of growth are
rarely observed. While the absence of blood in any of the tumor spaces
distinctly favors a lymphatic origin its presence is of less significance, since
abnormal communications form between the channels of tumors and the
blood-vessels.

According to Borrmann true hemendothelioma is extremely rare and he
accepts only a few cases, some of which were traced to capillary endothelium.
The endotheliomas of pleura and pericardium have been referred both to the
lining cells and to the cells of superficial lymphatics. It seems probable
that both elements give rise to tumors which differ somewhat in structure.

The rare and doubtful ovarian endotheliomas have been referred to the
perivascular lymphatics. While Rosthorn traced capillary blood-vessels
into the masses of tumor-cells he was uncertain to what extent the lining
cells of the vessels participated in the process. For the perivascular tumors
an origin from the lymphatic endgthelium lying outside of the lining cells
must be assumed. Endothelioma of lymph-nodes arises from the lining
cells of lymph and cavernous sinuses.

Thus in the great majority of cases it is the endothelium of small vessels
or lymph spaces which gives origin to endothelioma. Many authors have
claimed that they could trace tumors to more than one form of endothelial
structure, as lymph spaces and lymph-vessels, or serous lining cells and endo-
thelium of lymphatics (Volkmann), lymph spaces and lining cells of blood-
vessels (v. Ohlen, Franke) . I do not find that the data presented by these
authors is at all adequate for their conclusions, while some of them were
probably not dealing with genuine endothelioma.

From this chief source the growth proceeds either by extension of the
cells derived from the original territory or by the continuous transformation
of adjoining normal cells into tumor-cells. Ribbert and Borrmann maintain
that endotheliomas grow exclusively from their own resources. In various
endotheliomas Borrmann finds that the proliferating cells of lymph capil-
laries and spaces distend and enlarge these structures and eventually break
into other spaces, but they do not produce new capillaries and "contact
infection" does not occur. On the other hand Best and others describe
the gradual involvement of normal endothelium in the extension of the tumor
process. He finds this evidence chiefly along the 'growing edges of larger
tumors, while in the very early stages of small growths the increase seems to
be exclusively in the tumor-cells. The multiplicity of many endotheliomas
renders the decision in this question unusually difficult. In certain tumors
of the peritoneum Neelson and Glockner find a progressive involvement
of neighboring lymphatics, the lining cells of which actively proliferate,
producing a condition described as lymphangitis carcinomatosa (Schottelius,
or prolifera (Schweninger). Lubarsch saw this process extend from the
peritoneum into the liver. It has been held that secondary tumors may
arise in this way without the transportation of any tumor-cells (Schulz,
Neelson).

In many instances endothelioma appears to invade the tissues chiefly
or exclusively through preexisting channels, as lymph-vessels and spaces,
and fails to split up the tissues as do carcinoma and epithelioma. This
feature was especially notable in an endothelioma of the peritoneum studied
by WTichern.

The growth of endotheliomas is usually slow but progressive and in this

298

NEOPLASTIC DISEASES

respect they are comparatively benign. Especially in comparison with
the forms of carcinoma and sarcoma which they resemble histologically,
the course of endotheliomas is relatively favorable. When undisturbed by
the knife the growth capacities of some of these tumors seem to be confined
within certain limits which do not apply to carcinoma and sarcoma. In the
dura very slow growth characterizes most of the perivascular tumors and
pressure symptoms are often long delayed. On account probably of their
infiltrating character thorough extirpation is often difficult so that endothe-
liomas are notable for persistent local recurrence. Each recurrence is apt
to show increasing capacity for growth and changes in structure. This
fact encourages complete removal of the organ involved and not merely
extirpation of the tumor.

Extension to the neighboring lymph-nodes is also late or entirely missing.
Yet pleural endothelioma has invaded the lung and pulmonary nodes. As

FIG. 92. — Angio-endothelioma about tendon-sheath. A small, slowly growing tumor.

an exception to the rule certain endotheliomas of lymph-nodes described
by Zahn, Volkmann, and the writer were rather malignant.

Hemangio-endothelioma. — Many authors have endeavored to emphasize
and define a distinct group of tumors which they designate as above. (Borr-
mann, Limacher, Borst).

Among the tumors commonly included in this group are certain growths of
the type of angioma but exhibiting an excess of endothelial cells, and certain
well-known cases are specifically included in the group by the above authors
(Borrmann, Lit.). Yet Nauwerck's case was designated by the authors as
a simple hyperplastic telangiectasis. Langhans described a multiple pul-
sating cavernous angioma of the spleen. Borrmann's case seems to fall in
the group of simple angiomas with moderate excess of cells, while Steudener
describes a rapidly growing ulcerating tumor of the forehead which he
thought resembled carcinoma. None of these tumors seems to deserve a
special classification apart from angioma, or perithelioma.

EN DOTH ELI OM A

299

A second group includes the rare and somewhat obscure intravascular
endothelioma of corpus cavernosum which cannot be classed with angioma.
In several small encapsulated slowly growing subcutaneous tumors I have
been able to trace the abundant cells to proliferating endothelium of dilated
varicose veins. The circulation appeared to have been previously obstructed.
The endothelium grows first in broad papillary masses which later become
fused and enlarged distending the vessel-wall. The endothelial characters
of the cells were maintained, but the nuclei became enlarged and hyper-
chromatic. Schlagenhaufer has described such tumors arising in hemor-
rhoidal veins.

In the bones, while Narath's pulsating tumor of the tibia belongs with
cellular angiomas, Marckwald's remarkable multiple tumor of the bones
may well be designated as an endothelioma of vascular origin.

FIG. 93. — A type of papillary proliferation of endothelium arising in long distended lym-
phatics.

In the testis many authors have described as intravascular endothelioma
tumors which in all probability are derivatives of teratomas and do not merit
classification with any form of endothelioma. Of the old angiosarcomas most
authors are agreed that none can be regarded as hemangio-endothelioma
and Borst would discard the term angiosarcoma as misleading.

Thus on analysis it appears that the various tumors which at one time
or another have led various authors to employ the term hemangio-endothe-
lioma fall readily into other groups and that this term has a very limited
application and would include certain rare tumors as follows: (i) The
doubtful endothelioma of corpus cavernosum; (2) Marckwald's multiple
endothelioma of bones; (3) a fibrocellular tumor of the thyroid described by
Limacher in which the vessels were too scanty and the cells too numerous
for angioma and in which many endothelial cells had become disseminated

300 NEOPLASTIC DISEASES

from the vessels (in the ovary somewhat] similar endotheliomas may
possibly occur) ; (4) a slowly growing tumor of the skin in which a moderate
number of blood-vessels are lined by many layers of endothelium; (5) an
intravascular endothelioma arising in hemorrhoidal and other dilated veins.

Gross Anatomy.- — The gross appearances of endotheliomas are quite
as varied as their other characters. Solid circumscribed slowly growing
tumors occur regularly in the dura. In the serous membranes the growth
begins as multiple flat or nodular outgrowths, which coalesce and extend
gradually over a wide area of the membrane, producing thickenings and
adhesions. In the pleura the entire surface of both sides may be diffusely
thickened and the cavities obliterated. In the bones endothelioma tends to
replace preexisting tissues with little or no increase in the size of the bone
but with perforations. In the skin endothelioma is said to take the form
of large single tumors. In the ovary cystic endothelioma is said to occur.

In the lymph-nodes endothelioma produces solid tumors which may
reach considerable dimensions. They usually involve more than one node
and some become systemic. They are often mistaken for tuberculous-
nodes at first, later for carcinoma. Rarely they are cystic.

The various forms of secondary changes may chiefly determine the gross
appearance of the tumor.

Multiplicity is one of the most constant characters of endothelioma.
In the dura there may be a score of separate nodules. In the serous mem-
branes the tumors begin as multiple coalescing nodules. In the spleen
Weichselbaum observed a notable form of multiple endothelioma or cellular
angioma. In the bones many have classed multiple myeloma with endothe-
lioma (Zahn) and a remarkable case of multiple endothelioma involving
nearly all the bones is recorded by Marckwald.

Structure of Endothelioma. — The endothelial cell in tumors usually
retains some of its distinguishing features on which alone the recognition
of the nature of the growth may often be based. The form is polyhedral,
often pavement in type, and occasionally cylindrical. Under pressure it
assumes a spindle form and in edematous tissues it swells to spheroidal
form and considerable dimensions.

A well-defined cell-membrane, relatively clear cytoplasm, small pale
vesicular nucleus with minute multiple nucleoli are features so frequently
exhibited as to render them valuable diagnostic aids which are too often
neglected. Especially in separating endothelioma from epithelioma these
characters are of value since the epithelial cell usually exhibits a granular
opaque cytoplasm, prominent nuclei, and bulky acidophile nucleoli. Yet
in some malignant tumors the endothelial characters of the cells are lost and
embryonal epithelium resembles endothelium. In certain endotheliomas
the cells tend to become flattened and spindle shaped and to form compact
masses in which hyaline intercellular substance appears in increasing amount
until finally the tumor is largely transformed into hyaline fibrous tissue.
This process reveals the natural termination of old endotheliomas of the
dura. It is sometimes assumed that we have to deal with the production
of intercellular fibrils by endothelial cells and with the conversion of endothe-
lial tissue into connective. Yet it appears more probable that the fibrils
represent elongated and hyaline cell bodies and that the resulting hyaline
mass represents the gradual conversion of the compressed cells into homo-
geneous material. Definite formation of intercellular fibrils I have been
unable to detect in endothelioma. In dural endothelioma their absence
is conspicuous.

In various tissues normal endothelial cells show morphological differences

ENDOTHELIOMA 301

which dominate the tumors arising in these tissues. Serous endothelium
is notably flat, bulky, and pavement in type and these features long persist
in tumors of the peritoneum and pleura. Giant-cells of many forms have
been encountered in various endotheliomas but their occurrence is compara-
tively rare (Glockner, Lit.).

Syncytial masses with scattered nuclei were observed in cylindroma by
Sattler. In four pleural or peritoneal endotheliomas Glockner found mono-
nuclear and polynuclear giant-cells, in one case so numerous as to dominate
the picture. In an abdominal endothelioma which he derived from the
lymph-nodes Glockner found very large giant-cells measuring up to 176
micra. In an endothelioma of the pleura Brosch describes giant-cells
resembling the Langhans type in tubercle, and I have seen such cells in an
endothelioma of the scalp. In dural tumors multinuclear giant-cells are
not infrequent.

Retained secretion affects the appearance of endothelioma, and endo-
thelial tumors of lymph-nodes may be cystic. Extensive pigmentation
occurred in a peculiar tumor with numerous metastases which Rindfleisch
interpreted as an endothelial myeloma. In an endothelial tumor of the
sole of the foot attached to the bone I found considerable pigment evidently
derived from extravasated blood. Secondary changes in the cells and stroma
greatly alter or dominate the appearance of many of these tumors. Fatty
degeneration is not prominent but in a case of Ritter's it was quite pro-
nounced. Glycogenic degeneration has been noted in many cases of actively
growing endothelioma (Driessen, Volkmann). According to Best its abun-
dance may distinguish endothelioma as a class from sarcoma.

Hyaline degeneration frequently affects the cells, stroma, and vessels
of endothelioma. Involving the stroma of interfascicular growths it pro-
duces the appearance of cylindroma. In psammoma it is associated with
calcification of the concentric groups of cells and produces the sand grains.
Other dural tumors may be rendered quiescent by nearly complete hyalino-
sis. In a slowly growing angio-endothelioma of dura I found the walls of all
vessels thick and hyaline and many occluded by hyaline material, while the
cells were intact.

In the true endothelioma mucinous degeneration is of rare occurrence but
is observed in certain tumors of serous membranes, and in the group of ova-
rian endothelioma, in both of which it may become extensive with the forma-
tion of mucinous cysts.

Calcification overtakes many slowly growing endotheliomas, especially
the perivascular and psammomatous tumors of the dura. The deposits
appear in the cells, stroma, and walls of blood-vessels. In a subcutaneous
tumor of the foot Perthes found extensive calcification leading eventually
to ossification. In a remarkable form of endothelioma of the orbit I found
very extensive deposits of calcine nodules producing a form of osteoid tissue.

The various arrangements of the cells in endotheliomas yield characteristic
structures which form the basis of the plan of classification previously given.
These classes by no means exhaust the architectural peculiarities and as in
carcinoma combinations of several types may occur in the same tumor.
Likewise epithelioma may be simulated not only by the morphology of
the cells but by the formation of pearls with hyaline centers. Prickle
cells and keratohyalin granules, however, are absent in the endothelial
structures. The structure of sarcoma is simulated by many spindle-cell
endotheliomas and in this group it becomes desirable to recognize as types
of sarcoma certain tumors whose cells of origin may be ultimately of endothe-
lial nature, although modified by location and function.

302 NEOPLASTIC DISEASES

Vascular endothelioma tends to remain of smaller size and to assume
cuboidal or cylindrical rather than pavement types. From the lymph spaces
develop tumors of more embryonal type with cells lacking the above-men-
tioned adult endothelial characters. These cells are small with opaque
granular cytoplasm and very intimate connections with the tissue stroma.
From certain specialized derivatives of endothelial cells, as perithelium,
and the germ center cells of lymph-nodes, the tumors are almost wholly
lacking in endothelial qualities and constitute subvarieties of sarcoma.

An intimate relation to the supporting stroma is an important structural
peculiarity which distinguishes many endotheliomas from epithelial tumors.
The cells cling to the walls of spaces in spite of the shrinkage of hardening
and the cell bodies may seem to pass insensibly into the substance of the
stroma. Small fibroblasts and fine fibrils may ramify between the endothe-
lial cells. Yet it has repeatedly been shown that these same peculiarities
may be present in basal cell epithelioma and that they alone do not warrant
the diagnosis of. endothelioma.

Combination of Endothelioma and Sarcoma. — In some spindle-cell
sarcomas there is evidence that endothelial cells are commingled with the
main tumor element but they lose their endothelial characters among the
derivatives of fibroblasts. Borst mentions the occurrence of large spindle-
cell sarcomas in which are well-defined groups of neoplastic endothelial
cells which may resemble carcinomatous alveoli except for the intimate
relation with the sarcoma-cells. I have seen such appearances in teratomas.
He also describes angiomatous spindle-cell sarcomas in which the numerous
vessels are lined by proliferating cubical endothelium recalling gland alveoli.
In lymphangio-endothelioma the stroma may be very cellular, or one part
of an angioma may be very vascular and another part chiefly composed of
cellular stroma.

Differential Diagnosis of Endothelioma. — Although there have been
numerous attempts to establish differential diagnostic signs between endothe-
lioma and other tumors it must be admitted with Lubarsch that reliable
criteria of general application are lacking. On this account the personal
impressions of the individual observer have figured too prominently in the
steady expansion of this group of tumors.

The most reliable sign of endothelioma is found in the minute characters
of the cells as above described, but these characters are lost in many actively
growing tumors and in recurrences. Yet a thorough search for the translu-
cent polyhedral cells with pale nuclei devoid of definite nucleoli is often
rewarded in tumors the bulk of which fails to show such cell types. Espe-
cially in edematous foci the pavement characters reassert themselves.

The concentric perivascular arrangement is a convincing appearance
but is limited chiefly to dural growths. All other arrangements of the cells
exhibited by endothelioma are duplicated by other tumors.

The occurrence of endothelial pearls with hyaline or calcified centers, but
without prickle cells and keratohyalin granules, as emphasized by many,
stands in the opinion of Lubarsch and Ribbert a strong indication against
endothelioma. Prickle cells and specific granules are often absent in epithe-
lioma and with the exception of psammoma I have never seen definite
pearl formation in any undoubted endothelioma.

The relation of tumor-cells directly walling circulatory paths is a con-
vincing feature of some endotheliomas but it rarely exists unless the charac-
ters of the cells are even more indicative of endothelioma. The identification
of lymph paths is usually difficult, while endothelioma of blood-vessels is
rare. It must be recognized also that the presence of a column of blood

ENDOTHELIOMA 303

in immediate contact with tumor-cells is not a certain criterion of endothe-
lioma. Hemorrhage often fills the alveoli of carcinoma, and in epithelioma
of the skin blood sinuses invade the epithelial cell groups, lose their endothe-
lial lining and the blood lies in immediate contact with cuboidal epithelial
cells.

The intimate relation of the cells to the supporting stroma is regarded
by Borst and many others as a most important criterion. In soft tissues
the endothelial cells are said to grow out like young capillaries. Yet this
sign led to error in the case of the spurious endotheliomas of the parotid.

The desmoplastic properties of many endotheliomas assist in their
recognition, and a peculiar form of hyalinosis may sharpen this feature,
as in cylindroma. On the edges of endothelioma the tumor-cells may fade
in the advancing fibrosis in a manner quite foreign to carcinoma. Fine
fibroblasts and even capillaries may grow out between the cells of alveoli
both in endothelioma and carcinoma. The structure of cylindroma, especially
that form resulting from mucous degeneration in cellular alveoli, is not dis-
tinctive of endothelioma, since hyaline and mucous degeneration of cell
groups, stroma and vessels often occurs in carcinomas (Lubarsch, Schmidt).

On the growing edges the tumor-cells are said to pass insensibly into the
endothelium of lymph spaces (Volkmann, Hansemann), but this appearance
occurs also in carcinoma (Ribbert, Borst). Proliferation of endothelium
of vessels invaded by tumor-cells occurs both in endothelioma and carcinoma
but rather more in the former.

The location of the tumor may furnish important evidence, as when
multiple endothelioma develops in lymph-nodes, bone-marrow, or in any
tissue not containing epithelium. Yet unless the sources of primary tumors
are carefully eliminated this evidence is worthless, and there remains the
possibility of aberrant tissue rests.

Finally it should be urged that the diagnosis of endothelioma should be
accepted only when the evidence is clear and conclusive. Otherwise this
group will continue to represent the resting place of miscellaneous tumors
on which the data and study have been inadequate.

Etiology. — In the etiology of endothelioma the influence of chronic
irritation or trauma and low grades of inflammation must be given a promi-
nent place. In a few instances it has been possible clinically to establish
the existence of such factors. Endothelioma of lymph-nodes appears to
follow forms of chronic lymphadenitis. In the skin chronic trauma is
abundantly provided, especially in the sole of the foot. In the serous mem-
branes endothelioma in some cases appears to be connected with tubercu-
losis. As a rule, however, the tumor appears to develop spontaneously.
On the other hand it is necessary to assume a local predisposition to tumor
growth, and in certain cases efforts have been made to establish a relation
with definite embryogenic disturbances. It cannot be said that much
success has attended these efforts. Many endotheliomas first appear in
small encapsulated areas suggesting an embryonal isolation of the originating
tissue. Eberth and Spude have described a small teratoid endothelioma
of the dura mater. Ribbert suggests that endothelioma of the dura arises
from groups of cells misplaced during the separation of the original membrane
into pia and dura. Schmidt has described such collections of superfluous
endothelial cells in the normal dura. I have observed a small perfectly
isolated endothelioma embedded in the tissues of the spermatic cord. Yet
the great majority of endotheliomas fail to give any tangible evidence of a
relation to embryogenic disturbance.

The multiple origin of tumors appearing successively over many years

304 NEOPLASTIC DISEASES

(Marckwald), the genesis from minute lymph spaces and -vessels, and the
slow growth, all indicate that these tumors usually develop from adult
endothelium under the influence of chronic irritation.

CLINICAL TYPES OF ENDOTHELIOMA

A. Tumor-like Hyperplasia of Endothelium. — Under certain conditions
endothelium exhibits a grade of hyperplasia which is intermediate between
inflammatory and neoplastic overgrowth.

1. In chronic lymphadenitis a peculiar form of endothelial hyperplasia
may occur which exhibits some of the morphological and clinical features of a
neoplasm. These cases occur in the group of chronic enlargements of the
lymph-nodes of uncertain origin and they pursue the course of Hodgkin's
disease, but specific Hodgkin's structure and specific signs of tuberculosis
are missing.

Microscopically one finds irregular foci and broad sheets of large flat
endothelial cells, obliterating the normal structure, grading insensibly into
lymphoid tissues, and apparently originating in the sinus endothelium.
The cells are slightly granular, clearly outlined, polyhedral or elongated,
with large vesicular hyperchromatic nuclei. The appearance is quite
different from that of the large cell hyperplasia of tuberculosis or of the
common Hodgkin's structure and bears the stamp of a feeble neoplastic
process.

2. Primary Splenomegaly (Type, Gaudier). — This remarkable condition
consists of an extensive chronic overgrowth of endothelial cells of the spleen,
lymph-nodes, and bone-marrow, with secondary foci in the portal canals
of the liver, and is associated with anemia, hemorrhages, and pigmentation
of skin and other organs. It begins in early life, chiefly in females, commonly
affects more than one member of a single generation in the family, and pro-
gresses over many years (39 in Schlagenhaufer's case), proving fatal or
terminated by complications. The spleen reaches enormous size (6250
gms. Bovaird) and the liver is greatly enlarged, while the lymph-nodes are
much less prominent. The pigmentation affects skin, spleen, lymph-nodes,
and smooth muscle-tissues.

Microscopically the splenic structure varies in different stages. It
begins with the appearance of many large clear polyhedral cells lying loosely
in the pulp tissue occluding and replacing sinuses, cords, and finally the
Malphigian bodies. Scattered lymphocytes long persist but eventually
disappear. At the acme of the process, as in Bovaird's case, the tissue is
composed almost exlusively of closely packed, very large, clear polyhedral
cells forming diffuse masses or large alveoli. Occasional mitoses may be
observed and it is evident that the cells are not only well nourished but
possess considerable powers of growth. Yet the cells lack the hyperchro-
matic nuclei of tumor-cells and they carefully respect anatomical barriers.
Necrosis is rare but occurred in Schlagenhaufer's case. In the late stages a
slow fibrosis overtakes the process and the hyperplastic cells fade into a
form of hyaline or fibrillated tissue. In the lymph-nodes and marrow much
the same process is observed beginning in the sinuses. In the liver small
foci of the large cells appear in the lymphatics of the portal canals.

From the study of six cases (^Bovaird, Brill, four from New York Hospital)
I am satisfied that the hyperplastic cells appear first within the pulp cords,
that they are derived from the lining cells of the splenic sinuses is uncertain,
that the process originates secondarily in the lymph-nodes and marrow,
and that the hyperplasia falls below that of a true neoplasm. Whether the

ENDOTHELIOMA

305

process in the liver arises in that organ or results from cell emboli appears
uncertain.

In the etiology a chronic irritant affecting especially the lymphoid organs
must be assumed to exist. Many features suggest an atypical tuberculosis.
In two cases (Gaucher, Schlagenhaufer) tuberculous lesions coexisted. In
Collier's case there was a caseous mass in the mediastinum, while in other
cases tuberculosis was not eliminated. Lutz found an early stage of the
process in diabetic lipemia.

It has recently been shown by Anitschkow that a very similar condition
of spleen and bone-marrow may be produced experimentally in animals
by feeding large amounts of cholesterin. The material in the cells does not
give the staining reactions of myelin bodies, lipoids or fats, nor does it react

FIG. 94. — Structure of splenic lesion in Gaucher's splenomegaly. Note that the large
cells lie within the cords and do not line the splenic sinuses.

to Weigert's myelin stain. Yet it is probably a peculiar lipoid (Schlagen-
haufer, Lutz).

B. Endothelioma. — i. Endothelioma of Meninges. — This common tumor
appears in two main forms, (i) As a perivascular endothelioma, and (2)
as psammoma in which small perivascular units undergo hyalinosis and
calcification. The tumors are single and as large as a hen's egg, or multiple
and of miliary dimensions. They first appear as flat elevations on the inner
side of the dura which slowly enlarge with corresponding displacement or
atrophy of brain substance. They show little tendency to form adhesions,
but may be surrounded by a vascular capsule. An infiltration between the
thickened layers of the dura may occur. They are usually very firm in con-
sistence, gray in color, with nodular surface or lobulated structure. Strands
of connective tissue from the dura may be drawn into the growth separating

306 N EOF LA STIC DISEASES

lobules of endothelial tissue. The psammomas are extremely hard, usually
of moderate dimensions and the sand grains are visible in the gross. Occa-
sionally the tumor becomes pedunculated. On gross inspection the concentric
units may usually be discerned, but old hyaline forms exhibit a smooth,
glassy lustre.

The chief seats are the dura over the convexity, in the falx and tentorium,
and along the basal vessels, and they may develop over the medulla, and
down to the cauda. The cerebral tumors have been discussed by many
authors, while the less known spinal tumors were described in detail by
Eppinger. Schlesinger collected 18 spinal psammomas located chiefly in
the central and lower segment. Hippel found a large cellular psammoma
in the cerebellum and multiple calcified nodules throughout the spinal
meninges. Small tumors are said to arise from the pia (Borst), and atypical
forms have been observed in the ventricles arising from ependyma. The
predisposition of the dura may be associated with the frequent occurrence

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, J^

• .. >* •&''.

^ . ^ , e

.. V Y« * " » -- '.'. .' 4 ••?

FIG. 95. — Endothelioma of dura mater.

of "sand grains" on its inner surface producing the condition called by Virchow
meningitis arenosa. Virchow observed several cases in connection with
exostoses. Henschen describes multiple endothelioma of the spinal dura
associated with tuberculous pachy meningitis.

The structure is quite characteristic and the endothelial features are
so obvious that this tumor was the first to receive the designation of endothe-
lioma (Golgi, 1869). The tissue is composed of systems of cells concentri-
cally arranged about a central lumen, closed or patent, which represents a
rudimentary vessel. These units may be very small, numerous and sharply
defined or large and ill defined. Considerable areas may be composed of
diffuse cells without concentric arrangement, or the masses may be plexi-
form and convoluted. Borst in one case saw a uniform thickening of the
meshes of subarachnoidal tissue by cells lying loosely within these strands.
The cells are polyhedral or of elongated spindle form with the usual endothe-
lial characters. In some very cellular forms the cell borders are less distinct
and the nuclei hyperchromatic.

EN DOTH ELI OM A 307

The origin of the cells has been referred chiefly to the endothelium of
perivascular lymph spaces and to perithelium of proliferating vessels, while
Engert regards them as derivatives of the lining cells of the dura. On the
other hand M. B. Schmidt has made it appear very probable that most or all
of the endothelial tumors of the dura are derived from groups of endothelial
cells which he finds in a large proportion of adults lying in the meshes of the
pia, near small blood-vessels, and especially in connection with Pacchionian
granulations.

In a notable case described by Lindner with multiple tumors of dura and
similar growths in bladder and urethra, the cell masses inclosed spaces
communicating with blood-vessels and containing groups of nucleated red
blood-cells. According to Albrecht's bizarre interpretation of this case
the tumor was derived from vasoformative cells which retained their capacity
for red-cell formation.

The blood-vessels are usually scanty and are carried by the stroma
derived from the dura.

Secondary changes are frequent. A form of fibrosis overtakes old tumors
and may transform them into dense hyaline masses on the edges of which
islands of growing cells may be preserved. Here the cell bodies become
fused and hyaline without the intervention of any special intercellular
substance. Chronic edema may occur in small or large areas in which the
cells swell to large dimensions and polyhedral form.

Hyaline degeneration and calcification produce the characteristic struc-
ture of psammoma. These processes affect chiefly the central cells of the
concentric units, hyalinosis preceding calcification. Entire cell groups
may be calcified and almost the entire tumor may be composed of sand
grains with traces of concentric or irregular striation. The walls of vessels
may be extensively affected, hyaline changes altering the walls and the
contents, and calcification appearing in or about the walls and in the con-
tained material. According to Ernst hyaline material may first appear as
an intercellular secretion.

Numerous variations from the typical perivascular structure occur in
endothelioma of the meninges. Tumors that have undergone considerable
fibrosis are often called fibro-endothelioma. The appearance of alveolar
endothelioma is sometimes produced by cells growing in a fine network of
connective tissue derived from dura or pia. Very vascular tumors occur in
which the vessels seem to belong to the tumor process and these may be
designated as angio-endothelioma.

In some of the vascular tumors a peculiar structure is produced by the
growth of large cells in several layers covering or radiating from the vessels.
They may involve the pia mater and extend down the sulci. Borst and
others derive these cells from the perithelium of the blood-vessels and desig-
nate the tumors as perithelioma. Similar growths arise from the ependyma
and choroid plexuses where they produce papillary structures. An endothe-
lioma of the meninges of the dorsal cord, exhibiting the structure of perithe-
lioma, has been reported from this laboratory by Schlapp. It was rather
clearly referable to a severe trauma and while it grew rapidly, was completely
eradicated by curettage. It is difficult to determine the exact position
of these tumors but in Schlapp's case the cylindrical and pavement character
of the cells indicated true endothelial properties in the cells of origin.

Very cellular growths are frequently described as sarcoma or endothelial
sarcoma but it was long ago pointed out by Newmann and by Bizzozero and
Bozzolo, and lately by Zenorii, that these dural sarcomas are probably derived
from the endothelial cells. Yet the careful analvsis of Lens shows that true

308

NEOPLASTIC DISEASES

sarcoma of the meninges arises from the adventitial cells of the blood-vessels
while an extensive proliferation of arachnoidal endothelium occurs as a
secondary process which is not neoplastic. The true meningeal sarcomas
usually take the form of angiosarcoma or large round-cell sarcoma. The
clinical features of sarcoma are usually missing in the endotheliomas, which
pursue a slow course without metastases or wide local extensions.

The course of dural endothelioma is slowly progressive. Pressure symp-
toms are usually late in appearance and many cases are first discovered
at post-mortem. Even the vascular growths may fail to alter this course,
and I have observed an extremely vascular and very cellular diffuse endothe-
lioma compressing the pons which progressed slowly over a period of four
years.

FIG. 96. — Slowly growing angio-endothelioma of meninges of base of brain. Hyaline and
calcine material forms the walls of many vessels.

On the other hand pressure symptoms and recurrence after operation
marked a case of Taylor's, and a small tumor between falx and convexity
was found by Lunz in a case of cortical epilepsy. Henschen described a
remarkable case of multiple endothelioma of the spinal dura associated with
old tuberculous meningitis, while Dufour observed a somewhat similar
case in the horse. Metastases are extremely rare but Klebs found nodules
in the lung in one case, and Lindner is said to have observed a metastasis
in the bladder.

Psammoma of nerve-trunks has been described in a considerable group
of cases; in the optic nerve (Knapp, Ernst, Tailer, Braunschweig, Lit.);
or acoustic and facial (^Fester) ; but the exact nature of some of these tumors
is doubtful.

EN DOTH ELI OM A 309

Acoustic neurofibromas form a characteristic group of intracranial tumors
and are described under brain tumors.

Endothelioma of Nerve-trunks and Ganglia. — In many nerve- trunks and
certain ganglia endotheliomas, usually of the perivascular type, have repeat-
edly been observed. In some of the common neurofibromas the tumor-cells
present endothelial characters and are arranged in whorls as in plexiform
endothelioma. It is difficult to distinguish such tumors from true endothe-
lioma on the one hand and simple neurofibroma on the other.

In other tumors of nerve-trunks the structure is that of typical perivascu-
lar endothelioma as occurring in the dura mater, and psammomatous changes
may appear in them.

In the orbit perivascular endothelioma arising from the sheath of the
optic nerve is a well-defined condition. Of 12 extradural tumors of the optic
nerve collected by Parsons nine were this form of endothelioma. They
are usually of slow growth, 6 to 8 years, but reach considerable size (Billroth)
producing exophthalmos. They surround the nerve-trunk in conical form
or are attached by a pedicle or appear disconnected from the optic nerve,
in which case another origin may be assumed. The structure shows con-
centric masses of endothelial cells in which hyalinosis and calcification may
be prominent.

Of two orbital tumors belonging to this group and not distinctly connected
with the nerves, in one I found very extensive calcine deposits among con-
centric groups of cells showing very hyperchromatic nuclei and evidently
malignant; in another, 1X2 cm., the cells in broad concentric groups were
highly pavement in type. Both failed to recur.

In the extensive literature on tumors of the orbit it is clear that many
other tumors, especially carcinoma of the lachrymal gland, have been
interpreted as endothelioma. Thus in a full discussion of orbital tumors
not connected with the optic nerve Parsons includes many growths of cylin-
dromatous, peritheliomatous, and sarcomatous character but none of clearly
endotheliomatous type. Verhoef has shown that the common so-called
endothelioma of the orbit is a carcinoma of the lachrymal gland. Yet it
would be unwise to assume that all the suspected endotheliomas of this region
are spurious. Thus Frank describes a congenital tumor attached to the
periosteum of the inner wall, containing alveoli of cylindrical cells, diffuse
cell masses and vessels containing blood and lined by tumor-cells. Even
here an embryonal carcinoma is difficult to eliminate. In the Gasserian
ganglion Spiller describes a typical perivascular endothelioma with multiple
miliary tumors of the adjacent dura.

Endothelioma of Serous Membranes. — Highly characteristic conditions
are produced in the pleura and peritoneum by endothelioma of these struc-
tures and the gross and microscopical features were early recognized as the
results of a specific process differing from ordinary carcinoma. There are
such notable differences in the conditions produced in the pleura and in the
peritoneum as to require their separate consideration.

(a) Pleural Endothelioma. — The process first appears in the form of
multiple nodules or flat elevations widely distributed over one or both mem-
branes. These nodules fuse, the layers of the pleura become thickened and
adherent and converted into a diffuse firm opaque mass covering and com-
pressing the entire lung. In Gutmann's case the tumor consisted of a limited
number of nodules and distinctly papillary masses, and the pleura was only
slightly thickened. The costal pleura only may be affected (Scagliosi).
A sero-fibrinous or bloody exudate commonly accompanies the growth and
the fluid gathers in small cysts or in larger collections. Invasion of the

310 NEOPLASTIC DISEASES

lung may be entirely missing as in Wagner's and Benda's cases, or more of ten,
the tumor invades the septa and parenchyma producing irregular nodules and
masses, and metastases appear in bronchial, axillary, cervical, and medias-
tinal nodes, and in the liver and spleen. Perls observed metastases in the
dura and choroid, and Eberth found a second endothelioma primary in the
pia. The process may extend to the peritoneum or to the pericardium
(Bassoe), or from the peritoneum to the pleura (Rossier, Pollmann).

The structure in most cases is rather uniformly that of alveolar and tubu-
lar endothelioma. The cells are of moderate size, of polyhedral or flat form,
with hyperchromatic vesicular nuclei and faint nucleoli. They lie in small
alveoli or long single or multiple rows between cellular or hyaline connective
tissue to which they are usually intimately adherent. Evidences of secretion
are usually missing. Borst describes as an endothelioma of pleura a tumor
containing very large cells closely resembling squamous epithelium and
forming numerous pearls, but the massing of this tumor about the root of
the lung and its perforation of the chest wall as well as its structure render
the diagnosis uncertain.

The origin of the tumor has usually been referred to the cells of the
subpleural lymph spaces (Wagner, Bostrom, Neelsen, Volkmann, Adler),
which have been found affected in very early stages. Malassez, Rossier,
Pollmann, and others were unable to trace the origin exactly but were sure
that the tumor did not arise from any epithelial structures. Benda, and
Guttmann were able to trace the tumor to the lining cells of the pleura, which
several observers have found to show nodular thickenings due to proliferating
endothelial plates. All agree that the process begins over a wide area. It is
possible that two groups of serous endotheliomas should be recognized, one
invasive with metastases and derived from the endothelium of lymph spaces,
and another, superficial, nodular, or papillary, and originating from the
lining cells.

The clinical course is that of chronic pleurisy with thickening and adhe-
sions. Rossier especially emphasizes the inflammatory character of the
process, claiming that it begins as a chronic pleurisy, and the wide extent of
the growth suggests that it may signify a neoplastic process becoming
established in predisposed subjects on the basis of inflammatory hyperplasia.
Perls, Neelson, Glockner, and others even consider that an infectious agent
is concerned in the disease and that it is not a true tumor but a form of
tumor-like lymphangitis. The multiple or diffuse origin and gradual exten-
sion over normal areas have often been observed and Neelson claims that
the metastases are not caused by embolic cells but arise de now in the affected
tissue. It may be noted that Brosch in a very early case of pleural endothe-
lioma observed multiple nodules with caseous centers surrounded by pro-
liferating vessels and many giant-cells of Langhans type. The resemblance
to a hemorrhagic tuberculous pleurisy is mentioned by Kaufmann, and the
difficulty of distinguishing the early nodules from miliary tubercles is noted
by Wichern. Yet endothelioma of the pleura differs widely from the forms
of hyperplastic lymphangitis and whatever its etiology the process is neoplas-
tic. In the diagnosis Fraenkel and Kaufmann mention the importance of
blood and tumor fragments in the fluid and retraction of the chest wall.
The disease occurs chiefly in adults but Hibler has observed it in a child of
five years.

(b) Peritoneal Endothelioma. — Rokitansky, 1854, described primary
cancers of the peritoneum composed of multiple translucent nodules lying
under the serosa and covering many organs. Waldeyer found in primary
peritoneal growths the structure of plexiform angiosarcoma and cylindroma.

ENDOTHELIOMA 311

Birch-Hirschfeld, 1895, distinguished clearly between primary jelly-like
"angiosarcomas," which he derived from the lymphatic endothelium, and true
colloid cancer, a bulky tumor which he referred to an aberrant portion of
intestinal mucosa. A characteristic case of primary endothelioma with
hundreds of small nodules universally distributed he pictures and describes
as composed of small groups of endothelial cells which he traced to the
endothelium of dilated lymph-vessels.

In 1897 Glockner collected 75 cases of endothelioma of serous membranes,
pleura, peritoneum, or both, and since that time the condition has been
generally recognized as the result of a specific process.

The structure of these tumors generally follows the description given by
Birch-Hirschfeld and is fully presented in a recent case by Miller and Wynn.
They found the nodules composed of a framework of connective tissue carry-
ing numerous vessels and inclosing groups of large polyhedral cells with clear
cytoplasm. The cell groups often contained mucinous material, and a large
amount of mucilaginous ascitic fluid was present. Many small clear cells
and many multinucleated giant-cells were present. The authors trace the
tumor to the lining cells of the peritoneum, observing all stages of their pro-
liferation up to the large nodules. They found intimate connections between
the cells and the accompanying fine connective-tissue fibrils, and describe
the fibrillation of cell processes leading to the formation of connective tissue.
Hence they conclude that the tumor has sarcomatous qualities. The intes-
tinal walls were invaded as far as the submucosa, the general peritoneum
only in subserous tissue, and the lymph-nodes only in the capsular tissue.

The ascitic fluid was alkaline, s. g. 1017, when boiled solid still exuded
a mucinous fluid, reduced Fehling's solution only after boiling with HC1,
and gave the reactions of albumins which precipitated on half saturation
with ammonium sulphate.

A somewhat atypical case is described by Borst. The peritoneum was
everywhere covered with nodules, plates, and papillary elevations, and numer-
ous small and large cysts had resulted from inclosure of mucinous material
not in the tumor-masses but by adhesion of the inflamed peritoneum. The
diaphragm was perforated and the pleura involved. The cells were flat,
cubical, cylindrical, or syncytial. The structure was adenoid, interfascicular,
papillary, and often peritheliomatous. The organs were not invaded but the
abdominal nodes were extensively infiltrated. The origin seemed to be from
the subserous lymphatics and Borst suspected that the ovarian region had
first been involved.

A still further variation from the usual type is described by Kaufmann
(I.e. 542) who found multiple nodules, confluent plates, and flat masses
of partly caseous material surrounded by strata of hyperplastic cells derived
from the surface endothelium. In many alveoli there were cylindrical
cells in palisade order. The diaphragm and omentum were chiefly affected,
and a hemorrhagic exudate accompanied the process.

In cases reported by Nager and by Henke the tumor took the form of a
multitude of miliary or larger cysts covering all the organs, causing universal
adhesions, and marked thickening of the mesentery and omentum. Some
of the reports of endothelioma of the peritoneum raise the suspicion that
the authors are dealing with secondary carcinoma of intestinal origin in
which the primary tumor has been overlooked. Especially when there is
marked secretion of mucus the cases closely resemble the so-called pseudo-
myxoma peritonei which has been definitely traced to the rupture of com-
paratively benign ovarian cysts. This suspicion attaches to the cases of
Nager and Hueter, in which the secretion of mucus was abundant, the cells

312 NEOPLASTIC DISEASES

cylindrical, and the structure adenocarcinomatous. Very similar conditions
undoubtedly follow peritoneal dissemination of colloid carcinoma of the
colon. Further studies in this field are desirable.

The proper classification of endothelioma of pleura and peritoneum
still remains a somewhat fruitless matter of discussion. Ribbert insists
that the lining cells of the large serous cavities are of ccelomic origin and
epithelial nature and he describes these tumors as carcinoma. Kaufmann
adheres strictly to principle in separating endothelial tumors derived from
lymph spaces and carcinoma derived from lining cells, of both pleura and
peritoneum. The majority of authors, the writer among them, are less
impressed by embryological considerations than by the morphology and
physiology of the cells and the general characters of the tumors derived from
them, and they approve of the classification as endothelioma. The impres-
sion gained by Birch-Hirschfeld, Waldeyer, and Ziegler that all these tumors
have sarcomatous qualities is supported by the recent observations of Miller
and Wynn of connective- tissue formation by the tumor-cells. I cannot
trace this process in the few cases at my disposal, but consider that other
grounds fully support the grouping of these tumors among endotheliomas
(cf. Monckberg).

Endothelioma of Bone. — The existence of primary endothelioma of bone
has been established with difficulty and not yet to the entire satisfaction
of some critics. Since this tumor does not always produce structures that
can be positively identified as endothelial, and since the bone-marrow is a
frequent seat of metastatic growths, the diagnosis of endothelioma in bone
requires special caution and the rigid elimination of outlying primary foci.
This task is often difficult to accomplish for it is well known that small
carcinomas of stomach, thyroid, and prostate may yield numerous metas-
tases in the bone-marrow. Especially do adrenal tumors and carcinomas of
the kidney show a tendency to form early bone metastases, which may yield
the first and the chief symptoms of the disease.

It is further necessary to consider the possibility that primary tumors
of bone-marrow may arise from embolic cells from normal organs. It has
long been recognized as probable and Gierke especially has collected much
evidence to show that cell emboli derived from benign tumors of the thyroid
and even from simple goiter may lodge in the bone-marrow and give rise
to tumors. A certain number of tumors of bone described as endothelioma
are probably of this nature (Gierke, Lit.). A similar mode of origin for
certain bone endotheliomas which resemble hypernephroma has often been
suggested. Pick argues that the close contact of the blood-stream with
normal adrenal cells, and the discovery by Stilling of buds of adrenal cells
projecting into the veins in the regeneration which follows removal of the
adrenal in animals, reveal abundant sources for emboli of normal adrenal
cells.

Finally it is possible that misplaced islands of thyroid or adrenal or
other tissues may exist in the bone-marrow and give rise to tumors, since
the wide distribution of accessory thyroid and adrenal tissue is fully
established.

In view of these considerations the endothelial nature of many old cases
described as endothelioma of bone has been disproven or placed in doubt.

With these precautions it may be stated that two classes of tumors of
bone deserve consideration as primary endothelioma.

i. One group of cases consists of single, bulky, circumscribed growths
which arise from the marrow of long bones, early perforate the bone and
develop externally. Some become pulsating growths and they may be

ENDOTHELIOMA

313

imperfectly inclosed in a bony capsule. Mucoid and hyaline degeneration
is common and cysts may form. The structure is that of tubular or alveolar
endothelioma, and often the arrangement of cells follows the type of angio-
endothelioma. Volkmann describes two typical cases and collects reports of
others. In none is the endothelial origin proven and later critics have
specifically referred some of these growths to thyroid or adrenal cells.

There can be little doubt, however, that there is a primary tumor of the
bone-marrow of this peculiar struc-
ture. I have studied six cases of
this type, three of them located at
the lower end of the humerus. They
early perforated the shaft, infiltrated
the muscles, recurred after opera-
tion, and produced pulmonary metas-
tases. The structure presented thin
strands of connective tissue support-
ing one or more layers of large clear
cells inclosing spaces sometimes con-
taining blood. Or the cell masses
were compact with occasional central
necrosis. I have failed to find any
evidence of bone formation. In one
case, besides the clear cells there were
some areas resembling plasma-cells.

Hansemann, Herxheimer, and
Schlagenhaufer express the feeling
that some of these tumors are de-
rived from osteoblasts, without offer-
ing definite grounds for this impres-
sion.

2. Multiple small tumors of the
bone-marrow affecting nearly every
bone in the body occurred in a re-
markable case described by Marck-
wald which stands as a type of
genuine endothelioma of bone. The
tumors were most numerous in the
vertebrae and sternum but many were
found in skull and pelvis. Some had
perforated the bone. All other
organs were free. The patient was
a male, 53 years, duration 14 months,
with intermittent fever, pain and ad-
vancing anemia and cachexia. The

FIG. 97. — Angio-endothelioma of humerus.

general condition resembled multiple

myeloma but the structure of the

growths was entirely different. The tumors were composed of congeries of

clear polyhedral cells in diffuse islands and often surrounding capillary

channels containing intact blood. Neighboring tissue cells wrere pigmented.

The diagnosis of intravascular endothelioma seems fully justified.

Marckwald analyzed several cases from the literature with the conclusion
that similar tumors have been described by Rustizky, Zahn, Kahler, Wieland
and Klebs. Some of these, however, were clearly multiple myelomas.
Howard and Crile describe multiple tumors of the bones which closely

314

N EOF LA STIC DISEASES

resemble Marckwald's case and they offer an interpretation of the much
discussed cases in the literature. They conclude that endothelioma arises
from the endothelium of blood- or of lymph-vessels, and they follow
Borrmann in assuming that the so-called perithelioma arises from perivascular
endothelial cells.

While uncertainty still surrounds the origin of these tumors of the bone-
marrow it is not clear that they can be separated from multiple myeloma.
Their multiple character renders an origin from misplaced cell groups of
any variety highly improbable.

Periosteal endothelioma with calcification and bone formation has been
described by Perthes who also finds 30 cases in the literature which he inter-

FIG. 98. — Structure of angio-endothelioma of bone.

prets as such. A lymphangio-endothelioma of sternum without bone forma-
tion is recorded by Coletti.

Endothelioma of Skin. — In no department has the doctrine of endothe-
lioma^suffered such violent transformation as in the field of tumors of the
skin. Here several quite distinct neoplasms have gradually acquired a wide
or general acceptance as endothelioma only to lose their claims for recognition
in this category through the more careful studies of critical observers. These
tumors are the lymphangioma tuberosum multiplex of Kaposi, the endothe-
liomas of the skin of Braun and others, and the soft nevus with its derivatives.
With the elimination of these groups neither Darier nor Unna admit the
existence of any genuine endothelioma of the skin.

Lymphangioma tuberosum multiplex was first described in 1868 by Kaposi

EX DO THELIOMA 315

as a tumor composed of lymph-vessels filled with proliferating endothelial
cells. Although Jacquet and Darier in 1887 showed that these cell groups
are derived from the epithelium of dilated sweat-glands, numerous writers
continued to describe cases as endothelioma. Many authors have pointed
out their true nature (Frick, Lit.). Stockman has reviewed the history
of this tumor, fully supported its epithelial origin, and accepted its designa-
tion as hidrocystoma tuberosum multiplex.

A second group of tumors of the skin presenting the structure of cylin-
droma was long regarded as endothelioma. A typical case of this class and
one much referred to is that of Braun. This tumor was clearly shown by
Krompecher to be of epithelial origin and is now quite generally assigned
to the class of epithelioma adenoides cysticum.

With another group of somewhat similar tumors it has been more difficult
to reach a conclusion. In 1889 Spiegler described three cases of multiple
tumors of the scalp which grew over a long period and eventually covered
the head with numerous discrete tumors resembling small "billiard balls"
or " tomatoes." The clinical condition was extremely characteristic. Simi-
lar tumors are also observed in other parts of the body, especially of face,
chest, and abdomen. The clinical course, gross section and microscopical
structure show many resemblances to reticulated epithelioma, with which
they are classed by Borrmann, Ribbert and others. Mulert's case was
disposed of by Lubarsch. Many others closely resemble some of the varieties
of epithelioma extensively illustrated by Coenen. Juliusberger who reviews
this group at length regards most of the cases as epithelioma, but considers
Haslund's case and his own as true endothelioma. I do not find satisfactory
evidence that the tumor described by Juliusberger was derived from endothe-
lium, bat in Haslund's case the clinical history and structure are rather
distinct and it is difficult to eliminate an endothelial origin.

This patient suffered from multiple tumors of the scalp which grew
rapidly, involved the regional lymph-nodes and proved fatal in 18 months.
Microscopically the polyhedral or spindle-cells, the formation of long inter-
cellular fibrils, the absence of definite epithelial characters, the striking
relation to vascular spaces and channels, and the various stages of tumor
growth which were traced in great detail from the lymphatic endothelium,
all accord with an endothelial character. On the other hand their appearance
as multiple tumors of the scalp of the same general features as the character-
istic epithelioma of this region raises the suspicion that Haslund had to deal
with unusual histological features of an epithelioma. Nevertheless the
minute histological study of this case brings to light so many endothelial
characters as to leave in doubt the true nature of the growth, and with it
the existence of a true endothelioma of the skin. It has already been pointed
out that the pressure of circulating blood in immediate contact with tumor-
cells, which is the chief endothelial feature of Haslund's case, is not a reliable
sign of endothelioma but occurs also in epithelioma of the skin.

The cellular nevus has been the subject of much discussion and difference
of opinion. First regarded as an endothelioma derived from lymph-vessels
(Recklinghausen, Demieville, Lowenbach), the opinion of Unna who inter-
preted the cells as misplaced embryonal epithelium has found very general
acceptance by the majority of observers. Yet Kaufmann, Johnston, Schutz
and others believe that there are nevi of endothelial as well as those of epithe-
lial nature. I do not find the distinctions between these groups sufficient to
warrant any separation of the cases, which seem to me to fall in the class of
melanoma (q.v.).

Endothelial psammoma of the skin is described by Winkler. This rare

316

N EOF LA STIC DISEASES

tumor occurs in the form of multiple hard nodules in the cutis or subcutis
which follow the course of nerves and may be traced down to the periosteum.
They are probably derived from the endothelium of nerve sheaths and traces
of nerve-fibers may persist. They belong in the group of psammoma of
nerve-trunks. They consist of concentric masses of endothelial cells which
are often calcified. According to Winkler certain cases of calcified endothe-
lioma of the skin (Perthes, Linser, Volkmann) have a similar origin. Psam-
moma of deeper nerve-trunks is more frequent.

Angio-endothelioma of the skin and subcutaneous tissue occurred in several
cases which I have examined. They were slowly growing circumscribed
tumors of the sole of the foot, finger or face. They were composed of a

FIG. 99. — Fibro-angio-endothelioma. A circumscribed tumor beneath skin of thumb.

moderate number of small blood channels traversing wide groups of endothe-
lial cells. The preponderance of cells over vessels calls for the designation
of endothelioma (cf. hemangio-endothelioma).

Endothelioma of Corpus Caverno sum Penis. — This tumor appears in the form
of multiple nodules or flat infiltrations of the corpora cavernosa behind
the glans and along the dorsum of the penis. Four cases are recorded in
two of which the course was moderately slow, the growth circumscribed,
and operation was followed by recovery (Alexander, Hildebrandt), while in
the others the disease early involved the lymph-nodes and the patients died
with general metastases (Maurer, Colmers). The structure consists of the
cavernous spaces filled with large polyhedral or rounded, rather clear or
granular cells with large nuclei and prominent nucleoli. The central portions
of large cell groups are necrotic or occupied by circulating blood (Colmers).

ENDOTHELIOMA 317

Invasion of the urethra, septa, skin and especially of the nerve-sheaths is
observed. Occasionally concentric groups of cells appear. The origin of
this tumor from endothelium has not been fully determined, but primary
tumors of the urethra were excluded. Yet Hildebrandt considers the possi-
bility, and Borrmann assumes, an origin from urethral epithelium. In
Alexander's case I must agree with Dunham that the structure was different
from that of epithelioma and strongly suggestive of endothelioma.

Creite has described a peculiar urethral carcinoma of undetermined
origin in a child of two years which may have some bearing on the present
topic.

Endothelioma of Ovary. — Among the tumors of the ovary Leopold (1874)
described a very large growth which he derived from the endothelium of
lymph-vessels, while numerous small cysts composing the bulk of the tumor
he referred to dilated lymphatics. In 1879 Marchand described pap llary,
cystic, and tubular forms of ovarian tumor which he distinguished from sar-
coma and considered as very probably derived from endothelium of lymph-
or blood-vessels. Somewhat similar structures were next observed by
Flaischlen in a cystic tumor combined with a dermoid cyst.

A definite relation of the tumor-cells to the endothelium of blood-vessels
was claimed by Olshausen and Ackermann and by Eckardt, who described
their tumors as endothelioma intravasculare. On the other hand Pomorski
and v. Velits traced cystic and myxomatous tumors to lymphatic endothelium,
and Rosthorn referred a somewhat different structure, composed of large
cell groups inclosing blood-masses, to proliferation of perithelial cells. All
three structures seemed to Amann to deserve recognition as types of endothe-
lioma. In the disposition of the cells, L. Pick recognized three types com-
posed of (i) long rows and whorls of cells, (2) cell groups resembling adenoma
or carcinoma, and (3) diffuse masses of cells resembling sarcoma. In 1896 a
specific structure, designated as fibrosarcoma ovarii mucocellulare carcino-
matodes, was described by Krunkenberg and referred in all probability to the
endothelial cells of this organ (Krunkenberg's tumor).

Thus such a wide variety of structures of such uncertain origin were now
included under endothelioma that suspicion arose regarding the validity
of the rapidly growing scope of this ovarian tumor. Such obvious combina-
tions as pyloric cancer and endothelioma of ovary were misinterpreted
by Rosinski as multiple separate tumors, while Linck even saw in the pyloric
cancer a metastasis from the ovarian growth. Likewise Krunkenberg
found the typical structure of perivascular endothelioma in an ovarian
tumor in a patient who two years later required hysterectomy for a similar
tumor of the cervix. In Eymer's case also the cervix was involved.

The first inroad upon endothelioma of the ovary was accomplished by
Schlagenhaufer, 1902, who showed that the majority of bilateral tumors of
the ovary are secondary to epithelial neoplasms of stomach, intestine,
gall-bladder, or uterus, and the typical Krunkenberg tumor he and Glockner
observed as a metastatic growth from pyloric cancer with mucus cells.
Polano (1904) showed that ova-like structures and perithelioma could appear
in adenocarcinoma, that metastatic gastric cancer in the ovary produced
many of the structures of the so-called endothelioma, and that certain mucoid
endotheliomas were really thyroid struma in this organ. Papaioannou
also pointed out the close resemblance of metastatic ovarian carcinoma to
endothelioma and fibrosarcoma. Stone has recently reviewed at length
the subject of secondary ovarian carcinoma. Glockner denied the validity
of Pick's histological criteria of endothelioma, especially the absence of an
intact layer of endothelial cells in the invaded tissue spaces, and claimed that

318 NEOPLAST1C DISEASES

the diagnosis of ovarian endothelioma could not be based on histological
structure alone but required the elimination of other tumors, especially
of the uterus, by autopsy. Thus grave doubts arose as to the existence of
any genuine endothelioma of the ovary. R. Meyer was disposed to discard the
entire group, and Ribbert states (1912) the extreme view that the endothelial
origin of any ovarian tumor while possible is unproven.

During this long discussion lasting over thirty years it became apparent
that unusual difficulties surround the diagnosis of endothelioma in the
ovary. This organ does not meet one of the conditions laid down by Ribbert
for the probable endothelial nature of any primary tumor, viz., that the organ
should not contain epithelial structures. On the contrary, the remarkable
physiology and changeable morphology of the germ epithelium, Pfliiger's
tubes, Graafian follicles, and corpus luteum, offer unusual sources of atypical
epithelial tumors. The average quota of endothelial cells seems to be defi-
cient in the ovary if one can accept Polano's observation that no lymph
spaces lined by endothelial cells exist in this organ. Again it has transpired
that the ovary is peculiarly liable to implantation metastases by its exposed
position in the peritoneal c avity, and to deposits by embolism or permeation.
Finally the doctrine of overgrowth of one element in teratomas has offered
a peculiar source of certain supposed endotheliomas of embryonal type or
associated with dermoids (Flaischlen, Vogel) or teratomatous structures
(Ribbert, Yamagiva).

One of the most conclusive features of certain endotheliomas is the rela-
tion of cell groups inclosing blood-masses as in angioblastic sarcoma. Yet
this structure has been clearly traced in the testis to a teratomatous origin
and an epithelial derivation (Wlassow), and while Sternberg and Monckberg
have endeavored to establish the existence of a special variety of angio-
blastic sarcoma or endothelioma apart from teratoma and Pfannenstiel
recognizes such tumors in the ovary, their teratomatous nature cannot be so
readily discarded.

Thus critical research fully justifies the current scepticism regarding
the endothelial nature of the present group of ovarian tumors and especially
their origin from adult endothelial cells of any type.

There is nevertheless a restricted group of ovarian, tumors for which
very strong evidence points to an endothelial origin and their somewhat
peculiar clinical course, gross appearance, and histological structure warrant
their separate classification as probable endotheliomas.

These tumors are usually large, sometimes bilateral (22 per cent. Apelt)
chiefly solid, yet often cystic. The solid growths show marked lobulation
and the exterior is nodular, while the general form of the ovary is maintained.
The cysts are small and numerous as from dilated lymph-vessels, or larger
and exhibiting on minute inspection papillary outgrowths. A honeycomb
appearance is noted by Pick. The consistence is firm, and the color varies
greatly with the blood content. Hydropic areas and hyaline or colloid
degeneration alter the appearance of the section which in general resembles
sarcoma.

The clinical course is of an actively growing tumor appearing at any
period of life but chiefly in adults, v. Velits observed a case continuing
for nine years, and Kubo twelve years, while Glockner saw a fatal result
in six months. Local adhesions with ascites and permeation through lym-
phatics are variable but recurrence is frequent. Kubo found no case of
recovery from bilateral tumors reported as endothelioma but single tumors
have been successfully eradicated by several operators (Pfannenstiel). It is
generally agreed that the malignancy less than that of carcinoma.

ENDOTHELIOMA 319

The structure falls into several classes (Pick, Pfannenstiel) :

1. The cells are arranged in orderly rows or whorls between abundant
fibrils, an appearance which has been likened to strings of pearls. An
indefinite lumen between such single or multiple rows of small cuboidal cells
has often been interpreted as a dilated lymph-channel, yet the origin of
the cells from lymphatic endothelium has never been traced and it is obvious
that in a large tumor mass original lymph paths are wholly obliterated. On
the other hand the remarkable long and regular cell columns as pictured by
Kubo may well signify the reassertion of the physiological tendencies of
lymphatic endothelium in a desmoplastic tumor.

2. A definite lumen of small or large dimensions walled by one or more
rows of tumor-cells and containing lymph or blood characterizes a second
group of tumors designated as alveolar or intravascular endothelioma.
The structural evidence of endothelial origin of this group is unusually
striking, and there is little doubt that such cases as those of Marchand,
Pfannenstiel and Kubo are properly regarded as endothelioma. They show,
moreover, numerous transitions up to structures which really deserve the
name of angioma. Tumors consisting of one or more large cysts lined
by layers of endothelial-like cells, described by Schurman and by Lange,
are accepted by Monckberg as genuine endothelioma. If so they represent
extreme examples of dilated lymph-vessels. Larger plexiform masses of
cells often form in which small groups of cells surround marrow lumina
(Kubo) or wide lumina filled with mucinous material appear. Ova-like struc-
tures formed by mucinous degeneration of cells occur in certain tumors of
this type whose endothelial nature is doubtful. Similar bodies are found
in undoubted adenocarcinomas. Hyaline globules in and between the
cells may also become a prominent feature (Kworostansky). The lymph-
channels may become dilated and papillary projections of tumor-cells may
partially fill the small cysts (Eymer), or the channels may be filled with
blood (Rosthorn).

3. Diffuse growth of small cuboidal cells forms the bulk of some endothe-
liomas and appears in portions of many others. Here indications of alveolar
tendencies may be detected at many points and the tumors bear a resem-
blance to alveolar sarcoma. The true nature and origin of such tumors is, I
think, open to question.

4. In a group of cases (Kubo, Lit.) the tumor-cells surround vascular
channels which possess a well-defined wall of normal endothelial cells, giving
the structure of perithelioma. There seems to be little reason to doubt
that such tumors, e.g. Amann's case, are of endothelial nature, but the
attempt to derive the cells from specialized perivascular endothelium has
not been successful. Pfannenstiel interprets as angio plastic endothelioma
ovarian tumors described by Michel and by himself in which numerous
capillary blood channels without walls coursed throughout diffuse cell
masses. This tumor is probably of teratomatous origin and choriomatous
type, and while the cells may assume angioplastic qualities the tumor has a
different significance from the present conception of endothelioma.

In all of these structural forms the features of the tumor-cells strongly
indicate their endothelial nature. They are of very uniform small size,
cuboidal or rounded foim, pale staining cytoplasm, and regular oval nuclei
with minute nucleoli.

In the stroma mucinous changes may be prominent or hyaline degenera-
tion may yield the appearance of cylindroma.

In the effort to trace the origin the tumors many have assumed that they
could be subdivided into lymphangio-endothelioma, and hemangio-endothe-

320 NEOPLASTIC DISEASES

lioma, intravascular and perivascular, and Kubo has arranged the reported
cases according to this plan. Its validity, as well as the exact nature of
many of the tumors included, remain to be established. Especially for the
perivascular type the attempt to derive the growth from the hypothetical
perithelial cells deserves little encouragement. Polano could not discover
any traces of such cells in the ovarian vessels, and it is well known that this
structure may be produced by many tumois.

Endothelioma of Uterus. — In the uterine mucosa and muscularis and
in the cervix several tumors have been described as types of endothelioma,
and derived by the authors from lining cells of blood or lymph- vessels.
From the descriptions of these cases I have not been convinced that a well-
defined endcthelioma of the uterus has been demonstrated and would agree
with R. Meyer that, while such tumors may occur, it is more probable that
the alleged cases should be distributed among epitheliomas and sarcomas.
Meyer points out that a considerable grade of endothelial proliferation
may occur in the cervix and uterus as a result of inflammation, that the rem-
nants of Gartner's duct in the cervix have been overlooked as a possible
source of atypical epithelial tumors, and that many of the structures of
endothelioma uteri may be explained as atypical features of other tumors.

Neither in the clinical course nor in the gross or microscopical structure
have the reported cases shown uniformity. Thus Pick finds endothelioma
in a small portion of the mucosa connected with a myosarcoma. Hansen
describes a large vascular tumor of the myometrium which showed many
features of an angiosarcoma, and the structure in Silberberg's case falls in
the same general class. Amann who recorded the first case was content
to find no connections between the tumor-cells and the surface epithelium,
but his case and that of Braetz strongly suggest embryonal epithelioma.
Pohorecky, Kroemer, and Kirschgessner describe structures often duplicated
by epithelioma. Hurdon's case was clinically indistinguishable from cervical
epithelioma with wide extensions, and while portions of the structure suggest
endothelioma, other areas correspond to epithelicma. Rabb considered
his case clinically epithelioma, and such is the impression clearly conveyed by
Graefe's report.

Thus the recorded cases seem to fall into three groups, vascular tumors
of the angiosarcomatous type, embryonal epithelioma, and atypical foims
of ordinary epithelioma of the cervix. Further critical study would seem
to be demanded before the existence of endothelioma uteri can be accepted.

Endothelioma of Stomach.- — For many years a peculiar condition of cirrho-
sis of the stomach with pyloric stenosis has been recognized under various
terms and interpretations. From the surgical side the history of the subject
has been fully reviewed by Lyle who employs Brinton's term linitis plastica
for the general condition. It has long been known that some of these cases
were atypical diffuse carcinoma. In a second group the process has been
recognized as neoplastic and interpreted as endothelioma by Fick, Tilger,
Jungmann, Cignozzi, Aldegarmann, and others, and Hansemann and Borst
have lent some support to this view. Szobelew and others have found the
condition both at the pylorus and in the colon. Yet in none of these cases
has there been satisfactory evidence that the process is an endothelioma.
The structure shows a diffuse and scanty infiltration of large cells with
hyperchromatic nuclei but of wholly indefinite origin. Many of the cells
may show the mucous degeneration with signet-ring nuclei of gastric cancer,
and some small foci of such cells are usually found on careful search. I have
examined five cases of this type in all of which the characteristic mucous
cells have been found, and in three prolonged search ^revealed alveoli of

ENDOTHELIOMA 321

typical gastric cancer. Since the typical appearance of endothelioma may
appear in undoubted gastric cancer there appears to be no ground for the
assumption that endothelioma of this organ exists.

That the remaining cases of cirrhosis of the stomach and intestine with
pyloric stenosis in the adult are the results of a chronic inflammatory process
has been clearly shown by Krompecher who attributes the changes to
edema, fibrosis, muscular hypertrophy, and initation by foreign bodies.
Recently there has arisen a tendency on the part of clinicians to call many of
these cases svphilis.

Endothelioma of Lymph-nodes. — Primary endothelioma of lymph-
nodes was described by Cnambard in 1880 under the term primary carcinoma.
He recognized a local form of the disease affecting one node or one chain,
and a generalized form which was always fatal. The structure was alveolar.
Zahn had previously interpreted an alveolar tumor of the cervical nodes as
sarcoma aheolare epithelioides. In 1881 Hoffmann and Schottelius used the
term endothelioma in their report of a case. The endothelial nature of
these tumors became gradually accepted so that Ziegler, Birch-Hirschfeld
and Kaufmann admitted their occurrence and referred to single cases of
their own, and Recklinghausen pointed out certain distinctions between
primary endothelioma and secondary carcinoma of lymph-nodes. More
recently quite detailed reports of the gross anatomy, microscopic structure,
and clinical course of these tumors have been furnished by Ravenna, Gallina,
Parlavecchio, and the writer.

In the study of a series of cases collected during a period of several
years I have drawn the conclusions that endothelioma of lymph-nodes
is comparatively frequent in occurrence, that the tumors often arise on
a basis of chronic granulomatous inflammation, that they develop from the
endothelium of the lymph and cavernous sinuses and are then usually
classed as secondary carcinoma, that somewhat similar tumors arise from
the reticulum cells of the lymph-nodes but usually take the form of large-
cell lymphosarcoma, occasionally of carcinoma, and that the characteristic
clinical course and microscopical structure of the tumors constitute them
specific diseases.

Clinically the disease appears in the form of (i) a systemic involvement
of many lymph-nodes with a progressive and fatal course lasting from one
to several years, and (2) as single or multiple tumors of cervical, axillary,
or other lymphatic chains, often preceded by granulomatous infection, but
eventually or from the first declaring itself as a locally aggressive recurring
malignant tumor.

The systemic form of the disease usually suggests the diagnosis of pseudo-
leukemia, as emphasized by Parlevecchio. Most of my systemic cases were
regarded as Hodgkin's granuloma and in some certain of the nodes pre-
sented the typical Sternberg-Reed histology. In one case of lymphatic
leukemia, I found alveolar endothelioma of the bronchial nodes. Flournoy's
case ran a prolonged course of four years and developed cervical, thoracic,
and very large abdominal tumors. Gallina's patient lived 12 years.

The localized tumors develop chiefly in neck, axilla, and groin, and are
commonly regarded as tuberculosis. In one case I followed an originally
tuberculous infection of cervical nodes recurring repeatedly over a period
of five years, and gradually assuming the structure of a malignant endothe-
lioma with elimination of the tuberculous element. Usually the tumors are
endotheliomatous from the first. In some cases I have 'been unable to
separate the local, cervical or axillary tumors, from a systemic disease of the
type of Hodgkin's granuloma. The local disease has a lethal tendency,
21

322 NEOPLASTIC DISEASES

but some patients enjoy long immunity after operation, although the ulti-
mate outcome is usually unfavorable. Zahn and Volkmann describe rapidly
fatal cases. Extensive tumors of the neck may early cause asphyxia and in
others attempted removal proves fatal.

Gross Anatomy. — The systemic disease is marked by uniform enlargement
of several chains of nodes, some of which reach large dimensions and give
pressure symptoms. The tumors are smooth, at first firm, later very hard,
usually solid, opaque, and marked by areas of necrosis. Recklinghausen
saw cystic distension of the abdominal chains, and involvement of many
retroperitoneal nodes.

The local tumors are at first circumscribed and the capsules free, but
later they become large, hard, adherent, and multiple. The infiltration of
recurrent tumors involves the neighboring structures with compression or
destruction as in carcinoma, but the progress is usually distinctly slower

FIG. 100. — Perivascular endothelioma of lymph-nodes. Nearly all lymph-nodes were
involved in this case. (Flournoy's.)

than in epithelial growths. Very extensive fibrosis and large areas of re-
tained dessicated lymph or necrotic tissue appear in late stages. Almost
complete sclerosis may overtake some of the tumor-masses.

Metastases are difficult to distinguish from systemic extensions, but the
lesions tend to advance over wide areas, involving thoracic and abdominal
nodes, and spleen. There appear to be all gradations between the localized
and the systemic form. Definite metastases were found by Gallina in the
adrenal, and in the portal canals of the liver by Ravenna. Very extensive
lymphatic lesions from which skin and muscles were invaded, with edema of
chest wall, chylous hydrothorax, and metastases in pleura, stomach and
adrenals occurred in the case of Da Gradi and de Amicis. In Flournoy's
case a very large tumor, 1780 gm. surrounded the pancreas, nearly all lymph-
nodes were involved, and there were metastases in adrenal and thyroid.

Structure. — The structure encountered depends on the stage of the process

ENDOTHELIOMA

323

and on the rapidity of its development. On the one hand it may be difficult
to separate the early stages from granulcmatous inflammation, and on the
other the late stages resemble carcinoma. The earliest stages of many cases
appear as a granuloma in which groups or coherent syncytial sheets of sinus
endothelium or reticulum cells stand out prominently by virtue of their
size and nuclear hyperchromatism. The cells are large, elongated or polyhe-
dral with very large vesicular nuclei and diminutive nucleoli, and they
spring in multiple foci from the lymphatic tissue. The isolation of invading
tumor-cells is conspicuously absent. The lymphocytes are passive and
disappear. Ravenna emphasizes the imperfect outlines of the cells and
their occurrence in broad sheets of cytoplasm interspersed with large vesicu-
lar nuclei.

FIG. 10 1. — Diffuse endothelioma of cervical lymph-nodes.

In some cases fibrosis sets in early and then the tumor-cells become
isolated and very prominent and the structure resembles alveolar carcinoma.
Many patent lymph paths lined by tumor-cells may persist or cysts may form.
Large convoluted masses of coherent endothelium may make up the bulk of
large tumors in which irregular areas of necrotic tissue containing fatty
crystals may appear. This structure may be designated as plexiform
endothelioma.

In several cases I have found dilated lymph-channels lined by multiple
layers of opaque, elongated or polyhedral cells. Or the cells mingled
with lymphocytes may encircle small arterioles as in perithelioma. These
structures suggest the term perivascular endothelioma.

In some cases the whole node is replaced by a diffuse growth of large
polyhedral or rounded cells which may cohere or fall apart. Giant-

324

NEOPLASTIC DISEASES

cells with multilobed nuclei may appear in these tumors, which may be called
diffuse endothelioma. They may present the appearance of large-cell
lymphosarcoma.

Histo genesis. — Analysis of the origin of endothelioma of lymph -nodes
involves at once the somewhat complicated questions of the structure of
lymph-nodes. I have elsewhere discussed this subject in some detail with
the following conclusions:

The reticulum cells of the lymph-nodes are derived from connective
tissue cells, and form a meshwork in which lymphocytes gather from without.
The reticulum of the follicles and pulp does not produce lymphocytes but these
two cells constitute separate series (Saxer, Gulland). The reticulum of the
nodes is not covered by separate endothelial cells, but is itself a cellular

FIG. 102. — Diffuse endothelioma of lymph-nodes. Coherent masses of large cells with

clear cytoplasm.

syncytial structure which incloses spaces continuous with the lymph paths
of the node. In the cavernous and lymph sinuses the lining cells have
pavement qualities of adult endothelium, while in the cords and follicles the
reticulum cells retain more of their original mesoblastic tendencies. Hence
tumors aiising from sinus endothelium may be expected to show pavement
or epithelial characters, while tumors of reticulum cells should exhibit
some of the mesoblastic features of their parent cells.

To a large extent these expectations are realized in the study of the
tumors. To the sinus endothelium has been traced the origin of several
tumors presenting alveolar or perivascular structures composed of polyhedral
cells (Ravenna, Ewing). The reticulum cells of the lymph cords are
found multiplying in the early stages of many tumors, especially in the
outlying nodes, and it is probable that changes in the form of these cells

ENDOTHELIOMA

325

toward adult endothelium accounts for the preponderance of large polyhe-
dral cells in the whole group of tumors. From the reticulum cells of the
follicles 1 have repeatedly been able to trace the development of large round-
cell tumors of the type of large round and giant-cell lymphosarcoma, which
tumors must be separated from lymphocytoma.

That the tumors are not secondary carcinomas is sufficiently attested
by the failure to find any primary tumor and by the very wide diffusion
and slow course of the systemic disease. That they do not arise fiom
aberrant epithelial rests within lymph-nodes has been proven by the detec-
tion of early stages throughout the whole node or several nodes of a chain
(Parlavecchio).

FIG. 103. — Perivascular endothelioma of cervical lymph-nodes.

With this complex morphology and histogenesis it is difficult to establish
a legitimate nomenclature. The terms employed, endothelioma of various
types, emphasize the form of the tumor-cells and their probable origin.
The tumors of loose round-cells derived from the reticulum of the follicles
differ markedly from the others and it seems unwise to urge any change
in their usual designation as large-cell lymphosarcoma or reticulum-cell
sarcoma.

Etiology. — Many observers have been impressed by the apparent depend-
ence of endothelioma of lymph-nodes upon lymphatic infection. The clini-
cal features of the systemic cases closely resemble those of pseudoleukemia
or of Hodgkin's granuloma. Parlavecchio stated that the histological
structure revealed the transformation of an inflammatory into a neoplastic

326

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FIG. 104. — Unit structure in a tumor of lymph-nodes. Large cells growing in and about

small blood-vessels.

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FIG. 105. — Early stage of diffuse endothelioma of lymph-nodes. These cells are derived
from the reticulum and sinus endothelium.

EX DOTH ELI OM A 327

hyperplasia of endothelium and he clearly pictured these transitions. In
the recurrences of one case I was able, to trace an original tuberculous granu-
loma into the neoplasm with elimination of the tuberculous structure. I
have reported several other cases in which various phases of remarkable
endothelial overgrowth occurred in tuberculous or other granulomatous
lesions. Many of the localized tumors present in outlying nodes the changes
of frank or atypical tuberculosis. Most of the localized tumors and the
advanced systemic lesions fail to show any traces of granuloma, suggesting
that the tumor soon overgrows the granuloma or arises immediately in
response to the infection. Other infectious agencies besides tubercle prob-
ably figure in the disease, and of these Hodgkin's granuloma requires first
consideration. Syphilis has not thus far been implicated.

PERITHELIOMA

That a definite group of tumors exists which deserves recognition under
the term perithelioma must be admitted, but the exact origin of these tumors
and their relation to other neoplasms are questions requiring more extensive
data than we now possess.

The existence of a special type of cell about the blood-vessels of the pia
mater was first shown by Eberth. In salt solution he was able to isolate
a thin membrane composed of polygonal or multipolar cells surrounding
these vessels. These cells were distinct from the true adventitial cells and
formed an outer boundary between the vessel-wall and the perivascular
lymphatics. Although Eberth did not clearly separate these perithelial
cells from the endothelium of perivascular lymphatics, and Kolliker (1896)
describes only perivascular lymphatics about cerebral vessels, similar cells
have been described about the blood-vessels of the hypophysis (Waldeyer),
carotid gland (Paltauf), adrenal, breast, salivary glands (Eberth, Arnold,
Sertoli, Luschka), and testis (Henle). Nevertheless the existence of such
cells has not been accepted as a well-established fact in normal histology, and
the derivation of an important group of tumors from them rests on an un-
certain basis. The belief that certain tumors do arise from Eberth's peri-
thelial cells is suggested chiefly by the peculiar arrangement of the tumor-
cells, radiating out from the supporting vessels, but it must be admitted again
that all the tumors in this class do not exhibit this peculiar arrangement
of cells. Indeed one must agree with Ribbert that no tumor has yet been
clearly traced to perithelial cells.

Notwithstanding these obscurities the group of perithelioma maintains
its existence for the following reasons, (i) These tumors present as a structural
unit the blood-vessel, and it is clear that they originate from some cells in
the walls of the vessels. (2) Although originating from blood-vessels they
differ in structure from angioma on the one hand and from endothelioma on
the other. (3) Their gross and clinical characters differ from those of an-
gioma and endothelioma.

From this point of view the term perithelioma cannot be regarded as
fully applicable, and many other terms have been employed by different
authors, as angiosarcoma (Kolaczek), plexiform angiosarcoma (Waldeyer),
perivascular endothelioma, and peri -endothelioma (Borrmann). Yet many
types of sarcoma are derived from blood-vessels and it seems better to
limit the term angiosarcoma to the cellular and malignant forms of angioma.
The term endothelioma is inadmissible since the perithelial tumors differ
notably from recognized types of endothelioma and they have not been
traced to an endothelial origin.

328

NEOPLASTIC DISEASES

The position of perithelioma seems to be intermediate between sarcoma,
especially angiosarcoma, and endothelioma, and atypical and diffuse forms
tend to vary in either direction. Thus diffuse perithelioma may be difficult to
distinguish fiom large spindle-cell sarcoma, while certain cases which it is
difficult to eliminate from the peritheliomas (Paltauf, Hildebrand) resemble
alveolar endothelioma.

An important source of confusion which has been prominent in the history
of angiosarcoma and perithelioma arises from the fact that many other
actively growing and malignant tumors assume the structure of perithelioma,
either in the original tumor or in metastases or recurrences. Hence Roussy
recognizes perithelioma only as a peculiar morphological structure without
histogenetic significance. In primary carcinoma of liver and in the round-
cell teratoid carcinoma of testis a peritheliomatous structure is frequently
observed. In the third recurrence of a teratoma testis I found the entire

FIG. 1 06. — Low magnification of cross-section of perithelioma.

tumor composed of blood-vessels sheathed with large radiating cells. For
such structures the term secondary perithelioma may be suggested. Again
the tissue giving origin to a malignant epithelial tumor may be very vascular
so that the tumor from the first assumes the form of spurious perithelioma.
These conditions exist in kidney and adrenal, epithelial tumors of which
have often been described as perithelioma. Indeed it is open to question
if a considerable number of supposed primary peritheliomas may not owe
their structure to the excessive development of blood-vessels supporting
rapidly growing embryonal epithelial tumors. Metastatic melanoma has a
persistent tendency in this direction, so that one may well look for active
pigmented moles in all cases of perithelioma of groin or axilla.

Gross Appearance. — Perithelioma usually appears as a well-circumscribed,
very vascular, at first slowly, later rapidly growing tumor which may reach
considerable dimensions. It is very subject to hemorrhage, necrosis and

EN DOTH ELI OM A

329

ulceration. In early stages it may be freely movable in the tissues exciting
little local reaction, and may be firm, soft or almost fluctuating or pulsating.
On cross-section the tissue appears to be composed of thick-walled and
variously twisted blood-vessels. This appearance strongly indicates that
the predominant unit in the tumor is the blood-vessel and since this unit is less
pronounced in secondary and spurious perithelioma its presence is the best
indication of the nature of the growth. Local extensions and metastases
occur late but after imperfect removal, recurrence, rapid extension, metas-
tases and cachexia supervene, so that the general prognosis is unfavorable.
Structure. — (i) The typical perithelioma presents a very characteristic
structure. It is composed of a congeries of small vessels of the type of
arterioles sheathed with large polyhedral fusiform or rounded cells which

FIG. 107. — Topography of a true perithelioma.

radiate in numerous layers from the vessel-wall. At a certain distance from
the vessels nutrition often fails and the cells undergo anemic necrosis which
serves to isolate and emphasize the vascular units. In many tumors the
vessels disappear, the growth is of diffuse large spindle-cells and the tumor
resembles simple sarcoma. Giant-cells of small and large dimensions with
multilobed nuclei are a frequent and characteristic feature, especially in the
diffuse growths. Intercellular substance appears in many of these tumors
and completes the resemblance to sarcoma.

2. An alveolar arrangement of distinctly polyhedral or cylindrical cells
appears in another group of peritheliomas, especially in tumors of the carotid
gland, bone, and skin (Paltauf, Hildebrand, Hanke). Since the cells remain
polyhedral or rounded, and intercellular substance is scanty or absent, these
tumors resemble endothelioma. At present their exact position must remain
uncertain.

In both structural varieties of perithelioma, the walls of vessels and the

330 NEOPLASTIC DISEASES

stroma and tumor-cells may undergo hyaline and especially mucoid degenera-
tion. Some tumors described as myxosarcoma are probably myxomatous
forms of perithelioma. The hyaline degeneration may produce the structure
of cylindroma.

Clinical Types of Perithelioma. — i. The subcutaneous tissue is one of
the chief seats of typical perithelioma. The loose tissues of the anal region,
orbit, axilla, popliteal space, and regions of embryonal fissures, but not the
more exposed regions, furnish the exact points of origin, and this distribution
suggests a relation to embryonal disturbances of superfluous tissue.

The deep fasciae and intermuscular septa are sometimes the point of
attachment of peritheliomas which soon appear to be subcutaneous, as
described by Kolaczek, Tillmanns and others.

The buccal mucosa over the hard and soft palate is the seat of a well-
defined clinical group of typical perithelioma which has been emphasized
by Eisenmenger (Lit.).

2. The pia mater is the seat of a group of somewhat atypical perithe-
liomas. A well-circumscribed growth 5 cm. in diameter, displacing the brain
tissue, with cells concentrically arranged about numerous blood-vessels
as in angioma, was early described by Arnold. A flat tumor of the dura
mater of the base, involving roots of several cranial nerves and composed of
many small vessels lying among loose round and polyhedral cells, was inter-
preted as a peri-endothelioma by Wells. It contained calcific areas and bone
spicules. In the brain substance perithelioma has been described by Wald-
eyer and Billroth, and many others, and Waldeyer showed that these tumors
had previously been mistaken for primary carcinoma of the brain (Eberth,
Arndt). Probably the majority of bulky sarcomas of the brain substance
present this structure.

3. In the bones perithelioma appears as a soft vascular tumor, often
pulsating, which early perforates the shaft, may invade the surrounding
tissues and tends to produce distant metastases (Jaffe). Hildebrand has
collected a series of cases and describes one in which the congeries of vessels
was plainly evident in the gross. The origin he finds to be in the bone
substance and the growth is often preceded by trauma or fracture (Kocher,
Lucke). Howard and Crile interpret nine cases in the literature and three
of their own as arising from perivascular endothelium which they identify
with perithelioma. The cells are epithelioid in form and their arrangement
is either alveolar or tubular. It is not certain that all the tumors described
under this term have been clearly separated from endothelioma or from
epithelial tumors derived from aberrant cells groups. Many have been
described as angiosarcoma, and before the studies of Billroth and Waldeyer
they were commonly regarded as primary carcinoma of bone. They are
probably identical with angio-endothelioma.

4. In the breast perithelioma is one of the common forms of vascular
sarcoma. It occurs chiefly in adults after 50 years as a single circumscribed
small or large tumor movable in the breast but usually adherent to the skin.
The density, retraction of skin, and involvement of lymph-nodes of carcinoma
are absent. Growth is slow but recurrence after operation is frequent
(Schmidt).

In the ovary, among the many forms of so-called endothelioma there is
one described by Amann which has certain features of perithelioma.

5. In the kidney, Paoli and others have described large vascular tumors
which they interpreted as perithelioma, but it seems highly probable that
these growths should be divided among adenocarcinoma of the kidney and
hypernephroma. The cells exhibit epithelial characters. The cases of

EN DOTH ELI OM A

331

angiosarcoma of the liver described by Arnold exhibited the structure of
this type but whether they are primary or secondary remains to be shown.
In cases of primary carcinomas of the liver, areas of typical perithelioma are
very frequent (L'Esperance).

6. Perithelioma of Carotid Gland. — Since the appearance of the simul-
taneous studies of Marchand and Paltauf describing a characteristic tumor
of the carotid gland, many other cases have been reported, minute analysis
of the structure of these tumors has repeatedly been made, and the normal
histology and embryology of the gland itself has been thoroughly investigated.

While Marchand suggested the origin from perithelial cells, and Paltauf
fully accepted this view, later observers have been less confident regarding

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the exact nature of the growth. Kauffmann employed the term alveolar
tumor, and compared it to a hamartoma, in which all elements of the gland
participated. The complex structure of the organ, as shown by Kahn,
Stilling, and Monckberg, may serve to explain many peculiarities of the
tumors and the difficulty of devising a satisfactory designation. While the
tumor belongs in a class by itself, the term perithelioma recalls a prominent
structural feature and has been very generally employed.

These tumors arise usually about puberty and slowly reach sufficient
dimensions to protrude from the side of the neck, producing a deformity which
has been pictured in detail by Keen and Funke. Their location is first
upon and behind the bifurcation of the carotid artery which is often inclosed,
compressed and even invaded by the growth, Prolongations run in various

332

N EOF LAST 1C DISEASES

directions, upward toward the skull, inward tophaiynx (Reclus), and down-
ward. Most of the tumors are rounded, lobulated and encapsulated. Rup-
ture of the capsule may occur (Monckberg, Leithoff). They are firm or
soft, may yield a bruit, frequently pulsate, and Reclus was able to largely
obliterate a tumor by compression. On section they are vascular, grayish
red, or slightly brownish from chromaffine substance in the specific cells. The
markings show vessels, plexiform cell masses, concentric structures, and
hyaline areas.

The growth is slow, occupying years. Heinleth observed a very large
tumor existing over 30 years. While numerous adhesions form and vessels
may be infiltrated and penetrated, a skilful enucleation is usually successful
in preventing recurrence, but Licini estimates the mortality from the opera-
tion at 35 per cent. In several cases recurrence has followed operation,

FIG. 109. — Structure of a carotid gland tumor.

and the cervical lymph-nodes have been found involved (Kaufmann, Kretsch-
mar, Kopf stein). General metastases are not observed.

The structure is in general that of an alveolar perithelioma but varies
in many details. Post-mortem changes occur rapidly and only prompt
fixation of operative material in Zenker's or Orth's fluids preserves the
true structural detail.

The chief cells are distinctly polyhedral, granular, and may contain chro-
maffine substance. They are arranged in compact groups without lumen
but surrounded by hyperplastic endothelium lining the numerous capillaries.
Much larger cell groups are often observed, the central portions of which are
prone to degenerate and form cavities in which blood may be found. Definite
capillaries may also traverse the cell groups (Monckberg). Hyaline degen-
eration of the cells gives rise to intracellular globules, and affecting the stroma

ENDOTHELIOMA 333

produces peculiar knobs projecting into the capillaries (Kaufmann). The
numerous vessels may produce a cavernous tissue or they may be much re-
duced in hard tumors. They are lined by prominent endothelial cells which
sometimes grow out into the vessels in syncytial buds, or mingle with the
chief cells of the tumor, producing complex pictures. The stroma may be
scanty and acellular or hyaline, or infiltrated with tumor-cells, and Leithoff
describes a case in which he regarded the stroma as sarcomatous.

These and many other structural details which appear in many combina-
tions in the reports of numerous authors show that the tumors of the carotid
gland are sui generis. Both the specific cells and the endothelium paitici-
pate in the tumor process, yielding organoid growths involving the entire
gland. Although Monckberg thought he could identify ganglion-cells in one
case, the numerous non-medullated nerve-fibers of the normal gland appear
only in traces and do not participate in the tumor process. Since the tumors
arise about the period when a physiological regression usually overtakes the
gland, some disturbance in the course of this regression may be an etiological
factor (Heinleth). Advanced osteomalacia occurred in a case of Oberndor-
fer's, and various authors mention other possible etiological factors.

CHAPTER XXI

LYMPHOMA AND LYMPHOSARCOMA

Two important physiological properties influence the conception of
tumors of lymphoid tissues.

First, lymphoid tissue responds to irritation with inflammatory hyper-
plasia far more actively than any other tissue. Second, lymphoid tissues
are relatively mobile rather than fixed, and lymphocytes are not only ame-
boid but are structurally placed in easy access to lymph and blood paths.
Hence tumors and tumor-like processes in lymphoid tissues are frequent and
as a rule tend to become widely diffused. These same factors render unusually
difficult the distinction between simple and neoplastic hyperplasia of lym-
phoid tissue, by introducing special standards, both clinical and anatomical,
in the interpretation of lymphatic hyperplasia.

For these reasons the discussion of lymphoma in general necessarily
includes the consideration of various processes, some of which are chiefly
inflammatory, some neoplastic, and others intermediate in position. Lack of
knowledge of etiological factors, the intricate relation of many forms of
lymphoid hyperplasia, and the occasional transformation of one process to
another, render this method of treatment practically advantageous and
theoretically sound.

Extensive tumor-like hyperplasia of lymphoid tissues occurs in the
following scheme of clinical conditions: (i) Simple lymphoma; (2) leuke-
mia, lymphatic and myelocytic, in its various phases; (3) pseudoleukemia;
(4) Hodgkin's disease; (5) lymphosarcoma.

The complexities of the subject of lymphoid tumors depend chiefly upon
the lack of knowledge of etiology and partly upon the lack of accurate ana-
tomical classification. It seems to the author that some advantage would
result from the rigid application of simple anatomical principles in the classi-
fication of these processes, even at the risk of carrying the anatomical dis-
tinctions too far.

Anatomically there are three elements in lymphoid tissues capable of
originating lymphoid tumors, viz.: (i) lymphocytes; (2) reticulum cells of
follicles and pulp, and (3) endothelial cells of pulp and cavernous sinuses.
Connective tissue cells, endothelium of vessels, and cells of vessel-walls do
not appear to be concerned in the common tumors of lymph-nodes.

Classified according to present indications of histogenesis, tumors of
lymphoid tissue appear as follows:

Origin
Lymphocytes

Reticulum cells

Endothelial cells

Anatomical Type
Lymphocytoma

Large round-cell hyperplasia
or neoplasia

Endothelial hyperplasia or
neoplasia

334

Clinical Type
Simple lymphoma
Tuberculous lymphoma
Lymphatic leukemia
Pseudoleukemia
Malignant lymphocytoma

Granuloma malignum
Myeloid leukemia
Hodgkin's sarcoma
Large-cell lymphosarcoma

Endothelial hyperplasia -

of tuberculosis, etc.
Endothelioma

LYMPHOMA AND LYMPHOSARCOMA

335

Several difficulties stand against the finality of this classification.

i. The relation between lymphocytes and reticulum cells is not fully
determined. While the older anatomists, headed by Flemming, held that
reticulum cells of the follicles become transformed into lymphocytes, prac-
tically all the recent work indicates that the two types of cells are entirely
separate (Gulland).

It would greatly simplify the questions of histogenesis if separation of the
two types of cells were established. Most pathologists, however, the writer
among them, are unable to satisfy themselves that reticulum cells during the
course of inflammatory and neoplastic changes may not assume the form of
lymphocytes. Yet the separate nature of the two cell types is of such great
importance in the study of lymphoid tumors, that it seems wise to accept

FIG. no. — Multiplication of follicles in simple chronic lymphadenitis, in postpyloric
nodes draining a chronic ulcer of stomach.

the dictum of embryology until it is proven incorrect. In most pathological
processes the two cell types undoubtedly maintain their individuality.

2. The distinctions between reticulum cells and sinus endothelium are
much less definite. In fact, in the development of lymph-nodes both arise
from modified mesoblastic cells. Yet in a study of endothelioma of lymph-
nodes the writer has brought evidence to show that the reticulum cells
give origin to the large-cell lymphosarcomas, while the sinus endothelium
yields tumors of a different structure.

3. While the lymph-nodes in lymphatic leukemia contain an excess chiefly
of lymphocytes, the origin of the larger round-cells in the nodes of myelocytic

336 NEOPLASTIC DISEASES

leukemia is not satisfactorily determined. Their classification as derivatives
of reticulum cells must be regarded as tentative.

4. If a complete solution of the etiology of lymphoid tumors were provided
it might destroy much of the value of an anatomical classification. The
best known excitant of lymphoid enlargements, tuberculosis, produces over-
growth of lymphocytes, extensive or exclusive hyperplasia of reticulum
cells and endothelium, and also introduces many blood-cells by exudation.
Hodgkin's granuloma exhibits similar or identical tendencies.

Yet there is much value in classifying lymphatic tuberculosis from the
anatomical standpoint, and similar value may remain for the anatomical
subdivisions of other diseases when their etiology is known. For the definite
tumors of lymph-nodes this objection loses much or all of its force, but it is
difficult to determine when one is dealing with a granuloma or a tumor of
this tissue. ,

SIMPLE LYMPHOMA. LYMPHADENOMA. HYPERPLASTIC
LYMPHADENITIS

Local or regional, circumscribed, chronic enlargements of lymph-nodes
which are self limiting and do not lead to systemic invasion are rather
common pathological conditions (Le Count, Lit.). They appear in the
neck, axilla, groin, subcutaneous tissue, submucous tissues, parotid and
other glands, and occasionally in other regions. They form solid masses
of tumor-like dimensions and firm consistence, and on section exhibit a
smooth opaque uniform surface often presenting firm, light, more prominent
areas, and revealing little or no tendency toward degeneration or necrosis.
They may be composed of a single node or a congeries of nodes with fused
capsules. After reaching a certain limit of giowth they may remain station-
ary for months or years producing only local symptoms. The tendency
toward regression is slight. I have observed a simple lymphoma of four
years duration occurring beneath the skin of the scapular region which failed
to show signs of regression or fibrosis. The prolonged course is a feature of
many cases, that of Le Count continuing for 15 years but still showing
hyperplastic germ follicles. The tumor described by Wagner and Hewitt
reached dimensions of 7 X 5 cm. in six years. Internal growths of uncertain
history may be found at autopsy.

The structure varies at different periods but is dominated by diffuse
overgrowth of typical small lymphocytes. In early stages lymph follicles
are increased in size and number, are readily visible in the gross and exhibit
enlarged germ centers, the pulp tissue is composed of closely packed lympho-
cytes, the sinuses are indistinct or obliterated, the vessels compressed or
packed with lymphocytes; or the normal landmarks are obliterated by a
diffuse growth of lymphocytes and the distended capsule is infiltrated.
Simple lymphoma may be separated from leukemia by the blood test, and
from pseudoleukemia by its local character, but from neither on the histolog-
ical structure alone. From lymphosarcoma the diagnosis may be difficult,
and should be based on the absence of the usual signs of malignancy, as rapid
growth, mitotic figures, active destruction of trabeculae and capsule, and
atypical quality of the cells.

However obvious may be the inflammatory origin of many cases of
simple lymphoma, the excessive hyperplasia, prolonged course, and often the
apparently idiopathic origin renders the condition of interest in the field
of tumors and requires the recognition especially in chronic cases of certain
features of true neoplasms.

LYMPHOMA AND LYMPHOSARCOMA

337

I have observed one case, structurally requiring classification as lymph-
adenoma, persisting for 18 years and eventually proving fatal with rapid
local growth and asphyxia (Figs, in, 112, 113).

In the etiology of simple lymphoma many forms of chronic bacterial
infection appear to be concerned, especially tuberculosis. According to
Paltauf the regeneration of lymphocytes following an acute infection may
be excessive and prolonged, giving rise to a tumor-like overgrowth which
persists long after the removal of bacteria and their products. In the case
of tuberculosis, it has been shown by Bartels and others that the structure
of simple lymphoma may be exhibited by lymph-nodes harboring viable
but attenuated tubercle bacilli, and the frequency of simple lymphoma with-
out tubercle bacilli in tuberculous subjects suggests that this lesion may
be one of many which seem to be referable to atypical tuberculosis. Such

FIG. in. — Malignant lymphadenoma.

cases may be designated as paratuberculous lymphadenitis (Adami). In
certain cases it is impossible to establish any relation whatever to tuberculo-
sis, or any acute infection, or any chronic disturbance in neighboring mucous
membranes or tissues.

LEUKEMIC LYMPHOMA

The leukemic process in its entire scope illustrates many phases of hyper-
plasia of lymphoid tissue. This disease may exhibit as its anatomical
basis: (a) A transient leukemic blood picture with slight hyperplasia of the
cells of lymph-nodes or marrow; (b) acute leukemia associated with acute
hyperplasia of lymphoid tissues; (c) chronic leukemia, with leukemic lympho-
22

338 NEOPLASTIC DISEASES

mas and hyperplasia of bone-marrow; (d) chronic leukemia with partially
neoplastic hyperplasia of lymphoid and myeloid tissues; (e) chloroma.

While it is impossible to prove that leukemia is always caused by a single
infectious agent or that it represents anything more than a clinical entity
comparable to leukocytosis, these various lesions belonging to essentially
the same condition illustrate every gradation from an acute inflammatory
process up to a chronic and somewhat malignant neoplasm.

The lesions of leukemia both lymphocytic and myelocytic, involve the
bone-marrow, lymph-nodes, spleen, and the other preexisting lymphoid
tissues, while heterotopic growths of lymphoid tissue appear in the liver,

FIG. 112. — Malignant lymphadenoma. Same as Fig. in.

kidney, lung, skin, serous membranes, and many other organs. The picture
is that of a diffuse systemic involvement of blood-forming organs with
secondary invasion of other tissues.

In the bone-marrow the process begins in multiple hyperplastic foci
which enlarge, coalesce, and eventually extend the limits of lymphoid marrow
throughout all portions of the skeleton. At the height of the process the
new tissue is firm, light colored, opaque, or pyoid, or beset with foci of
infarction, necrosis, hemorrhage or mucoid softening. Fat cells, sinuses,
and all other normal structures of the marrow are commonly obliterated by a
diffuse growth of hyperplastic round-cells. Banti describes an initial hypere-
mia with widening of sinuses and atrophy of fat-cells. Islands of hyper-

LYMPHOMA AND LYMPHOSARCOMA

339

plastic marrow-cells then appear in and about the sinuses and these are
followed by pure lymphoid growths starting from the walls of arterioles and
gradually invading the entire marrow. The spongy trabeculae are often
absorbed and even the shafts may be thinned, but a distinctly aggressive
destruction of bone as in true tumors is missing. In rare cases of myelemia
there is widespread osteosclerosis (Schmorl).

In the lymph-nodes the disease appears in one or more chains spreading
to other chains and involving all the mdes of the chain simultaneously.
Bulky tumors are thus produced in which all the nodes remain discrete
or the capsules are fused by inflammatory reaction. The process in the
lymph-nodes differs in the two main types of leukemia. In myelemia the
pulp cords first show increase in size by the appearance of myelocytes which
gradually distend the cords, obliterate the sinuses, cause passive atrophy

*$^^,..,

FIG. 113. — Malignant lymphadenoma of cervical nodes. Detail of Fig. in.

of the lymph-follicles, and even infiltrate the capsule or the surrounding
fat tissue. Giant-cells and nucleated red blood-cells may be present, but
in the more pronounced lesions only large myelocytes are present.

In lymphemia the condition in the lymph-nodes varies. In some cases
there is hypertrophy of lymph follicles which become greatly enlarged and
fusing with the pulp cords convert the entire node into diffuse lymphoid
tissue. In such nodes the lesion is primary and these cases may be desig-
nated as lymphoplastic lymphemia (Pappenheim, Meyer, Heinicke,
Hirschfeld). In other cases the lymph-follicles fail to enlarge but seem
passively compressed by new growth of lymphocytes beginning in the pulp
cords. Opinions differ as to the relative frequency of the two types of
lesions. According to Walz, Pappenheim, Grawitz, Kelly, Gulland, and
Goodall, lymphemia is always primarily myelogenic, while Ehrlich and Pin-

340

NEOPLASTIC DISEASES

cus maintain that the whole lymphoid system may be primarily involved.
My own cases seem to illustrate both conditions but I have not seen active
growth of germ centers in lymph-nodes of leukemia. The extent of the
affection of lymph-nodes varies greatly. Thus Walz found scanty changes
in nodes, much in spleen and marrow; Pappenheim describes absence of
changes in nodes, few in spleen, much in marrow: while Meyer and Heinicke
record early and extensive lesions in nodes, later in spleen, and later and only
focal hyperplasia in bone-marrow. Turk ventures to conclude from clinical
signs that marrow lesions may be absent in early stages of lymphemia and
this view is substantiated by Rosenfeld and others who believe that the
marrow lesions may appear late in the disease.

The splenic lesions are very similar to those of the lymph-nodes. The
organ exhibits a diffuse enlargement, a smooth opaque surface and section,
areas of infarction and necrosis, but seldom any localized tumor growth. In
myelemia there may be a simple myeloid transformation of pulp with atrophy
of follicles. Here myelocytes, giant-cells, nucleated red blood-cells and

FIG. 114. — Advanced chronic myelocytic leukemia.

phagocytes are mingled, much as in the marrow. More often there is a
diffuse infiltration with cells of the myelocyte class. In late stages and
especially in very large spleens the cells are greatly reduced and fibrosis,
hyaline degeneration, hemorrhage and necrosis are prominent. In lymphe-
mia the follicles may be intact and enlarged but more often they are oblit-
erated by a diffuse growth of lymphocytes which lie loosely in the disordered
cords and sinuses.

In the submucous lymphoid tissues the process resembles that of the
lymph-nodes.

The heteroplastic deposits of leukemia occur chiefly in the liver. Here
there is a diffuse growth of round-cells in the capillaries which has little
tendency to destroy liver cords but miliary or larger lymphomas occur in
the portal canals. A certain grade of these lesions is practically constant
in all forms of leukemia. In lymphemia the portal nodules are more exten-
sive than in myelemia.

In the kidney leukemic infiltrations, focal or diffuse, frequently occur.
The cutaneous manifestations of leukemia are varied and complex (Oertel,

LYMPHOMA AND LYMPHOSARCOMA

341

Lit.). Lymphemia has been observed with spindle-cell sarcoma of the skin,
with multiple lymphomas, and with mycosis fungoides (Nekam, Pincus,
Lit.). The characteristic lymphomas appear as multiple nodules chiefly on
the face and neck or widely distributed as a papular eruption. They may
be preceded by or associated with other eruptions. The older lesions may
ulcerate (Nicolau). They are composed of lymphocytes grouped about
the vessels of the corium.

Cutaneous lesions occur with moderate frequency but in great variety,
and illustrate in their course many phases of a granulomatous inflammation
unfolding into a tumor-like process. The lesions include petechiae and
hematomas, vesicles and bullse, macules, papules, and pustules, and localized

FIG. 115. — Bone-marrow in lymphatic leukemia. Focal hyperplasia of small lymphocytes

in center of femur.

or diffuse tumors. There may be marked pruritus and terminal bronzing
(Hazen, Lit.). Very similar conditions occur without leukocytosis, as in
Hodgkin's disease, pseudoleukemia, and mycosis fungoides. In rare cases
the lesion is diffuse and universal (Arndt). Other organs and tissues are
occasionally the seat of leukemic infiltrations.

There has been much discussion regarding the origin and nature of the
heteroplastic deposits. Perhaps the majority of observers have concluded
that in both forms of leukemia the hepatic deposits arise from hyperplasia
of preexisting lymphoid structures in this organ which undergo simple
hyperplasia in lymphemia and myeloid changes in myelemia (Sternberg,
Lit.).

Some authors assume the existence of latent myeloid foci in liver, lung,

342

NEOPLASTIC DISEASES

etc., which serve as a source of the new tissue in myelemia (Dominici,
Hirschfeld, Walz). From these foci may arise the myeloid changes so often

!^*C»w|j^^Vra»»iR*1'*

%&^3$*Mtteas&S&*

FIG. 1 1 6. — Lymph-node in chronic lymphatic leukemia. Note the very uniform size and

distribution of the cells.

FIG. 117. — Chronic myelocytic leukemia. Section of lymph-node showing diffuse growth

of cells of uniform size.

seen in certain infectious diseases attended with anemia (Meyer, Heineke).
Others accept the local origin of the heteroplastic lymphomas of lymphemia,

LYMPHOMA AND LYMPHOSARCOMA

343

but deny the existence of myeloid foci. Thus Sternberg distinguishes
sharply between lymphemia and myelemia in the origin of their heteroplastic
deposits, and Meyer and Heineke deny that any myeloid foci exist in normal

FIG. 1 1 8. — Structure of spleen in a case of lymphatic leukemia. Focal and diffuse
overgrowth of lymphocytes, which are found in cavernous sinuses, pulp sinuses, pulp cords,
and in enlarged follicles.

nodes, spleen, or liver, although they find the source of lymphemic growths
in slumbering lymphoid nodules. At the other extreme Banti holds that all
heteroplastic leukemic nodules represent metastatic growths of embolic
cells.

FIG. 119. — Liver in lymphatic teukemia. Lymphocytic infiltration of portal canals and

hepatic capillaries.

At present it seems impossible to offer proof of the entire validity of any
of these theories. I believe, however, that too much importance may be

344

NEOPLASTIC DISEASES

placed upon the hypothetical lymphoid foci of such organs as the liver and
kidney. In the normal adult human organs such foci are conspicuously
wanting, but in lymphemia such organs rapidly develop lymphomas. For
the more distant lymphomas of skin, brain, and serous membranes, espe-
cially those which reach a bulky growth, it is more difficult to accept an origin
from preexisting lymphoid foci, while the origin from embolic leukocytes seems
much more probable.

Finally in those cases in which the lesions exhibit more definite neo-
plastic properties, as in the leukosarcomatosis of Sternberg and in chloroma,
it is highly probable that the laws of neoplasms control the development of
the heteroplastic nodules. Hence it is necessary to assume that in mild

FIG. 120. — Miliary lymphocytomas in the liver of lymphatic leukemia.

forms of lymphemia the heteroplastic nodules arise in loco while in the
more intense grades of leukemic hyperplasia they are chiefly embolic in
origin or else one must accept their embolic origin throughout. The latter
position seems to me the more logical and more in accordance with observed
facts.

In myelemia the evidence in favor of the embolic origin of heteroplastic
foci is much more direct. Myeloid foci do not exist in normal adult liver,
or spleen, and while they develop there in infectious diseases and in anemia
their constituent cells have not been satisfactorily traced to preexisting
cells in these organs. In leukemia the blood-vessels in and about myeloid
areas often contain thrombi of myelocytes and giant-cells which offer the
readiest explanation of heteroplastic nodules (Meyer, Heineke, Schwartz,

LYMPHOMA AND LYMPHOSARCOMA

345

Michaelis). Yet an embolic origin does not involve a neoplastic nature, if
as Sternberg claims, leukemic cells are normal marrow-cells produced in
large numbers, for sarcoma-cells are atypical and grow without normal
restraint. Yet Ribbert and others find that the leukemic cells are undiffer-
entiated and abnormal and exhibit in some degree the characters of tumor-
cells. In ordinary myelemia the myeloid areas show little of these neo-
plastic properties, but in the atypical and rare forms bulky tumors arise,
tissues are invaded, cells are atypical, and neoplastic characters are rather
obvious.

FIG. 121. — Leukemic deposits in the heart-muscle. Similar tumors in spleen and kidneys.
Enlargement of thymus and many lymph-nodes. (After Seelig.)

Changes in Blcod. — Closely dependent upon the organic lesions aie the
changes in the blood, the full discussion of which falls outside the scope of
this work. Briefly they consist in extensive increase of leukocytes and pro-
gressive anemia. In lymphemia the cells are small and medium sized lym-
phocytes in chronic cases, and larger undifferentiated lymphocytes or mononu-
clear cells in acute cases. In myelemia the new cells are chiefly neutrophile
myelocytes, many of which are of abnormally large size, atypical eosinophile
myelocytes, excess of polynuclear neutrophile and eosinophile cells, mast
cells, and various degenerative forms. While in typical cases the leukocytosis
is the first demonstrable symptom, it varies greatly in degree, in its relation
to the extent of the organic lesions, and in its permanence. While the
leukocytes may outnumber the red cells, leukemia occurs with small numbers
of atypical cells in the blood, and their numbers are subject to extensive
variations from numerous factors.

346 NEOPLASTIC DISEASES

The cause of the access of large numbers of cells to the blood-stream still
remains obscure. It is not dependent essentially on involvement of the bone-
marrow, since apparently identical marrow lesions in pseudoleukemia fail to
give leukocytosis. Multiplication in the blood-stream is a negligible factor.
The theory of circulating chemotactic agents is unsatisfactory (Gulland,
Goodall). In many cases it seems to be dependent upon the activity of the
hyperplasia in the organs, but the more aggressive the local process, in the
neoplastic sense, the less is the leukocytosis. It may appear in the late stages
of formerly aleukemic processes, and its inception has once been clearly
traced to rupture of the tumor mass into a large vein. Essential conditions
seem to include the association of a certain grade of hyperplasia with integrity
and patency of many small blood and lymph paths.

The course of leukemic lesions depends much on the rapidity of the proc-
ess. Acute cases steadily progress until the fatal issue. In chronic cases
there is a definite tendency for the cellular phases of the lesions to be followed
by fibrosis and there is a distinct limit to growth. Likewise the leukemic
lesions as well as the leukocytosis may be much altered by intercurrent
infections, treatment by arsenic, #-ray, or without assignable cause.

Atypical Leukemia. — Certain atypical forms of leukemia vary widely
from the common type and reveal the extensive scope of the anatomical
processes associated with the condition.

Leukanemia. — Under this term Leube first described a condition of pro-
gressive pernicious anemia with pronounced leukocytosis and cellular infil-
trations in the organs resembling those of leukemia. It has long been known
that in certain cases of pernicious anemia the marrow changes may be very
similar to those of leukemia (myeloblastic degeneration of Naegeli).

In such cases the leukocytes are increased and myelocytes are present in
considerable numbers. Meyer and Heineke report cases of pernicious anemia,
leukanemia, and atypical leukemia in which the organic lesions are practically
identical, and Preis and Nauwerck and Moritz describe cases in which the
blood picture at certain periods resembles that of pernicious anemia. These
observations seem to indicate that the leukemic process in a mild degree
may be established in many states of anemia which call forth excessive
proliferation and degeneration of blood-forming cells.

Mixed-cell Leukemia. — In rare cases of lymphemia myelocytes have been
found in the blood and slight myeloid changes in the organs ^ Weber). While
these cases suggest a mixed form of leukemia, Pappenheim and others inter-
pret the myeloid changes as a secondary process of compensatory myelocy-
tosis resulting from the anemia of the disease. More often a frank myeloid
leukemia appears to change into a large-cell lymphemia (Seelig, v. der Wey,
Wilkinson, Mellard, Turk). In these cases it appears probable that in the
advanced stages of the disease degenerative processes affect the myelocytes
so that they lose their granules without any genuine change in the type of
the disease. Thus Wolff and Michaelis describe cases of leukemia in which
they interpret the proliferating cell as the mother cell of both lymphocyte
and myelocyte. They believe that the acute leukemias are chiefly of this
nature. While Turk, Hirschfeld, and others argue strongly for the existence
of mixed and transitional cases of leukemia the evidence in favor of their
views is based chiefly on blood examinations, lacks the support of anatomical
studies of the organs, and is unsatisfactory.

Aplastic leukemia is a term applied by Wolff to a condition marked by
anemia, slight leukocytosis with 96 per cent, of large atypical lymphocytes,
lymphomas in the liver and a deficiency of colorless cells in the marrow.
The significance of such cases is not clear but the condition appears more

LYMPHOMA AND LYMPHOSARCOMA 347

closely related to pseudoleukemia. Extensive fibrosis occurs in the bone-
marrow in late myelemia so that this organ becomes virtually aplastic
(LehndorfT, Zak).

Leukosarcomatosis (Sternberg). — While the neoplastic nature of the
entire leukemic process has never received general endorsement it has long
been recognized that in certain cases the anatomical condition varies from
the standard type in the direction of a true neoplasm. The more conspicuous
features of such atypical cases have been emphasized by Banti who in view of
this evidence has claimed that the leukemic process, at least the lymphatic,
is always neoplastic. They consist of marked invasion of bone by the hyper-
plastic marrow, the penetration of the shaft and invasion of periosteum with
miliary leukemic nodules, the fusion of leukemic lymph-nodes, the appear-
ance of multiple nodules in serous membranes, the invasion of intestinal
and cardiac muscle by lymphomas, and the atypical structure, large size, and
indefinite character of the cells of leukemic infiltrations.

In a considerable series of cases a large sarcomatous tumor of the thymus
with leukemic blood picture has been the chief feature (Fabian, Lit.), so
that leukemia ^vith involvement of the thymus came to be recognized as an
atypical and malignant variety. Orth speaks of these growths as malignant
leukemic lymphoma. With thymic tumors the other lesions of leukemia
have not always been fully developed (Heubner). Lymphemia is not infre-
quently associated with an infiltrating process in the tonsils (Askanazy).

Other regions have also been the seat of lymphosarcomatous tumors with
leukemic blood picture. In a case of Warthin's the ileum was extensively
involved in a large abdominal tumor which extended to the kidneys, stomach,
and regional lymphatic system, but the marrow was normal. Of 90,000
leukocytes 86.6 per cent, were atypical mononuclears resembling those of the
tumor. Moritz reports a somewhat similar case of tumor of the cecum in
which spleen, nodes, and marrow were involved. Pernicious anemia with
terminal leukocytosis suggesting leukemia may occur with extensive sar-
comatous tumors of bones, lymph-nodes and spleen (Grawitz, Lazarus).

At this point is encountered the possibility that tumors essentially dif-
ferent from leukemia may discharge many cells into the blood and simulate
leukemia. The well-known case of Lucke's illustrates this event. Here a
round- and spindle-cell sarcoma of the axilla ruptured into a subclavian vein
and the patient died with extensive leukocytosis as in leukemia. That this
case was not leukemia is shown by the absence of lesions in spleen and lymph-
nodes. The blood contained many large round and spindle-cells. Martin
and Matthewson report several cases of lymphosarcoma with leukocytosis
in which they found it difficult to establish the diagnosis of leukemia. Where
the usual systemic lesions are present there seems to be no other alternative
than to class the condition with leukemia. In nearly all these atypical
cases the blood picture has varied from the usual types, and the abnormal
cells, not always very numerous, have belonged in the class of large undif-
ferentiated mononuclear leukocytes.

Out of this group Sternberg attempts to establish a special variety of
leukemia, leukosarcomatosis, which he would sharply separate from the
ordinary type, on the ground that it represent a true tumor process. The
atypical characters of the cells he regards as the expression of a neoplastic
quality, and he gathers from the literature a series of cases described chiefly
as lymphatic, acute and chronic, in which the presence of these cells and the
infiltrating characters of the organic process indicate the existence of a
neoplasm. Sternberg's views have been attacked by Turk and others,
who have shown that many of the anatomical features of leukosarcomatosis

348 NEOPLAST1C DISEASES

are observed in otherwise typical leukemia. Nevertheless Sternberg's
studies have been of service in contrasting different types of leukemia and
in showing that there are different grades of hyperplasia associated with
leukemia and that in some cases the process closely approaches a malignant
tumor.

Lymphoid-cell leukemia is a term applied by Wolff to certain cases in
which the blood contains many large indifferent mononuclear cells which he
interprets as leukocytic metrocytes. The structure of the organic lesions
in these cases shows many features of a neoplasm composed of proliferating
atypical leukocytes (Babes). This condition does not differ essentially
from Sternberg's leukosarcomatosis.

Chloroma. — The occurrence of greenish tumors of skull, vertebrae, ribs
and other organs had been recorded by many others before 1853 when King
employed the term chloroma for these growths. In 1854 Aran with Lebert
contributed an important study of the condition, but Recklinghausen in 1885
first recognized the lymphomatous nature of the process and its probable
relation to leukemia, as a systemic disease of the lymphatic system. The
association with a leukemic blood picture seems to have l^een recognized
first by Huber in 1878, but observations on the blood remained imperfect
until after Recklinghausen's study. In 1893 Dock fully reviewed the
history of the disease, confirmed the relation to leukemia, and later with
Warthin established the primary myelogenous origin of the tumors in their
case. Detailed hematological studies by Turk, Klein and Steinhaus, Stern-
berg and Fabian, have completed the parallel with leukemia by showing the
existence of both lymphatic and myelocytic types of chloroma.

The disease occurs chiefly in young males, average age 18.8 years, and runs
an active course terminating fatally within an average observed period of
5.5 months. More prolonged cases occur in older subjects. The tumors
appear chiefly in the skull, affecting the orbit, dura, sinuses, auditory region,
sphenoid and ethmoid sinuses, nares, antrum, pharynx, palate and alveolar
processes. The early symptoms are therefore often referable to the eye,
ear, nose and throat. Very often the tumors affect the sternum, vertebral
column, ribs, pelvis, and occasionally the long bones. In such cases the
distinctions from multiple myeloma are not clear. In the lymphatic system
the cervical, axillary, mediastinal, or other deep chains are always involved
in the lymphatic type, and have escaped in only one myelocytic case (Klein,
Steinhaus). The bone-marrow is regularly involved, sometimes rather
slightly or not at all, often very extensively (Sternberg). The spleen is much
enlarged, and the gastro-intestinal lesions may be extensive. The hetero-
topic deposits while irregular are a very prominent feature, occur in almost
every organ and tissue, and illustrate the widest scope of the leukemic
process. The liver and kidney frequently show deposits, and the pancreas
thyroid, thymus, ovaries, mamma, and prostate have been found involved
with tumor-like growths. A special tendency to invade the muscles and
their tendinous insertions is observed, the infiltration passing out from the
bone-marrow. The walls of vessels also suffer more than in typical leukemia.
In several cases there have been infiltrations, eruptions, or tumors in the skin
(Stevens, Hitschmann, Bramwell).

The most conspicuous gross feature is the color of the growths which
varies from a grass green to a faint greenish-yellow tinge, may be very pro-
nounced throughout the marrow and all the tumors, or may be limited to a
few areas. The heart clots and the sedimented leukocytes have been found
greenish (Trevithick). A similar color may be observed in the marrow
of typical acute leukemia. Its source is undetermined, but it has been

LYMPHOMA AND LYMPHOSARCOMA 349

referred to transformed blood pigment (Risel), or to fatty products of cell
metabolism (Sternberg). Huber and Chiari attributed the color to greenish
refractive lipoid granules which they found in the cells. Lang's surmise
that pigment-producing bacteria are present has been disproven by Lubarsch.
Since the coloration is not constant and may be observed in typical leukemia,
its presence is inadequate to separate the disease essentially from leukemia.

In form the tumors appear as broad flat masses 1-2 cm. thick, firm or
fibrous, surrounding the bones, invading muscles, tendons, and vessels,
stripping up the periosteum, or yielding more circumscribed nodular growths.
In the skull and spinal canal flat masses separate the dura from the bone or
perforate the meninges and invade neighboring tissues. The lymph-nodes
may reach large dimensions and become fused with each other. The lesion
in the marrow is diffuse or focal. Diffuse infiltrations in the mucous mem-
branes of eye, mouth, nose, throat, larynx, or gastro-intestinal tract produce
deformities and ulceration.

The blood picture in chloroma' varies extremely. The cases fall into
the two main groups, lymphemia, and myelemia, while in certain instances
the leukocytosis has been absent or transient. Hence one may assume that
there are leukemic and aleukemic chloromas of both lymphocytic and mye-
locytic types. The lymphocytic type is much the more common. Here
the circulating leukocytes have usually shown a large proportion of large
indifferent mononuclear cells. Yet the cells have varied greatly in size,
being small lymphocytes (Rosenblath, Stevens), or large lymphocytes (Dock
et a/.), while Trevithick commented on the extreme size of many cells. The
numbers of leukocytes also vary greatly, Bramwell finding only 8000, Stevens
491,000, while the increase appears early or late or is transient. Similar
variations occur in the myelocytic variety. Dock and War thin describe
many peculiar cells, including eosinophile myelocytes, which were abundant
in the tumor-tissue. Waldstein described a case of extensive chloroma in
which the blood picture of pernicious anemia suddenly became leukemic
in the terminal weeks.

The structure of the tumors accords with that of lymphocytic and mye-
locytic leukemia. In the former class there is diffuse infiltration with large
mononuclear non-granular cells displacing normal structures and exhibiting
considerable power to invade capsules of nodes, blood-vessels, and other
surrounding tissues. In the latter class the evidences of the myeloid charac-
ter have been pronounced and neutrophile myelocytes have been abundant.
In a case interpreted as lymphatic Warthin found a very large proportion
of eosinophile cells.

The chief significance of chloroma lies in the fact that it represents a
leukemic process of a pronounced neoplastic type. The bulky tumors, the
destructive local infiltrations, the distant heterotopic metastases, the atypical
character of the cells and their very active proliferation, provide all the
essential features of a malignant neoplasm. The process belongs with the
systemic sarcomas of blood-forming organs, affecting primarily either the
lymphatic system proper or the bone-marrow. It appears to differ only in
degree from the other more aggressive leukemic processes, so that Sternberg
includes it in his class of leukosarcomatosis. While the clinical course may
resemble acute leukemia the process is quite different from the ordinary
acute febrile leukemia, in that the cells are much more atypical, the local
process more aggressive, and the secondary growths are more clearly of
embolic origin and of much wider distribution. The evidence furnished
by chloroma especially the myeloid type, tells strongly in favor of the metas-
tatic origin of all heterotopic deposits in leukemia. Chloroma illustrates

350 NEOPLASTIC DISEASES

also the access to the blood-stream, permanent or transient, in small or
large numbers, of specific tumor-cells.

There has been much discussion of the relation between chloroma and
the lymphosarcomatosis of Kundrat, but the two conditions are anatomically
distinct. Being clearly a tumor of lymphocytes and myelocytes the observa-
tions on chloroma indicate that it has no relation to myeloma, although
albuminosuria has been detected in one case (Weinberger) and myeloma
may yield many tumor-cells to the blood-stream. Regarding the etiology of
chloroma nothing is known, but a combination with tuberculosis has been
observed in several cases (Horing, Schmidt, Lubarsch, Risel).

Plasma-cell Leukemia. — Turk has described the frequent presence in the
blood of a peculiar mononuclear cell with eccentric nucleus and amphophile
cytoplasm, the "reizungsformen," and Hoffmann has identified them with
plasma-cells. In a case of myeloma Schridde found in the blood typical
plasma-cells in small numbers, but Gluzinski and Reichenstein report a case
of myeloma in which a large proportion of 39640 leukocytes were of the
plasma-cell type, and they speak of plasma-cell leukemia. This isolated
observation of an unusual number of tumor-cells reaching the blood is,
however, quite inadequate to establish any relation between myeloma and
any form of leukemia. Myeloma varies in other directions than toward
leukemia, and it may be recalled that various tumor-cells even of cancer
have appeared in the blood.

Nature of Leukemia.— The foregoing data relating to the anatomical
process in leukemia seem to warrant certain conclusions regarding the nature
and position of this disease. The ordinary picture of leukemia is so character-
istic as to lead to the impression that it is a definite disease of uniform etiology,
but when the wide scope of the clinical features and anatomical lesions of
atypical leukemia are considered, the suspicion arises that this is not a
definite disease, but merely a variable symptom complex of diverse etiology.
From this point of view leukemia is comparable to leukocytosis. Both
conditions represent a response of the blood-forming organs to irritation,
but highly essential differences exist in the nature of this response. In
leukocytosis there is a transitory multiplication of leukocytes of normal type
which in its various phases may be regarded as covering the entire scope of
simple hypetplasia. The organic changes may be considerable but soon
subside when the irritant is removed. In leukemia on the other hand, the
response is from the first of a different type. Although transient leukemic
blood pictures occur, yet with rare exceptions the appearance of signs of
leukemia means the beginning of a progressive process which will terminate
fatally. It is possible that some peculiar etiological agent will be found to
explain this progressive quality, but it seems more probable that it depends
on the nature of the process rather than on its cause. Two main anatomical
features separate leukemia from leukocytosis, the abnormal types of cells
produced, and the permanence and extent of the organic lesions.

While there is much difference of opinion regarding the variations of
leukemic cells from normal leukocytes and their progenitors, it is acknowl-
edged that even in ordinary leukemia the new cells vary from the normal,
and that new, possibly ancestral forms appear, while in atypical cases the
cell changes may be quite pronounced. It is this variation in cell type
even more than increased numbers that distinguishes the leukemic process,
so that in recent times diagnoses are made of leukemia without leukocytosis.
Nor is this variation in cell type degenerative for it is not paralleled by
any of the severe, acute or chronic degenerative processes in leukocytosis.
Moreover it is accompanied by evidence of great proliferative capacity, such

LYMPHOMA AND LYMPHOSARCOMA 351

as mitotic figures in the circulating cells, increase in number beyond any
limit of leukocytosis, and by permanent enlargements of the blood-forming
tissues. That all these variations are steps in the direction of a neoplasm
seems to the writer an inevitable conclusion. Leukemia represents more
clearly than any other condition the phases of neoplastic transformation.

Yet it is not necessary to dismiss all leukemias as frank tumor processes.
In the numerous discussions of the neoplastic theory of leukemia, controversy
has arisen not so much regarding the existence of neoplastic tendencies which
have always been recognized but on the hasty classification cf leukemia with
tumors.

Thus Banti, who emphasizes the tumor nature, especially of lymphemia
(of myelemia he is less certain), seems to overlook important distinctions
between acute febrile leukemia and prolonged chloroma. In the former,
local aggressive properties are almost entirely wanting, the infiltrating cells
show great respect for the invaded tissues, the lymph-node lesions may be
very moderate, local lymphomas may be scanty, and any neoplastic quality
present is confined to simple multiplication of atypical cells, while an acute
toxic process is prominent. In chloroma on the other hand a very different
grade of neoplastic properties is present, and the effects are so different that
it seems unwarranted to exactly identify the two processes. Sternberg
assumes a more defensible position in drawing the tumor line at the locally
aggressive lesions of leukosarcomatosis. Below that line leukemias are for
him peculiar forms of leukocytic overgrowth, above it they are neoplasms.
Yet for the reasons mentioned there seems to be no ground for assuming that
the specific quality in the leukemic process is anything other than neoplastic.
Admitting that there are all grades of neoplastic hyperplasia this theory
accounts for the essential -peculiarities of leukemia and admits of a uniform
conception of the process in all its phases. The conception of leukemia as
essentially neoplastic does not exclude the most complex etiology nor a close
dependence of the process upon irritants or parasites. The general facts of
the disease rather strongly suggest the continued presence of an irritant, of
toxic or bacterial nature as the exciting cause of the hyperplasia. If any one
known bacterial agent is chiefly concerned it is the tubercle bacillus. The
comparatively frequent association of some form of tuberculosis with lym-
phemia and the known tendency of tuberculosis to induce extensive lymphoid
hyperplasia even without the demonstrable presence of the bacillus, creates
a strong suspicion that this organism is a frequent excitant of leukemia.
It seems possible that in tuberculosis may eventually be found a connecting
link between lymphemia, pseudoleukemia, some cases of Hodgkin's disease,
and some forms of lymphosarcoma. Among the other possible factors has
been suggested the impulse toward lymphoid hyperplasia given by the
typhoid process, a field in which specific data remain to be gathered.

For the etiology of myelemia there are even less definite indications but
here the numerous factors which excite anemia, call forth the regeneration
of granular leukocytes, and injure the bone-marrow, may well be kept in
mind. That local and general predisposing factors exist can only be assumed
from analogy. Leukemia is chiefly a disease of early years when the blood-
forming organs are relatively active.

PSEUDOLEUKEMIA

In 1865 Cohnheim applied the term pseudoleukemia to a condition
anatomically resembling leukemia but with reduction of leukocytes in the
blood. His patient in the course of nine months developed a greatly enlarged

352 NEOPLASTIC DISEASES

spleen with prominent follicles, diffuse hyperplasia of cervical, inguinal,
mediastinal and retroperitoneal lymph-nodes, miliary lymphcmas of liver,
and extensive diffuse lymphoid infiltration of the kidneys.

Since that time many authors have described as pseudoleukemia miscel-
laneous forms of systemic disease of the lymphatic system without leukocy-
tosis, so that the term came to have a very wide scope. In recent years
extensive inroads have been made upon the domain of pseudoleukemia,
so that to-day it is somewhat doubtful in the minds of many if there is any
condition to which this term may properly be applied.

The first definite condition to be separated from pseudoleukemia was
lymphatic tuberculosis.

Lymphatic Tuberculosis.- — That general tuberculous lymphadenitis can-
not always be distinguished clinically from pseudoleukemia was early recog-
nized and the scope of the disease was by some widened to include such cases.
Many of the cases of intermittent fever with swelling of lymph-nodes de-
scribed by Pel, Ebstein, Renvers and others, probably belong in this class
(Combemale). In 1887 Del afield showed that the course of pseudoleukemia
could be exactly imitated by lesions of lymph-nodes which were typically
tuberculous, with miliary tubercles, foci of necrosis, and stainable bacilli.
Waetzoldt, however, found nodes which showed pure lymphoid hyperplasia,
with scanty foci of hyaline material and yet many tubercle bacilli in sections.
Finally Brentano and Tangl described a\:ase in which with tuberculous ulcer
of cecum and peritonitis the thoracic and retroperitoneal lymph-nodes showed
only lymphoid hyperplasia, no bacilli in sections, but inoculation proved
positive. In Sabrazes' case of " lymphadenoma " the firm nodes showed
lymphoid hyperplasia without caseation, while in lungs, liver, spleen, and
peritoneum were miliary Iymphomas5 microscopic criteria of tuberculosis
were absent, but rabbits inoculated died with tuberculosis.

It thus appears that the clinical picture of pseudoleukemia may be asso-
ciated with: (i) Ordinary miliary and caseous tuberculosis of many lymph-
nodes (Delafield); (2) Frank tuberculous lesions in one locality and pure
lymphoid hyperplasia of many nodes which yield no stainable bacilli but
prove infective (Brentano, Tangl); (3) pure lymphoid hyperplasia without
stainable bacilli, but giving positive results by inoculation (Waetzoldt,
Sabrazes).

In all these cases in which a tuberculous infection has been demonstrated
it appears that the extent of the lesion is rather less general and locally
more destructive than in many examples of pseudoleukemia. Yet the purest
forms of the disease exhibit these same characters as compared with leukemia.
That the tuberculous infection in all these cases may be secondary or unre-
lated to the pseudoleukemic process appears to the writer quite unworthy
of consideration. On the contrary there can be no doubt that the clinical
picture and anatomical lesions of pseudoleukemia are often produced by
tuberculosis.

HODGKIN'S GRANULOMA. LYMPHOGRANULOMA

A considerable group of the cases formerly classed as pseudoleukemia
present a specific histological structure which is now regarded as pathogno-
monic of Hodgkin's disease. The Vienna school of pathologists early recog-
nized this characteristic structure and Sternberg clearly described it in a
group of cases in most of which he claimed to find tubercle bacilli. This
specific histology has been emphasized by Reed. The structure shows
diffuse cellular hyperplasia with varying proportions, sometimes excessive,
of proliferating endothelial cells, endothelial giant-cells, plasma-cells and

LYMPHOMA AND LYMPIIOSARCOMA 353

eosinophile leukocytes. While there are numerous variations in the pro-
portions of these cells, especially of the endothelium, the typical picture of
Hodgkin's granuloma with the confusion of so many cell forms is unmistaka-
ble, is very probably caused by a single agent, and forms a rational basis
for classification of many obscure cases of clinical lymphomas.

Unfortunately the clinical picture of Hodgkin's disease is not always asso-
ciated with this particular histological structure. It is the common experience
of pathologists, as stated by Christian and Warthin, to find an absence of the
typical picture described by Sternberg, in nodes removed under the diagnosis
of Hodgkin's disease, and in its place indefinite forms of lymphoid hyperplasia.
Without the knowledge of the etiological factor it remains almost as difficult
as before to determine the true scope of this infectious granuloma, for all
the phases of the disease cannot be recognized with the same certainty.
It is not known for example whether a pure lymphoid hyperplasia, or a pure
plasmoma (myeloma), or pure endothelial hyperplasia belong in this group,
and these questions cannot be settled until the problem of etiology is
determined.

In this dilemma one may follow the plan adopted by H. Ziegler and include
under Hodgkin's disease all conditions which seem to have any probable
relation to the specific process. This plan means hardly less than to replace
the term pseudoleukemia with Hodgkin's disease. Thus Ziegler describes
Hodgkin's disease as (a} Acute, (b) Localized, (c) General, (d) Mediastinal,
(e) Larval, (/) Splenic, (g) Osteitic, (h) Atypical (Intestinal form, Mikulicz
disease), (i) Mycosis fungoides.

In the description of these forms he includes many histological processes
which differ considerably from Hodgkin's granuloma and whose relation
to which is far from certain. Nevertheless there is a strong probability
that the scope of this disease is very wide and that the above classification
deserves adoption as a working hypothesis, The writer would prefer to
exclude from Ziegler's scheme such diseases as multiple myeloma, mycosis
fungoides, and any form of systemic pure lymphocytic hyperplasia.

Clinical Course. — The disease occasionally exhibits as prodromal symp-
toms an itching or eczematous eruption of the skin which may precede other
symptoms by months or years, bears considerable relation to the subsequent
course of lymph-node lesions, and may result in the definite and progressive
cutaneous lesions of Hodgkin's disease. Gastro-intestinal disturbances
may also be observed (Rolleston, Bramwell).

More often the initial symptom is enlargement of a chain of lymph-nodes,
cervical (50 per cent.) axillary, inguinal, and the continuous or irregular
extension to other chains. A splenic tumor develops in 60—70 per cent, of the
cases, and may reach very large proportions. At the same time and with
equal frequency the liver enlarges. With this generalization of the disease,
fever, night sweats, anemia, and cachexia appear. The fever occurs early
or late, may be slight or absent, but is often of sharply intermittent type,
and may dominate the clinical picture.

The anemia is of the secondary chlorotic type and may become severe or
pernicious. The leukocytes are usually under 10,000, often there is leuko-
penia, occasionally leukocytosis of 30,000 or more. Relative or absolute
lymphocytosis usually prevails, but the neutrophile cells are much increased
in exacerbations. Eosinophilia is so frequent and marked as to form an
important diagnostic sign (Bunting). Mast cells may be increased. Evi-
dences of a hemorrhagic tendency are frequently observed, as minute hemor-
rhages in skin, petechiae, or purpura hemorrhagica (Sabrazes, Hippel). The
terminal cachexia is marked by numerous extensions or inflammatory

354 NEOPLASTIC DISEASES

complications in many organs, and in about 25 per cent, of the cases by
miliary tuberculosis (Ziegler). Amyloidosis of spleen and other organs is
recorded in 22 cases (Fabian). The duration varies from a few weeks in
acute cases to many years, but is usually about 18 months. The cutaneous
lesions are more chronic. Clinical types are numerous.

Clinical Types. — (i) Acute cases lasting four and six weeks, marked by
fever, anemia, swelling of cervical and axillary nodes and spleen, or by general
swelling of lymph-nodes, lymphomas in liver, and cutaneous ulcers are
described by Hirschfeld and Isaak, and Beitzke. The structure of the
lesions is characteristic of Hodgkin's granuloma. Focal necrosis in liver,
nodes, and spleen are prominent in this group.

2. Chronic generalized lesions accompany the usual clinical course de-
scribed above. In this group several chains of superficial nodes, usually
the cervical, are extensively involved, and the lesion extends to thoracic
and abdominal nodes, spleen, liver, and bone-marrow. All the lymphoid
tissue of the body may be slightly hyperplastic. Secondary deposits in lungs
and serous membranes are often observed.

3. Splenic Hodgkin's disease occurs as a primary lesion of this organ or as
a part of the generalized infection. The peculiar color of the organ led
Benda to apply the term " porphyry spleen" to this condition. The primary
splenic lesion is extremely rare, some authors denying its existence. Yet
in a case described by Symmers and studied in this laboratory the structure
was practically identical with Hodgkin's granuloma. Primary splenic lesions
extending to the lymph-nodes appear to have been observed also by Kummel
who found tubercle bacilli in the tissues, while Doncaster has reported a case of
primary splenic lesion which is probably genuine. The great majority of
cases of primary splenomegaly which resemble Hodgkin's disease prove
on examination to belong elsewhere, chiefly among splenic neoplasms. For
the primary splenomegaly of Gaucher a relation to tuberculosis or Hodgkin's
disease seems improbable.

The secondary invasion of the spleen in Hodgkin's disease is common
and not infrequently the splenomegaly becomes the dominant symptom.
Here the primary lesion may appear in the peripheral nodes (Nowak) or in
deeper chiefly retroperitoneal chains. Remittent fever, anemia, and ca-
chexia are leading clinical symptoms. In a case lasting 16 months and
marked by severe febrile attacks with intermittent swelling of cervical nodes,
the spleen continued to enlarge and at autopsy was found to contain very
numerous necrotic foci surrounded by typical Hodgkin's granuloma. The
lymph-nodes showed only hyaline areas. Tubercle bacilli could not be
identified. Many of the cases of Ebstein's disease must be classed in this group.

4. G astro -intestinal Hodgkin's granuloma is an ill-defined condition
difficult to separate from tuberculosis on the one hand and lymphosarcoma on
the other. The group of diffuse lymphomas affecting a large portion of or
the entire gastro-intestinal mucosa (Stoerk, Wells, Symmers) must, I believe,
be given a separate position, since they differ widely in structure and dis-
tribution from typical Hodgkin's granuloma. There remains a considerable
group of locally destructive hyperplastic lesions located in any portion of
the gastro-intestinal tract, especially in stomach, ileum, and cecum, in
which the structure is distinctly granulomatous and in which tubercle bacilli
are missing. I have studied several cases of this type, with local ulceration
and extensive swelling of regional nodes, in which the lesions resembled
Hodgkin's granuloma. Coupland and La Roy have described typical cases,
but reports in the literature are scanty since most of the cases are interpreted
as lymphosarcoma.

LYMPHOMA AXD LYMPHOSARCOMA 355

5. Mediastinal tumors may form the chief lesion in Hodgkin's disease, and
their structure is usually typical of the granulomatous or of the sarcomatoid
process arising in the thymus. With or without enlargement of palpable
nodes it forms a bulky tumor of the mediastinum, compressing bronchi,
vessels and nerves with corresponding pressure symptoms. Extensions to
pleura, and pericardium, heart muscle, lung, liver, supraclavicular and axillary
nodes, have been observed. (Palma, Lorrain, Schottelius, Jacquet, Brigidi,
Piccoli). In the case of Weber and Ledingham a high grade of pulmonary os-
teo-arthropathy was observed. Although in this last-mentioned case the
structure was typical and extensions were chiefly regional, yet in most cases

FIG. 122.- — Retroperitoneal region in a case of Hodgkin's disease. Lymph-nodes,
mesentery and perirenal tissues are fused into a mass of granulomatous tissue \vhich oc-
cludes vena cava and constricts aorta.

the tumor is bulky, local invasive properties are pronounced, distant second-
ary deposits occur, and the tissue is composed chiefly of large round-cells
with few lymphocytes and no necrosis, so that many have regarded this
condition as true lymphosarcoma. In a case studied in this laboratory by
Symmers a bulky but encapsulated tumor occupied the mediastinum and had
caused ulceration of the trachea. The nodes on both sides of the neck were
difficult to separate from the tumor and the bronchial nodes were also
included in the mass. There were no distant deposits. The structure ap-
proached the sarcomatous type being composed of regularly placed bands of
dense connective tissue inclosing areas of large round cells derived from the

356 NEOPLASTIC DISEASES

reticulum, a few lymphocytes, giant-cells, and eosinophile cells. Here some
relation to Hodgkin's granuloma is probable but neopkstic characters seemed
to be present also. Leukemia occurs with somewhat similar processes in the
thymus, and in a case reported by Coenen it is difficult to determine whether
leukemia or granuloma should be recognized (cf. Tumors of Thymus).

6. Abdominal Hodgkin's granuloma often appears clinically as a larval
form of the disease, since enlargement of palpable lymph-nodes is late or want-
ing. In this group intermittent or continuous fever is common, the course
may be rapid, and a typhoidal condition is established. Local pain, gastro-
intestinal symptoms, jaundice and a diazo-reaction of the urine strengthen the
resemblance to typhoid fever.

The lesion usually begins in mesenteric or retroperitoneal nodes and
extends along the spine into the thorax. It may remain in the abdominal
nodes producing a bulky tumor (Symmers, Longcope), or more often extends
widely involving spleen, liver, lungs, bone-marrow, and eventually superficial
nodes. Or a primary affection of the cervical nodes may subside after
extensive invasion of the thorax and abdomen (Gutig). The lesions are
therefore the most extensive occurring in the disease.

The structure illustrates the typical granuloma and most of its varia-
tions. Focal or bulky necroses are common in severe febrile cases. Ziegler
describes excess of plasma-cells in lesions in some of his cases. The gross
appearance may strongly suggest a neoplasm and many cases have been
described as lymphosarcoma. In Symmers' case the tumor was composed
almost entirely of large, flat, endothelial cells.

7. Mikulicz1 disease is an infectious granuloma affecting the salivary and
lachrymal glands, occasionally the lips and eyelids. It has sometimes been
associated with leukemia; with systemic involvement of the lymphatic sys-
tem interpreted as pseudoleukemia; and with tuberculosis (Brun, Fleischer).
The cervical and axillary nodes, spleen and liver are often involved in the later
stages, and many of the symptoms resemble those of Hodgkin's disease. The
structure varies but in certain cases it has resembled Hodgkin's granuloma
(Haeckel, Jacobeus).

8. Bone-marrow lesions of typical structure are commonly observed in
generalized Hodgkin's disease, but as a rule the bone tissue and periosteum
remain intact. Ziegler, however, believes that many peculiar osteal and
periosteal lesions attributed to primary tumors of bone and marrow or to
obscure inflammatory processes belong in this group, and he has collected a
series of such cases, including myeloma with plasma-cells, and lymphosarcoma,
which he would class with Hodgkin's granuloma.

9. Dermal lesions occur in the course of many cases of Hodgkin's disease.
The itchy eczematous or urticarial exanthem that marks the,; prodromal
stages may be repeated throughout the later course and may lead to excoria-
tion, scarring, and pigmentation so marked as to suggest a complicating
affection of the adrenal. Or a bullous eruption may appear with extensive
erythema and scaling. A second group of lesions, clinically and anatomically
specific, have been designated as lymphogranulomatosis cutis. The specific
nature of certain multiple, nodular or ulcerated infiltrations of the skin,
formerly classed as pseudoleukemia, was pointed out by Groszin 1906, who
found in them the typical structure of Hodgkin's granuloma. Several cases
of this character, with or without systemic lesions have since been described
(Arndt, Lit.). Pick emphasized the prominent eosinophile cells, and Arndt
detected scanty acid-fast bacilli in one case. Extensive ulceration of the
skin occurred in Beitzke's acute case. Ziegler would here include nearly
all the cases of generalized lymphosarcomatosis of the skin, and it seems very

LYMPHOMA AXD LYMPHOSARCOMA

357

probable that some of the sarcoid growths in dermatological literature may
eventually be placed in this group. Ziegler finds many resemblances between
mycosis fungoides and lymphogranulomatosis, but the structure of the two
processes, as well as the clinical aspects, show notable differences, and Arndt
from a careful comparison is not disposed to identify the diseases.

10. Besides these more definite clinical varieties, lymphogranuloma has
been observed in many other organs as thyroid, pancreas, adrenal, heart and
voluntary muscles, esophagus, tonsils, breast, and ovary (Fabian, Lit.).
Jessup has described a typical case in the uterus. In the lower animals
the disease appears to be not infrequent (Ziegler, Lit.).

Structure. — Typical Hodgkin's granuloma presents a characteristic
structure on which depends its recognition as a specific disease. It consists

FIG. 123. — Diffuse growth of reticulum cells in a case of Hodgkin's disease.

of a recticulum in which lie a few small lymphocytes, large lymphocytes,
plasma cells, eosinophile cells, proliferating endothelium, and endothelial
giant cells. There are many variations in the proportions of these cells.
In the early stages lymphocytes are abundant but follicles and sinuses are
soon obliterated. The nodes on the outskirts of invaded chairs may show
a simple hyperplastic lymphadenitis, but the specific process attacks the
supporting tissue and endothelium and seems to cause little hyperplasia of
lymphocytes. Later the lymphocytes largely disappear with the multi-
plication of other cells. Endothelial proliferation is prominent from the
first, so that large, loose, rounded cells with clear cytoplasm and single or

358

NROPL A S TIC DISK A SES

multilobed hyperchromatic nuclei are an important diagnostic feature.
These cells may increase in size and number so that they may compose the
bulk of the tissue. When in excess they may appear as large, flat, almost
pavement-like cells, or as a collection of giant-cells, or as a diffuse growth
resembling sarcoma. They long resist the advance of fibrosis.

Eosinophile cells are usually numerous, sometimes extremely abundant,
occasionally absent. They are mononuclear or polynuclear, and they proba-
bly arise as a result of small extravasations of blood which mark the early
lesions. A peculiar brownish-yellow color of the Hodgkin's nodes on section
may perhaps be connected with this tissue eosinophilia Polynuclear neutro-

« %*^* *'

FIG. 124. — Diffuse endothelial overgrowth in atypical Hodgkin's disease. '

phile cells are not prominent. A few plasma-cells are regularly present and
they may become so numerous as to lead to the designation of plasmoma.
Necrosis is missing in the characteristic stages of the process, but in acute
febrile cases and in old and bulky lesions there may be focal or extensive
necrosis. Fibrosis becomes established in many advanced lesions and
acellular connective tissue in bands and masses composes a considerable
portion of certain bulky tumors.

Apart from the specific structure presented by typical stages of the process
and the variations which are readily derived from it, the scope of this granu-
loma is difficult to determine. Very early lesions are often typical and the
terminal stages are commonly recognizable. Besides the typical picture
described by Sternberg and Reed, characteristic cases may be associated with
pure lymphoid hyperplasia, various forms of proliferation of reticulum

LYMPIIOMA AXD LYMPHOSARCOMA 359

cells, as well as with subvarieties of tuberculosis (cf. endothelioma of
lymph-nodes).

The locally invasive and destructive properties of lymphogranuloma
constitute a notable feature. While the capsules of nodes long remain
intact, yet from many primary foci the surrounding tissues may be invaded
by a process which is typically granulomatous. The walls of blood-vessels
may be extensively invaded, and the lumina may be occluded by the new
cells. These appearances have often suggested that the process is sarcoma-
tous. Yet similar lesions are observed in tuberculosis and so long as the new
tissue maintains a typical structure it should not be classed with malignant
tumors.

Hodgkin's Sarcoma. — -The transformation of Hodgkin's granuloma into
a sarcomatous process occurs in a certain proportion of cases, and since the
new cells are of endothelial origin this tumor might be classed with endothe-
lioma. Yet the proliferating cells lose their endothelial characters and appear
as large round-cells, the tumors differ markedly in behavior from other
endotheliomas, and they constitute a considerable group of the processes
commonly called lymphosarcoma or pseudoleukemia, so that it seems admissi-
ble to consider them in this connection under the term " Hodgkin's sarcoma."

This process runs the clinical course of Hodgkin's disease, especially that
form which terminates in invasive and destructive lesions resembling
sarcoma. It also appears in single chains of nodes, chiefly the cervical, but
recurring after operation it goes on to a fatal issue. These cases correspond
to Billroth's malignant lymphoma. Mediastinal Hodgkin's disease furnishes
a large proportion of the cases terminating in sarcoma. The spleen and bone-
marrow are commonly involved but the more malignant the growth the less
extensive is its distribution. Metastatic growths of considerable extent are
found in the liver or lung. In Welch's case there was a metastatic tumor of
the spinal dura causing paraplegia. On section the tumors are soft and of
peculiar brownish yellow tint or more often firmer, fibrous, and opaque.

The structure varies from a close counterpart of Hodgkin's granuloma
to a tissue composed exclusively of large round-cells with faintly staining
granular cytoplasm and moderately chromatic vesicular nuclei. Large,
round giant-cells with multiple or multilobed nuclei may predominate.
The proportion of lymphocytes may be considerable, as in Karsner's case,
but in more definite neoplastic processes these cells are missing. The struc-
ture may not be uniform in all the lesions nor at all periods. The cells
are not lymphocytes but derivatives of the reticulum cells. That a true
lymphosarcoma composed of neoplastic lymphocytes may develop in
Hodgkin's disease has not been demonstrated. The original process does
not tend to stimulate the growth of lymphocytes.

That the sarcomatous structure represents a terminal stage of Hodgkin's
disease is strongly indicated by the observations of Yamasaki, Karsner,
and others, and has been clearly shown in Welch's case. Here a cervical
node removed six months before death showed Hodgkin's granuloma, while
the tumors removed at autopsy from neck, dura mater, liver, and lung showed
replacement of lymphocytes, chiefly by large round-cells resembling sarcoma.

Cases of this type are by no means uncommon. Many cases described
in the literature as lymphosarcoma are probably of this nature. Several
have been observed in this laboratory, including Welch's. From a com-
parison of their very characteristic structure with that of certain malignant
lymphomas I am led to believe that localized tumors of lymph-nodes of this
same origin are relatively common.

The exact position of this form of sarcoma it is difficult to determine.

360 NEOPLASTIC DISEASES

Its clinical malignancy may depend on the dissemination of an infectious
agent or its toxins, and the local recurrences are probably recrudescences in
new lymphoid structures. Yet the metastatic growths in dura and lung
and the changes in the type of the cells demonstrate that it is a malignant
tumor.

The histological signs of malignancy are not very pronounced. The per-
foration of capsules of nodes is slow, and liver tissue seems to be passively
displaced. A large mediastinal tumor I found still well encapsulated and an
ulceration of a bronchus appeared to be mechanical. The nuclei of the chief
round-cells are uniform and only slightly hyperchromatic. The tendency
to fibrosis is marked. Hence Hodgkin's sarcoma differs distinctly from true
lymphosarcoma, in the type of cells, in its slight invasive power, and in its
origin. Since Hodgkin's sarcoma is established by increasing proliferation
of cells incited by an inflammatory agent there must be transitional stages of
the change, and it becomes a difficult matter to decide when certain lesions
should be classed with the granuloma and when with sarcoma. This diffi-
culty has long disturbed the surgeon, and it appears throughout the case
reports of Hodgkin's disease collected by Ziegler. I believe that clinical data
are inadequate in this field and that the microscopical evidence of complete
predominance of one atypical cell, and usually the presence of metastases,
should be secured before the diagnosis of sarcoma is made. Hodgkin's
sarcoma is therefore unique among tumor processes and a disease sui generis.
It illustrates in the same patient and in its various gradations as a primary
tumor, the transformation of an infectious granuloma into a true neoplasm.
It demonstrates the relation of a tumor to the presence of a microorganism
or its toxins. Its malignancy is apparently founded upon peculiar features,
rather less upon cellular anaplasia than upon the association with a toxic
agent which is readily disseminated and seems to prepare the soil for its
subsequent changes.

Since the etiology of Hodgkin's disease is not determined, one is reduced
to speculation regarding the mode of dependence of the tumor process upon
the irritant. It seems reasonable to suggest that this condition is analogous
to the epithelioma arising upon lupus or syphilis and to assume that the
microorganism is present only in early stages, and that the tumor process,
established indirectly, progresses of its own momentum and apart from the
parasite.

In a recent study of thymus tumors I have collected evidence suggesting
that many of the cases of Hodgkin's disease exhibiting sarcomatous qualities
originate in the thymus, and that the peculiar characters of the infiltrating
cells are referable to their origin from the epithelial reticulum cells of the
thymus.

Etiology of Hodgkin's Granuloma. — The cause of Hodgkin's disease still
remains imperfectly determined, the majority of writers holding that it is
not tuberculous. The evidence supporting this position consists in the usual
absence of tubercle bacilli in sections, the negative results of inoculation,
and the specific structure. Karsner holds that the tuberculous lesion resem-
bling Hodgkin's may be distinguished by somewhat minute characters of the
giant-cells. Sternberg who originally described the condition as a peculiar
form of tuberculosis has partly modified his position and is inclined to admit
the existence of a non-tuberculous Hodgkin's granuloma.

The evidence in favor of the tuberculous origin is nevertheless somewhat
formidable.

In the material as gathered in New York where the disease is very common,
tuberculosis follows Hodgkin's disease like a shadow. Tuberculous stigmata

LYMPIIOMA AXD LYMPHOSARCOMA 361

or tuberculous family history or tuberculous lesions in the body are the rule.
In a case of phthisis I was much impressed by finding in three small adjoining
bronchial nodes miliary tubercles in one, diffuse lymphocytes in another, and
typical Hodgkin's granuloma in the third. The association of local or wide-
spread tuberculous lesions with Hodgkin's granuloma is frequently observed.
According to Ziegler about 20 per cent, of the cases show tuberculous lesions
in the organs, and in 10-12 per cent, tubercle bacilli have been demonstrated
by inoculation. Acute miliary tuberculosis often terminates the disease.

The idea of a mixed infection co-extensive with such widespread lesions
is a strained hypothesis. An examination of the protocols of many inocu-
lation tests shows that they were carried out in a perfunctory or incompetent
manner. Some observers used rabbits. Others employed small quantities of
single nodes in single guinea-pigs. In this laboratory four cases of Hodgkin's
disease have infected guinea-pigs with tubercle after a period of nine months
to one year. Yet Longcope failed to infect monkeys, and I have had negative
results in this animal with fresh emulsions and concentrated antiformin
sediment. While the stainable bacilli are usually missing, yet. Sternberg
found them in many cases. I have never found them numerous, but after
prolonged search have occasionally detected scanty acid-fast rods. It is
clear that acid-fast tubercle bacilli are practically absent in these tissues.
Yet they are regularly absent in many known tuberculous lymphomas.
Much's claim that a granular form of the tubercle bacillus exists in many
lesions demands attention in this field. Fraenkel and Much claim to find
many of the granules in the antiformin sediment of Hodgkin's nodes and in
sections of the bone-marrow stained by intensified Gram. O. Meyer found
them in eight of nine cases, the remaining case giving tubercle bacilli. I have
found these granules but am not convinced of their tuberculous nature. Long
ago Arrigo found slightly acid-fast tubercle bacilli and granules in old tubercu-
lous nodes. Such granules are regularly present in Hodgkin's disease but
again their nature appears uncertain. Sticker states that tubercle bacilli,
probably bovine, may be demonstrated in Hodgkin's granuloma by repeated
passage of material through guinea-pigs.

All of these data seem to me to require further consideration of the
tuberculous theory of Hodgkin's disease. Yet before this view can be
accepted several deficiencies in the evidence must be supplied. Espe-
cially the absence of stainable bacilli, and the negative results of inoculation
must be satisfactorily explained. Besides the tubercle bacillus, some other
microorganisms, including the sporothrix of Beurmann, and the oidia seem
to deserve consideration. Pick claims to have found Hodgkin's granuloma
in the nodes of a case of prolonged staphylococcus infection, and Mosler
found a very similar structure in leprosy. Several cases have occurred in
active syphilitic subjects (Fabian, Lit.). Syphilitic lymphoma may clinically
simulate Hodgkin's disease but it regresses promptly under iodides and it
has not been shown that syphilis can produce the characteristic structure of
Hodgkin's granuloma.

Recent studies by Bunting and Yates have centered attention on the
diphtheroid bacilli of Hodgkin's disease. These microorganisms are very
frequently but not constantly to be isolated from Hodgkin's lymph-nodes,
but they are present in many other diseases and their pathogenic powers in
monkeys are unsatisfactory. Torrey reports the isolation of five different
varieties, aerobic and anaerobic, of diphtheroids from Hodgkin's as well as
some other diseased lymph-nodes. He describes the constant presence of a
very minute anaerobic bacillus in the nodes, but its pathogenic properties
are feeble. Bloomfield has also identified this same minute anaerobic bacillus.

362 NEOPLASTIC DISEASES

SYSTEMIC ALEUKEMTC LYMPHOMATOSIS. TRUE PSEUDOLEUKEMIA

The observation of Cohnheim that the anatomical picture of leukemia
may occur without leukemic blood changes is constantly being verified.
While it may very well be that the blood changes are of secondary importance
and that their absence does not call for the separation of this form of pseudo-
leukemia from leukemia, nevertheless the enormous increase of leukocytes
in leukemia forms a very notable morphological feature of this disease, and
one which may prove to be of fundamental importance. Moreover the
pseudoleukemic counterparts of leukemia present some other peculiarities
not observed with leukemia, so that, adhering to the morphological criteria
on which we are chiefly dependent, there seem to be certain grounds for
recognizing a somewhat separate, although closely related position of this
group of cases.

The general features of aleukemic lymphomatosis have been clearly
stated by Wunderlich: "There is a peculiar disease, pseudoleukemia, which
is chiefly characterized by a gradual development of very numerous and
sometimes very large swellings of superficial and internal lymph-nodes, and
by peculiar deposits in the internal organs, especially in the spleen, also in
liver, less often in kidneys, gastro-intestinal lymphatic system, lungs, pharynx,
and elsewhere."

Histologically these widespread lesions have been found to consist in hy-
perplasia of lymphocytes, so that this form of pseudoleukemia is the counter-
part of the lymphatic type of leukemia.

Uniform microscopical distinctions between the pseudoleukemic and the
leukemic process have not been demonstrated. There is the same oblitera-
tion of sinuses and follicles, the respect for capsules, the wide diffusion of the
process, the tendency to fibrosis, and the exclusive participation of lympho-
cytes, as in leukemia. Baumgarten found that the leukemic nodes permit
the passage of injection fluids, while the pseudoleukemic do not.

The blood shows a relative lymphocytosis, and Ehrlich and Pincus find
that a slight absolute increase of lymphocytes is characteristic of pseudo-
leukemia, but this condition is inconstant. The anemia is less severe
than in lymphemia. The persistent lymphocytosis and low proportion
of neutrophile and eosinophile cells distinguish pseudoleukemia from
lymphogranuloma.

There are also certain clinical and anatomical features which frequently
separate pseudoleukemia from leukemia. Acute forms of pseudoleukemia
are very rare, most of the rapidly fatal lymphoid hyperplasias without leuko-
cytosis proving sarcomatous. Moritz' cases of acute pseudoleukemia bear
a suspicious resemblance to typhoid fever which may give very extensive
lymphoid hyperplasia. As a rule the pseudoleukemic tumors of lymph-
nodes are larger than the leukemic, and the invasions of organs while not
destructive are more circumscribed and tend to reach a large size. The
confluence of hyperplastic lymph-follicles in nodes and spleen I find rriore
frequently than in lymphemia. The exclusive presence of typical normal
lymphocytes is perhaps more uniform in pseudoleukemia. In the pseudo-
leukemic processes in the dog and fowl these distinctions are often quite pro-
nounced. None of them seems to furnish any ground for assuming that the
processes are essentially different.

The necessity of recognizing clinical subvarieties of this form of pseudo-
leukemia is not urgent. A pure lymphoid splenic pseudoleukemia with dif-
fuse hyperplasia of lymphocytes I do not find in the literature. Pappenheim,
who recognizes splenic pseudoleukemia, states that the group is heterogeneous

L I 'MPIIOMA A XD L \ 'MPIIOSA RCOMA

363

and imperfectly studied. Of the many forms of splenomegaly none shows
lymphoid hyperplasia. French writers recognize a cutaneous pseudoleu-
kemia (Jaccoud), but these cases seem to fall rather with lymphosarcoma.
Medullary lesions of general pseudoleukemia are often pronounced and con-
sist of focal or diffuse lymphoid hyperplasia. That a primary or predominant
medullary pseudoleukemia exists remains doubtful. The custom once com-
mon of interpreting the marrow lesions of certain cases of pernicious anemia
as medullary pseudoleukemia terminated with Litten's argument in 1877.
The excess of lymphocytes in the marrow of pernicious anemia, which may
sometimes approach a leukemic picture, is probably a secondary condition
and is not comparable to a primary pseudoleukemia (cf. Bloch and Hirsch-
feld). More recently a few cases of apparently pure and primary lymphoid
hyperplasia of the bone-marrow have been described. In the cases of Baum-
garten and Rubinstein this process
was associated with extensive osteo-
sclerosis and in one there were also
lymphomas of liver and dura mater.
Xothnagel's "lymphadenia ossium"
probably belongs in this group. In
a case of severe pernicious anemia
of acute aplastic type, Senator found
diffuse lymphoid hyperplasia of the
marrow. He interpreted the condi-
tion as medullary pseudoleukemia.
A similar observation is recorded by
Domarus.

The exact relation of these cases
to other forms of pseudoleukemia is
uncertain. Senator has collected a
series of cases in \vhich the marrowr
showed active lymphoid hyperplasia
and which, he thinks, indicates a
relation between pernicious anemia,
leukanemia, lymphemia, and pseudo-
leukemia. The identity of this
apparently secondary tissue lym-
phocytosis with the true pseudoleu-
kemic process appears doubtful (cf.

FIG. 125. — Ileum in diffuse gastrointes-
tinal lymphomatosis, showing enlarged soli-
tary follicles and Peyer's patches.

Hirschfeld).

Gastro-intestinal Pseudoleuke-
mia.— The gastro-intestinal tract is
the seat of a remarkable form of primary lymphoid hyperplasia which lacks
the destructive character of lymphosarcoma and fails to give lymphocytosis
in the blood. The process may be chiefly limited to a portion or involve the
whole of the gastro-intestinal tract, or it may be associated with widespread
lesions of most other lymphoid structures.

The disease wras first mentioned by Briquet in 1835, wras fully described
by Stoerk, and Symmers collected ten cases from the literature. The first
symptoms may be enlargement of cervical nodes, or gastro-intestinal irritation
with persistent diarrhea.

In Symmer's case, studied in this laboratory, the extent of the lymphoid
growth was enormous. The entire gastro-intestinal tract from cardia to
anus was the seat of myriads of discreet pea-sized nodules projecting into the
lumen. Peyer's patches were represented by flat polypoid tumors. In the

364

NEOPLASTIC DISEASES

stomach the lesion was diffuse and this organ was greatly thickened and
enlarged. Cervical, mediastinal, retroperitoneal, and other chains of nodes
were much enlarged or formed compact masses of nodes of which the outlines
were still preserved. The spleen was much enlarged, and the bone-marrow
diffusely affected. There was general peritonitis without demonstrable origin.
The structure of the lesions was peculiar, consisting of extensive multi-
plication of lymphoid follicles which became greatly enlarged and eventually
fused, a true lymphadenoma. Yet the cells in the centers of these aggre-
gations of follicles were medium-sized lymphocytes. Mitoses were
missing. The process showed no capacity to invade resisting structures.

FIG. 126. — Pseudolcukcmia. Anatomically, gastrointestinal, mediastinal, and cervi
cal lymphomatosis. Structurally, lymphadenoma. Section of spleen showing lymph-
follicles in pulp and sinus.

The changes were more localized in the gastro-intestinal tract and the
pylorus was partly occluded in the case of Wells and Mayer.

Stoerk observed many superficial ulcers and peritonitis from perforation
of a deep ulcer. He found considerable variations in the cell types, some
foci resembling germ centers of follicles. In one of his cases the process
penetrated the wall of the colon and invaded pelvic organs, thus exhibiting
a transition to sarcoma. Ulceration of Peyer's patches may partly simulate
the lesions of typhoid fever.

The etiology of this remarkable condition is quite obscure. The chief
location of the process suggests the action of a diffusible irritant of intestinal
origin, but the cervical nodes may be involved very early. Tuberculosis

LYMPHOMA AND LYMPHOSARCOMA 365

was present in one of Stoerk's cases, and in Glinski's case, limited chiefly
to the colon, there was advanced pulmonary tuberculosis and foci of necrosis
with giant-cells in the mesenteric nodes. The process illustrates the most
extreme degree of orderly proliferation of lymphocytes, which seems to occupy
the position of a relatively benign neoplasm. The occasional appearance
of infiltrating properties illustrates the transition to and the sharp distinction
from lymphosarcoma. Flexner describes two cases which seem to belong
in this intermediate field. This form of pseudoleukemia is never followed
by leukemia.

Myeloid Pseudoleukemia. — That the spleen, lymph-nodes and marrow
may be the seat of an extensive myeloidization, as the result of blood destruc-
tion and regeneration in many forms of infection, has recently been shown by
numerous observers. The absence of leukocytosis places this condition
in the light of a myeloid pseudoleukemia. Apart from these infectious
diseases and their immediate sequels the existence of chronic myeloidization
of the organs is imperfectly established. Sternberg, however, refers to cases
of general myeloid transformation of the spleen and lymph-nodes without
leukemic blood changes. In certain cases of splenomegaly with anemia
the splenic changes approach the type of chronic myeloidization. It is
possible to interpret the "anemia infantum" of v. Jaksch as a chronic myeloid
pseudoleukemia.

Certain multiple myelomas, especially those composed of plasma-cells,
have been compared with medullary pseudoleukemia, with the chief result
of emphasizing their sharp morphological distinctions. The transformation
of pseudoleukemia into lymphatic leukemia has been described in a consider-
able series of cases, thereby establishing a close relation between these
processes.

Not all of these cases withstand critical analysis, as I have elsewhere
noted, but some of them appear to be genuine. As a rule the leukemic
blood changes appear a short period before the termination of the disease,
and persist. Or the leukocytosis may diminish shortly before death. Turk
observed intermittent leukemic changes in the blood of pseudoleukemia.
On the part of leukemia approach to a pseudoleukemic condition is exhibited
by those cases in which there is a temporary decline in the leukocytosis.
That the histological structure of the lesions in the two conditions cannot
be sharply separated has already been pointed out. Klein and Turk have
especially emphasized the close parallel between leukemic and aleukemic
lymphoma and lymphosarcoma. All of these features point to the conclusion
that leukemia and pseudoleukemia are essentially the same disease (Turk,
Klein).

On the other hand it is clear that the great majority of cases of pseudo-
leukemia never show any tendency to develop leukemia. The transforma-
tions which are exclusively of the lymphatic type, do not reproduce the
typical picture of chronic lymphemia, but the leukocytosis is a terminal,
or antemortem, or transitory condition. It does not reach the extreme
degree of typical lymphemia but recalls the leukocytosis of certain malignant
tumors. There are some minor anatomical distinctions between leukemic
and aleukemic lymphomas and some of the latter never run into leukemia.
Hence there are many considerations which favor the view, emphasized
especially by Pincus, that leukemia and pseudoleukemia are not different
stages of the same disease. Until they are connected by an etiological
factor there seems to the writer little advantage in merging the two
conditions.

366 X EOF LA STIC DISEASES

LYMPHOSARCOMA

A true malignant neoplasm arising in lymphatic tissue from proliferation
of atypical lymphocytes occurs as a (i) localized or a (2) diffuse process.
The former is more malignant than the latter, but its rapid course, as well
as the occurrence of intermediate types of cases, indicate that there is no
other important distinction between them.

Lymphosarcoma, formerly included with pseudoleukemia, secured an
independent position chiefly through the studies of Kundrat and Paltauf,
who recognized very notable gross and microscopical distinctions between
this process and other aleukemic lymphomas. From the surgical side,
Billroth especially found it necessary to recognize under the term malignant
lymphoma, locally destructive and recurring tumors of lymph-nodes, but he
could not separate the different types of such processes.

Kundrat described lymphosarcoma as a tumor arising only from groups
of lymph-nodes, not from single nodes, and from adenoid tissue of mucous
membranes, from which points it extended to neighboring nodes and the
surrounding tissue, or along the submucous tissue. The systemic character
of leukemia and pseudoleukemia was missing, and the spleen, marrow, and
liver were rarely involved. Secondary tumors occurred almost exclusively
in the intestinal mucosa, serous membranes, and lymph-nodes, and were
joined by continuous growth through lymph-channels, two features dis-
tinguishing this process from true metastatic cancer. Robust males between
the ages of 25-55 were chiefly attacked, and a tuberculous history was rare.
Structurally the tumor was composed of lymphoid cells of variable size
lying in an atypical reticular tissue. Cellular and fibrous stages of the process
could be distinguished -but necrosis was rare.

Kundrat separated this process from the true neoplasms on the ground
that it was not a spontaneous growth of multiple origin and with extensions
by metastasis, but a regional disease of lymphoid tissues which propagated
itself through the lymph paths. Yet it was one of the most malignant
of diseases, resisting attempts to extirpation, and proving a veritable
"noli-me-tangere." It was more closely related to pseudoleukemia and
"granuloma malignum," from both of which he had observed the develop-
ment of lymphosarcoma.

The picture drawn by Kundrat is now generally accepted as depicting
a specific group of cases which require separation from other lymphoid
tumors. The extension of the process solely by permeation of lymphatics
is probably not invariable, but in other details his criteria may be followed
rigidly in diagnosis.

Anatomical and Clinical Features. — Lymphosarcoma is distinguished
from other forms of lymphoma by its local destructive capacity and by the
formation of true metastases in distant organs.

The tumors arise in a chain of lymph-nodes or in a localized lymphatic
structure, and rapidly produce bulky growths which obliterate the outlines
of the separate nodes, infiltrate surrounding tissues, and tend to result in
necrosis and ulceration of skin and mucous membrane. The more rapid
cases are fatal while the growth is chiefly local, but widespread extensions
and metastases are commonly observed. Fever is usually a prominent
symptom, and anemia and cachexia early develop. Leukocytosis is usually
present, and may be so marked as to suggest leukemia (Sadler). The excess
is usually of polynuclear cells (Grawitz) occasionally of lymphocytes (Turk)
rarely of eosinophile cells (Reinbach). Atypical cells found in the tumor
may also appear in the blood and in such numbers as to suggest leukemia

LYMPHOMA AND LYMPHOSARCOMA 367

(Martin-Matthewson, Warthin). In fact the distinctions between lympho-
sarcoma and leukemia cannot always be sharply drawn (cf. Leuko-
sarcomatosis).

Extension of the process in the earlier stages appears to be exclusively
by way of the lymphatics as stated by Kundrat, but in many advanced
cases true metastatic growths form in the lungs, brain, kidneys, skin, and other
organs, which are satisfactorily explained only by invasion of the blood-vessels.

The duration of the disease varies widely. Birch-Hirschfeld observed
an intestinal case following typhoid fever which was fatal in six weeks.
Kaufmann refers to a mediastinal tumor which caused suffocation after
three months. Libmann's cases resembling appendicitis were very rapidly
fatal. The usual course is progressive and fatal within a few months. Wide
extensions are observed chiefly with more prolonged course. After local
treatment, extirpation, internal use of arsenic, or application of x-ray,

FIG. 127. — -Lymphosarcoma of cervical lymph-nodes.

the disease has often appeared to be arrested only to recur after a brief
period. Yet not a few cases have been reported as cured (Chiari, Lit.).
The true nature of some of these older cases is uncertain, but Ruff has col-
lected a series of more recent reports illustrating the regression of lympho-
sarcoma after infectious diseases, and irradiation. Koscher reports regres-
sion of a tonsillar growth after removal of a portion of tissue for diagnosis,
followed by a recurrence in abdomen. Longcope reports the complete
spontaneous disappearance of extensive lymphosarcomatous tumors followed
by death of the patient from asthenia.

The structure of lymphosarcoma is rather specific. It presents a diffuse
growth of lymphoid cells lying in reticular tissue. The structure of the
•affected node or follicle is obliterated. The cells I find to vary in size, being
small, medium, or large. The nuclei are compact or vesicular, always
hyperchromatic, and nucleoli are not prominent. Giant-cells do not belong
to this process but large multinuclear cells are occasionally seen.

368 N EOF LA STIC DISEASES

In the origin of lymphosarcoma two specific cells participate, giving
rise to two specific forms of the tumor. These cells are: (i) the reticulum
cell of the germ centers of follicles and pulp cords, and (2) the lymphocyte.
Thus arise two types of lymphosarcoma which may be designated as

1. Reticulum cell sarcoma, or large round-cell lymphosarcoma.

2. Malignant lymphocytoma.

It may sometime be possible to establish these two histological' varieties
as separate diseases. In the great majority of cases they retain permanently
their separate identity, and they appear to arise under different clinical
conditions, and from different causative factors. But until the relation
of the lymphocyte to the reticulum cell is fully established the two conditions
may' be discussed together.

The reticulum of the tumor is irregularly distributed, being deficient in
places, and thickened in areas tending toward fibrosis. Kaufmann and
Ribbert recommend washing out the cells for its demonstration.

FIG. 128. — Reticulum in a lymphosarcoma. Tannin-silver stain. (After Hulisch.}

The pure lymphoid type of structure is not always present. In certain
cases there is an admixture of plasma-cells, eosinophile cells, and normal
lymphocytes, which may signify a secondary inflammatory process (cf.
Kanter). When these features of an infectious granuloma are pronounced
the diagnosis of lymphosarcoma must remain uncertain.

Regressive changes in lymphosarcoma are rare, but the occlusion of
vessels in bulky growths may lead to extensive necrosis, while superficial
ulceration is common.

The local aggressive quality of the process is a notable feature. The
capsules of nodes, muscle tissue, and periosteum are readily penetrated
and destroyed. The adventitia of large blood-vessels is invaded but the
media resists.

The primary lesions of lymphosarcoma in mucous membranes usually
begin with swelling of many lymph nodules, followed by ulceration and widen-
ing of the lumen, while secondary invasions, as of pharynx and intestine, are
diffuse and may cause constriction.

LYMPHOMA AND LYMPHOSARCOMA

369

The histological characters of the process, together with its gross anatomy,
usually separate typical cases of lymphosarcoma from pseudoleukemia,
leukemia, and Hodgkin's granuloma, and from other tumors of lymph-nodes.
Yet since some of the above conditions may occasionally give rise to lympho-
sarcoma it is impossible always to distinguish between them without -very
full clinical data. Pseudoleukemia and lymphatic leukemia are lympho-
cytomas; in myelocytic leukemia the cells resemble those of lymphosarcoma
but are more evenly distributed, less atypical, and the process is less aggres-
sive. Any group of lymph-nodes or any lymphoid structure, with the
exception of the spleen and bone marrow, may be the primary seat of lympho-
sarcoma. Round-cell sarcomas of spleen or bone-marrow differ from the
tumors of lymph-nodes, but secondary invasion of these organs is frequent.
Harbitz and Wieland describe primary myelogenous lymphosarcoma, but

FIG. 129. — Lymphosarcoma. Reticulum-cell- sarcoma of lymph-nodes.

the true nature of their cases is uncertain and they probably belong among
multiple myelomas. Yet several well-defined groups of cases mayjbe sepa-
rated according to location and clinical course.

Clinical Subvarieties. — The most frequent form of lymphosarcoma
is a primary affection of a definite chain of lymph-nodes from which the
disease extends to other chains of nodes, and often to the spleen and other
organs. The cervical, mediastinal, retroperitoneal, and mesenteric nodes
are commonly involved and in the order named, less often the inguinal
and axillary.

With the cervical nodes the lesion may invade the wall of the pharynx,
tonsils, base of skull, or it may lead to extension into thorax and abdomen
(Freudweiler). With the mediastinal type the bronchial nodes may be
involved with extensions to pericardium, or pleura or lung, with marked

370 NEOPLASTIC DISEASES

pulmonary symptoms. Schlagenhaufer and Kundrat each report two
cases of lymphosarcoma of bronchial nodes with extensive infiltration of
esophagus. From the cervical, mediastinal, or peritoneal nodes very exten-

FlG. 136. — Beginning reticulum-cell sarcoma of lymph-nodes. Proliferation of reticu-
lum cells in centers of three follicles.

FIG. 131. — Malignant lymphocytoma of cervical lymph-nodes.

sive invasion of the pleura and peritoneum may occur, in the form of diffuse
infiltration, globular masses, or myriads of miliary nodules (Kundrat,
• Martin).

LYMPHOMA AND LYMPHOSARCOMA

371

Most of the mediastinal lymphosarcomas arise from the thymus and
are to be considered as varieties of thymoma (q.v.).

Primary pharyngeal lymphosarcoma is a very common type, and the
fact that with the cervical forms they constitute the majority of the cases,
suggests that an infectious agent commonly enters through this area (Chiari,,
Lit.). The initial symptom is swelling of lymphoid tissue and diffuse infiltra-
tion of mucosa of tonsillar ring or pharyngeal wall, and the early appearances
are characteristic (Kundrat). According to Eisenmenger the process
regularly begins in the pharyngeal mucosa and not in the tonsils. Yet
in several cases at the Memorial Hospital the disease was recognized shortly
after removal of enlarged tonsils. In a fatal case with gastro-intestinal

FIG. 132. — Lymphosarcoma of stomach. Invasion of arteriole.

metastases I found the original ulcerative lesion of the sinus laryngis com-
pletely healed. Ulceration is soon established and remains a persistent
or recurring complication. The process extends to the nares, cervical nodes,
base of skull or cranial cavity, orbit, larynx, and thereafter in the usual
manner to internal nodes, intestinal wall and other organs. Local treatment,
extirpation, and internal use of arsenic may cause marked or complete
regression of the original lesion but with rare exceptions the process recurs.

In the advanced stages the tissues of pharynx, face, and neck may
become fused in a bulky infiltrating tumor which compresses the vessels
without rupturing into them, and causes marked symptoms from involve-

372 NEOPLASTIC DISEASES

ment of vessels, nerves, trachea, and special sense organs. Many cases
terminate without notable extension to other regions.

Lymphosarcoma of the gastro -intestinal tract is a common type. The
seats of election are the stomach, lower ileum, and rectum.

The literature on this subject presents a chaotic picture in which morpho-
logical details are obscure and the data regarding histogenesis and etiology
are imperfectly presented. From the reported cases it is necessary to exclude
first, an infectious granuloma which is probably a form of Hodgkin's disease
but in which the structure is atypical, characteristic giant-cells being usually
absent (cf. Haberer). Diffuse pseudoleukemia must also be excluded.
Some of the so-called round-cell sarcomas of the stomach are probably of
myogenic origin. Finally, it must be noted that diffuse carcinoma of the
stomach may produce lesions which closely resemble lymphosarcoma in
the gross, and a structure which can be identified as carcinomatous only
when care and industry are used in the examination.

i. True lymphosarcoma of the stomach, which is always separated with
difficulty from the granulomatous pseudosarcoma, occurs chiefly in young
subjects and produces a bulky circumscribed or diffuse growth in the pylorus
or in the curvatures. Tt is often difficult to determine whether the primary
growth is in the wall of the organ or in adjacent lymph-nodes which are
commonly involved. The majority of these tumors are diffuse (Kundrat,
Cayley, Hammerschlag, Menge, Thursfield); others produce several pro-
jecting, submucous masses (Kaufmann) ; some are polypoid or pedunculated
(Pitt); and a few become quite bulky (Stahelin, Howard). Ulceration and
pyloric stenosis are frequent (Fleiner), and local or widespread extensions
or metastases are common. Maas described a bulky subserous lympho-
sarcoma. The gastric tumor is often only a part of a very general lympho-
sarcomatosis, as illustrated by the case of Ziesche and Davidsohn. Here a
very extensive tumor of the stomach was associated with lymphosarcoma
of tonsils, mediastinal and retroperitoneal lymph-nodes, and the entire
small intestine, while other growths occurred in the heart, kidney, and bone-
marrow.

2. Lymphosarcoma of the intestine is an important type of the disease.
While usually found in the lower ileum it may appear at any point from
the duodenum to the anus. The rectal tumors are less frequent but equally
characteristic (Glinski, Key, Lit.). Rarely the appendix is the primary site.
The earliest stages appear as a localized thickening of the submucosa with
or without ulceration. The process extends laterally and invades and
destroys the muscular layers and appears as a subserous tumor which soon
forms adhesions. Thereafter central ulceration excavates the tissue or
produces aneurysmal dilatation which with peripheral growth yields a large
tumor with roomy cavity. Large polypoid growths protruding into the
widened lumen without ulceration are also observed (Baltzer). Rarely
marked stenosis results and perforation may occur. Chronic peritonitis
with chylous ascites is often observed.

Metastases appear early in regional nodes and they may extend to many
of the organs (Libman). The disease often occurs in childhood as well as at
other ages and usually runs a rapid course, terminating fatally in a few weeks
or months. Acute cases resemble appendicitis (Libman, Jopson, White).

The structure of the growths is that of small or large round-cell lympho-
sarcoma. The reported cases are variously designated but there is no satis-
factory evidence that more than one type of tumor is represented in this
group. The cells are large or medium mononuclears with liberal cytoplasm,
lying irregularly in a meshwork or fine fibrils. Fragile blood-vessels and

LYMPHOMA AXD LYMPHOSARCOMA

373

many small lymphocytes may accompany the tumor-cells. It is especially
in this group of cases that the process may resemble an infectious granuloma.

Retro peritoneal lymphosarcoma is a characteristic type of the disease.
It produces a large abdominal tumor composed of fused lymph-nodes, while
the extensions may be either very wide or rather limited. Such tumors may
be associated with intestinal lesions so that it is difficult to determine the
primary seat. Various complications arise in the course of these tumors,
including peritonitis with chylous ascites, constriction of intestine, occlu-
sion of bile ducts with jaundice, and compression of vessels with edema.

Cutaneous lymphosarcoma occurs only as a metastatic process from other
regions (Sedziak) ; mediastinum (Romberg, Packard) ; mesentery (Kutzner) ;
antrum (Kaposi). The cutaneous tumors appear early or late in the disease
and form multiple papules or subcutaneous nodules of varying size. They
may regress spontaneously or after arsenic (Arning), and Kaposi saw a very
large lymphoid tumor of the skin rapidly disappear. The exact nature of
many of the cases in the literature is uncertain.

FIG. 133. — Malignant lymphocytonia. Invasion of venule in retroperitoneal fat.

Lymphosarcoma of the tongue has been reported by several observers but
Schleinzer was able to collect only four cases which could be regarded as
genuine, two of which recovered after operations. In one case the tumor
distended the buccal cavity after 12 years' growth, and recurred after
operation. In 3 cases the tumors early became ulcerated and invaded the
cervical and once the abdominal nodes. Fripp and Iwan have collected
cases of round-cell sarcoma of the tongue, the exact nature of which it is
difficult to determine. Some of the difficulties of diagnosis in this field are
illustrated in the case of pseudosarcoma described by Foote, in which the
very chronic lesion consisted of a diffuse infiltration of large mononuclear
cells somewhat resembling plasma cells. In this case there were also anal
lesions.

Lymphosarcoma of the testis has been a common diagnosis, especially
among French writers, but Chevassu has pointed out that many of these
cases were probably embryonal carcinoma. Yet true lymphosarcoma has
been described by Malassez, Ehrendorfer, and Debarnardi. I have studied
two cases which seem to be genuine.

374

NEOPLASTIC DISEASES

The disease occurs chiefly in young subjects, usually involves both testes,
develops cutaneous and internal metastases, and runs a rapid course with
fever. The exact origin of this tumor is uncertain. The testicle is some-
times the seat of metastatic lymphosarcoma.

The kidney is a favorite seat of metastatic lymphosarcoma in the form of
minute foci, diffuse infiltrations, or bulky masses. In Turner's case both
kidneys reached an enormous size from diffuse infiltration and much of
the renal tissue was destroyed. The existence of primary lymphosarcoma
of the kidney is uncertain. In a case of Dowd's I found the organ largely
replaced and moderately enlarged by many round masses of tumor-tissue
composed of atypical lymphocytes with hyperchromatic nuclei.

Extramedullary Plasma-cell Tumors. — In a rather numerous group of
tumors of mucous membranes and lymph-nodes the growth is composed
exclusively of plasma-cells. Considering their comparative frequency and

FlG. 134. — Malignant lymphocytoma of groin, infiltrating fat tissue, walls

lumina of small veins.

of vessels and

rather peculiar1 clinical course, they have received inadequate^attention
(Kusunoki, Frank, Lit.). The growths occur chiefly in the nasopharynx,
alveolar borders, tongue, lips, and cervical lymph-nodes, but they have been
observed in many other regions. The course is relatively slow, but they
may recur after extirpation, and become associated with a chronic cachexia.
They are commonly classed as lymphosarcoma, but being as a rule benign
processes with very indistinct neoplastic properties, it is highly important
that they should be separated from the malignant lymphosarcoma. The
structure presents a diffuse growth of more or less typical plasma-cells.

Etiology. — Lymphosarcoma, representing a lawless proliferation of
reticulum cells and their derivatives, may be attributed, a priori, to any
irritant which influences these unstable cells over a considerable period or in
a specific manner. There is no urgent necessity for assuming the existence
of any unknown micro-organism or any other occult factors in the origin
of this process, for when the above principle is applied in the study of cases
a large proportion of lymphosarcomas are reasonably accounted for.

LYMPHOMA AND LYMPHOSARCOMA 375

Thus Birch-Hirschfeld observed a rapidly fatal case which was prac-
tically a continuation of typhoid hyperplasia. The older observers were
in the habit of attributing many of these cases to syphilis, but the grounds
for this assumption have not been strengthened in recent years.

The more generalized forms of lymphosarcoma are not infrequently the
sequel of pseudoleukemia or leukemia, for which an infectious origin is
probable. The usual type of sarcoma following Hodgkin's granuloma has
a specific structure which differs from that of lymphosarcoma and has been
separately described.

Tuberculosis occupies a prominent position as an excitant of lympho-
sarcoma. In fact many observers, finding frank tuberculosis so intimately
associated with lymphosarcoma, have been willing to identify the two con-
ditions. Since the discovery of tubercle bacilli in pseudoleukemic tissue by
Weigert, in pure lymphoid hyperplasia by Brentano and Tangl, and in
generalized lymphomas of nodes, spleen, liver, and serous membranes by
Sabrazes, only a. slight difference has separated lymphosarcoma from the
immediate or distant presence of tubercle bacilli or their toxins. Frank
tuberculosis associated with lymphosarcoma is reported by Ricker in a case
terminating after 14 years with sarcomatous infiltration of neck, lung,
adrenals, spinal canal, and widespread caseous areas, with giant-cells and
tubercle bacilli. Yet the structure of the sarcomatous tissue in this case
suggests Hodgkin's granuloma. Muller, however, saw general sarcomatosis
from a primary tumor of breast in which miliary tubercles were nearly co-
extensive with large sarcomatous masses. A significant case is that of
Brandt's in which, with tuberculosis of left apex of lung, there was sarcomatous
invasion of ileocecal region, many lymph-nodes, pharynx, Eustachian tube,
parotid, middle ear, adrenal, and ovary. Inoculation of the pure sarcoma-
tous tissue yielded only lymphoid hyperplasia of intestinal follicles in
guinea-pigs, but inoculation of the tissue of these follicles gave frank tuber-
culosis in a second series of pigs.

Gastro-intestinal lymphosarcoma is especially difficult to separate from
tuberculosis or some form of infectious granuloma. These lesions often
exhibit lymphocytes, plasma-cells, eosinophile cells and necrosis, and cases
in which tubercle bacilli are missing may closely resemble hyperplastic
tuberculosis in which acid-fast bacilli are present but scanty. Tuberculous
intestinal ulcers closely associated with widespread sarcomatous lesions in
mesentery or retroperitoneal nodes are described by Nothnagel, Freudweiler,
Munk, and others. Thus it seems highly probable that many cases of lym-
phosarcoma arise on a tuberculous basis and that the process thus established
progresses of its own momentum and eventually apart from the presence of
any bacilli or their toxins.

That tuberculosis is not always the exciting factor must be granted.
Kundrat stated that tuberculosis is not commonly implicated in lympho-
sarcomatosis. Lubarsch assumes that any infectious agent may serve as
the exciting cause, and chiefly because of the close dependence of the
process upon microorganisms and their products he would separate lym-
phosarcoma from other or true neoplasms. For the same reasons Borst
anticipates the ultimate identification of lymphosarcoma with infectious
granulomas. It may here be noted that the local aggressive quality which
chiefly distinguishes lymphosarcoma from pseudoleukemia fails entirely to
separate this process from the infectious granulomas, which also infiltrate
and destroy tissues.

Not a few lymphosarcomas arise in infants and appear to have a con-
genital basis. The testicular cases are often of this character. The dis-

376

NEOPLASTIC DISEASES

covery of epithelial elements in the tumor-masses indicates an origin from
misplaced tissue-masses (Finkler, Martland).

Ribbert assumes that all true lymphosarcomas arise from aberrant and
undifTerentiated cell groups, and that tuberculosis often serves as the neces-
sary incitant to growth. Such a view seems reasonable for very malignant
localized tumors, less so for the generalized forms resembling pseudoleukemia.

SARCOMA OF SPLEEN

While primary sarcoma of the spleen is rare, several varieties of this
tumor have been reported (Jepson, Albert, Foix, Roemmele, Lit.)- Three
varieties of splenic sarcoma were briefly described by Weichselbaum in 1881,
spindle-cell sarcoma, endothelial sarcoma, and lymphosarcoma, and although

FIG. 135. — Structure of a primary diffuse sarcoma of the spleen.

it is impossible to determine the exact nature of many cases in the literature,
most of them seem to fall in one of the above groups.

1. Spindle-cell sarcoma occurs as a small or bulky circumscribed tumor.
The case of Jepson and Albert stands as a typical example of this rarest of
types. The structure showed spindle- and round-cells with trabeculse and
solid areas of fibrous tissue. This tumor is comparatively benign. A
capsular sarcoma has been described by Heinricus, and angiosarcomas by
Langhans, Theile, and Jores.

2. The endothelial sarcoma is the most frequent variety. As a rule it
produces multiple nodules in a greatly enlarged organ, and many of these
nodules may fuse into larger diffuse masses. Metastases are commonly

LYMPHOMA AND LYMPHOSARCOMA 377

present, having been observed by Bunting in liver, pancreas and skin, and
by Foix and Roemmele about the adrenal. This tumor is, therefore, quite
malignant.

The structure consists of large cells with single or multiple vesicular nuclei
and pale cytoplasm. They are round or elongated or polyhedral, and giant-
cells may form. The arrangement may be diffuse or alveolar. Bunting,
in an alveolar tumor, concluded that the cells arose from the endothelium
of the splenic tissue.

Foix and Roemmele in an elaborate analysis trace the origin to the
reticulum cells of the splenic follicles. They liken the process to a neoplasm
arising on an inflammatory hyperplasia of these follicles and are prepared
to accept an infectious agent or an irritant of endogenous origin as the ulti-
mate cause of the proliferation. Their designation of the tumor as "reticulo-
splenome nodulaire" is non-committal on the endothelial origin of the growth.
Many of these cases resemble the endothelial sarcoma arising in Hodgkin's
granuloma. A relation to "splenomegalie primitive, Gaucher'1 has not been
indicated by any transitional cases so far described.

(3) Primary lymphosarcoma of the spleen, derived from the lymphoid
cells of pulp or follicles, has been described by several observers but it is
difficult to determine which of the recorded cases belong in this group.
This tumor produces diffuse enlargement of the spleen, as in the cases of
Kocher, Grohe, Clarke and Kocher, or it may appear in the form of one or
more large discrete masses (Warren, Herczel). Regional metastases are
common but not invariable. The normal structure of the spleen is largely
destroyed by diffuse growth of small or large round-cells of the type of lym-
phocytes. Menetrier designates the tumors with small cells as lymphocy-
toma, and those with large cells as splenoma. I have studied one case of the
latter type, reported by Janvrin, in which the entire organ, much enlarged
but with capsule intact, was composed of somewhat peculiar, large round-
cells resembling the splenic lymphocytes. On account of the partial pres-
ervation of sinuses of follicles the truly neoplastic nature of the process
appeared doubtful. Grohe's case which appears to belong in this group
gave extensive metastases.

CHAPTER XXII
TUMORS OF BRAIN

General Considerations. — Occurrence. — The frequency of occurrence of
brain tumors cannot be accurately stated. Probably about i per cent, of
deaths are from this cause. Bruns saw 210 cases among 11,500 nervous
patients, but Hirsch saw only 14 brain tumors among 8000 nervous cases.
Tooth collected 500 cases in the service of the National Hospital, London,
during ten years. Among 14,005 autopsies at Munich and Heidelberg, 135
brain tumors were recorded by Seydel and Beck. In Gurlt's tables covering
14,630 tumors, 218 of the brain are included.

Sex .—Including a small proportion of tubercle, males were affected in
744 cases, and females in 428, in the series collected by Cowers, Bruns, and
Tooth.

Age Incidence. — Of Tooth's 500 tumors, excluding tubercle, 139 occurred
between i and 20 years (27.8 per cent.); 123 from 21-30 years (26 per cent.);
137 from 31—40 years (27.4 per cent.); 65 from 41—50 years (13 per cent.);
33 from 51-60 years (6.6 per cent.) ; and 3 after 61 years.

Starr shows that cerebellar tumors are relatively frequent in children.
Of 45 cortical tumors 3 occurred under 19 years, while of 29 cerebellar growths
ii were found under 19 years. The gliomas, endotheliomas and sarcomas
show much the same age incidence. Gliomas, cholesteatomas, and dermoids
are rarely congenital. Cowers found only the first five months immune.

Heredity was a negligible factor in Tooth's analysis, a cancerous family
history being obtained in only 37 cases (7.2 per cent.). In no case was a
history of brain tumor noted. There are, however, occasional exceptions
to this rule.

Trauma. — The frequency of the traumatic origin of brain tumors has
been variously estimated by different observers but as a rule the estimates
are notably high. Gerhardt accepted the traumatic origin of 10 among 60
reported cases of glioma, and in 4 of 1 1 cases of his own. Bruns holds that a
direct traumatic origin is rare. Adler collected 1986 cases, accepting a
relation to trauma in 8.8 per cent. He details 118 cases of various types,
illustrating many possible relations to trauma, some of them quite direct.
Lowenthal found n gliomas which on somewhat uncertain evidence he
referred to trauma. A traumatic origin of certain sarcomas resembling
granulation tissue is more acceptable than with gliomas.

The trauma may have no influence whatever on the tumor. This rela-
tion must be assumed to exist in the cases in which the trauma is incapable
of producing a lesion of the brain tissue, and may be assumed as probable
when a long interval elapses between the injury and the appearance of
symptoms.

The trauma may cause the outbreak of symptoms of a previously existing
latent tumor. Such cases are observed when an unsuspected glioma causes
epileptic attacks with head injury in falling (Bruns).

The trauma may accelerate the growth of a previously existing tumor.
Burns refers to the rapid growth after trauma of mildly indicated gliomas, and
supposes that the trauma produces hemorrhage in the vascular tumor.

378

TUMORS OF BRAIN

379

Oppenheim states that trauma may indirectly excite tumor growth by estab-
lishing a condition of epilepsy which eventually induces the neoplastic pro-
liferation of glia-tissue. Such cases are reported also by P. Knapp and Osier.
Trauma may be the direct exciting cause of the tumor. In order to
prove such a relation it is necessary to show that a sufficient injury has caused
.a lesion of the dura or pia with affection of the brain tissue. Evidences of
old hemorrhage, with adhesions of brain to membranes beneath the point
of injury, are the only satisfactory data that can be offered as proof. Such
cases have been fully reported by Hitzig, Eppinger, Thomas and Bartlett,
Keen, Annandale, Adler, Carara and others. Both sarcoma and glioma are
observed under such conditions. Somewhat less satisfactory and more
numerous are the cases in which the tumor does not appear at the point of
injury, but owing to the influence of contrecoup the brain lesion may be far
removed from the point of the blow. Additional evidence may appear in the

FIG. 136. — Location of a series of brain tumors, (v. Eiselsberg.)

clinical history, when it is shown that the tumor symptoms were continuous
with or appeared shortly after the injury. With increasing intervals between
trauma and tumor the relation must be regarded as less direct. Starr's
assumption that a cerebral hemorrhage or contusion may pass directly into a
tumor process is rejected by Oppenheim and Bruns, but such an interpre-
tation is fully in accord with histological findings as well as clinical history.
In the organization of a cerebral blood-clot the growth of capillaries and glia-
tissue may be very active.

The relative frequency of the different types of tumors may be judged
by Tooth's analysis of 258 cases verified at operation or post-mortem as
follows:

Glioma, 132 (55 per cent.); endothelioma, 37 (14.3 per cent.); sarcoma,
21 (8.1 per cent.); carcinoma, 15 (5.8 per cent.); tubercle, 14 (5.4 per cent.);
fibroma, 13 (5 per cent.); cysts, 5 (1.9 per. cent.); ventricular papilloma,
3 (i.i per cent.); cholesteatoma, 2 (0.7 per cent.); pituitary, 2 (0.7 per cent.);
pineal, 4 (1.5 per cent.).

380

NEOPLASTIC DISEASES

Fibrogliomas and fibromas belonged to the cerebellum. The endothe-
liomas were confined to the anterior portion of the falx in 35 of the 37 cases.
Of the carcinomas only one was certainly primary.

The general distribution of brain tumors is indicated in the following
table in which are included the series of cases of J. Collier and Tooth, together
with those of Stern.

Frontal 129 Optic thalamus .

Parietal 73 Pons

Temporosphenoidal 63 Medulla

Occipital 17 Base

Corpus callosum 34 Pituitary

Mesencephalon 57 Pineal

Lateral ventricles

Third and fourth ventricles ^ Extracerebellar

Cerebellum 112

632

Including tubercle and gumma the following table of incidence results
from combining the figures of Birch-Hirschfeld and Bernhardt:

Tubercle Gumma Sarcoma j Glioma Osteoma Cholesteatoma

Cortex

Lobes

Basal ganglia

Corpora quad

Pons

Medulla

Cerebellum

Hypophysis

Pineal. .'

50
18
.17

2
30

57
o
o

183

'.S
8

7
o
6

4
3

16
39
14

8
5

3
4

12
II

32
O
O

127

Multiple brain tumors are not infrequently observed. In the same case
Hanel saw a cystic round-cell sarcoma, a ganglionic neuroma, a spindle-
cell sarcoma, several lymphangiomas and a tumor-like thickening of the
dural vessels.

Operability. — Conclusions regarding operability of brain tumors have
not greatly changed in recent years, notwithstanding isolated reports of
brilliant successes. In 1889 Starr concluded that of 300 brain tumors in
children only 19 cases warranted operation, and only 16 could have been
successfully removed, of which 10 were tubercle.

In 1914 Kuttner reports that in 100 clinical cases 30 tumors were removed
and 34 others were later demonstrated to exist, 45 died from the operation,
14 died in i to 3 months, and 5 in 4 to 5 months. In 13 cases it was later
shown that no tumor existed. Four blind cases recovered sight, and n
cases remained well for 6 months to 6 years.

Henschen reports that of 205 operations 48 patients died from the opera-
tion and 88 more in one month, while after 2 years all but 14 were dead.
Bergmann and v. Eiselsberg both report operative mortalities of 38 per cent.,
while among 371 cases Bergmann reports in not improved and 88 (23 per
cent.) improved. Eichelberg concludes that 70 to 80 per cent, of brain
tumors can be localized and of these 5 per cent, are enucleable. Among 33
cases of brain tumor Cramer and Hippel found only 4 suitable for operation,
three of which were cysts. Duret analyzed 400 operative cases, finding

TUMORS OF BRAIN 381

that 78 (19.5 per cent.) died immediately, 20 very soon from meningitis,
and 47 within one month, so that a total of 145 (36 per cent.) received no
benefit. Improvement in varying degree followed in 258 cases, among which
there were 41 recurrences of the tumor. The surgical possibilities in favor-
able cases are well illustrated in the report of Alexander and linger who
located a calcine subpial endothelioma,7 X 7 X 5 cm., by means of the oxray
and removed it under cocaine with complete cure, although the lateral
ventricle had been opened.

Miscellaneous statistics are of practically no value in determining the
probable outcome of any given case, whereas a very thorough clinical study
of every feature of the condition, accurate localization, rate of growth of the
tumor, age of the patient, a knowledge of the natural history of the different
types of tumors and of their pathological anatomy, may together yield a
comparatively reliable prognosis.

All of these subjects form a very extensive department of our knowledge
of brain tumors and furnish the chief topic of several comprehensive works,
such as those of Oppenheim, Bruns, Duret, Henschen, Stern, Starr, F. Krause
and many others.

The duration of brain tumors without operation was found by Tooth
as follows: Glioma 10.1 months for 21 cases, extremes 9 years and 24 days.
Endothelioma, 20.2 months for 6 cases unoperated. In 31 cases operated
upon the average duration was 4 years, extremes 20 years and 2 months.
Sarcoma, 5 cases survived 11.2 months, or, omitting one which lasted 4 years,
the average was 5.1 months. Of 7 cases diagnosed as pituitary the average
survival period was 7.5 years. A notable fact was the long survival period
of 6.5 years of 51 cases not localized.

Secondary Effects of Brain Tumors. — The continued growth of an intra-
cranial tumor usually induces secondary changes in many intracranial
structures, giving rise to complex and confusing cerebral symptoms and com-
plicating the anatomical relations of the tumor. These effects are the result
of many factors, including the pressure of the tumor mass, circulatory dis-
turbances in the vicinity of the tumor and in the whole cranial cavity, inter-
ference with the paths of ventricular fluids, and local invasion and dissemi-
nation of the tumor.

(a) On the brain tissue. The tumor may act on the brain tissue by
compression, by irritation, or by actual destruction of cells and fibers. Simple
compression is best observed with tumors of the meninges, or encapsulated
growths which displace the adjoining brain substance. Pressure atrophy
gradually follows with loss of cells and myelin sheaths, but complete loss of
functional capacity of the affected region is generally slow to appear. Exten-
sive displacement of affected parts may result, especially in the cerebellum.
Here bulky tumors have been known to force the medulla or even the cere-
bellum tightly into the foramen magnum or spinal canal. Compression
effects are often observed at a distance, as when a tumor of one side com-
presses the structures of the opposite cerebral hemisphere with convulsions.
Cerebral tumors may even compress the cerebellum, although the tentorium
usually limits such effects in both directions.

Very extensive hernial protrusion of the brain may follow opening the
skull. In some cases the relief of pressure accelerates the growth of an
underlying or distant glioma or sarcoma which forces brain tissue or tumor-
tissue, or both , through the opening. Eichelberg describes a hernial protrusion
almost as large as the brain itself. Compression of the cranial nerves yields
some of the most reliable of localizing symptoms. These nerves may be
directly compressed by the tumor, or displacement of portions of the brain

382 N EOF LA STIC DISEASES

may strangle the blood-vessels or the nerve-fibers or actually sever the nerve
trunk (Wernicke).

The imperfectly formed blood-vessels of gliomas are especially susceptible
to intermittent distention, producing intermittent pressure symptoms. Or,
after rupture, extensive hemorrhage in or about the tumor may come from
these vessels. Irritation of brain tissue usually precedes the pronounced
stages of compression. The mechanism of the resulting spasms and para-
esthesias is not clear, but probably consists of local vascular disturbances
with edema and exudation.

Destruction of brain tissue follows prolonged pressure, results from
the gradual extension of glioma, and is rapidly effected by infiltrating
sarcomas and especially by carcinomas. Inflammatory reaction about the
tumor or extending over considerable portions of the brain, is frequently
observed and may greatly complicate accurate localization of the original

FIG. 137. — Acute edema of brain in region surrounding a hard, slowly growing tumor.

(After J. Collier.)

growth. Collier analyzed false localizing signs occurring in 20 of 161 cases,
finding, as the source of the symptoms, extensive edema about slowly growing
tumors, thrombosis or hemorrhage at a distance from the tumor, areas of
softening, ventricular hydrops, and distortion of cranial nerves. These
signs were encountered in 13 per cent, of supratentorial growths and only
twice in cerebellar tumors. In two fibrosarcomas the false signs resulted
from intracranial metastases.

General edema about small gliomas may involve an entire hemisphere
and lead to rapidly deepening coma, convulsions, and paralysis. About a pial
sarcoma invading the brain tissue Merzbacher observed very marked pro-
liferation of glia-cells which he interpreted as a reactive glioma. In a series
of 12 cases he found no reaction of the glia-tissue against carcinoma but
considerable reaction in the presence of sarcoma.

The disappearance of localizing symptoms, which is a well-known feature

TUMORS OF BRAIN 383

of brain tumors, may result from a change in anatomical relations, with
relief of pressure and subsidence of edema and exudate. Interesting cases
of relief from symptoms of brain tumor are recorded by Hawthorne. In
many brain tumors, especially gliomas, the entire brain tissue may be the
seat of structural changes resulting probably from general disturbance of
circulation. They consist in increase of glia nuclei, especially in the deep
cell layers, disturbed polarity of the cells, partial or complete tigrolysis,
shrinkage or complete atrophy of cells, pyknosis, karyolysis, or homogeni-
zation of nuclei, and marked increase of pericellular nuclei (Stern) .

(b) Disturbance of the circulation of blood, lymph and cerebrospinal
fluid becomes pronounced in the late stages of most brain tumors and leads
to general cerebral compression, with symptoms of headache, increasing
dulness, coma, slowing of pulse and respiration, and choked disc. On
exposing the brain the convolutions may appear flattened and pulsation
is absent. The essential feature of general cerebral compression appears
to be capillary anemia. In nearly all cases there is ventricular hydrops,
and this condition develops early in most tumors of the base, cerebellum,
and fourth ventricle. It is generally indicated by deep coma and muscular
spasticity. Secondary pressure effects of ventricular hydrops may be traced
in several directions: as upon the plexus veins, vena Galeni, and the great
sinuses; upon the surrounding brain tissue with atrophy; and upon the
chiasm and cranial nerves with false localizing symptoms.

Choked disc may be referred chiefly to the mechanical effects of general
cerebral compression. The fluid in the arachnoid spaces passes directly
into the lymph sheath of the optic nerve, distends the sheath and the lymph
vessels of the nerve, obstructs the blood flow of the central vein writh vari-
cosities in the retinal veins, and edema, hemorrhages, and eventual atrophy
of the optic cusp. Secondary exudative and degenerative changes may fol-
low and have led to the assumption that the changes are of toxic origin.
(Elschnig). The essential dependence of choked disc upon mechanical
edema best explains the sudden changes which this condition may exhibit.
A similar edema of the auditory labyrinth is also observed (Schwalbe).

(c) Spinal cord degeneration, affecting the posterior columns and ganglia,
results from distention of the spinal arachnoid with stretching, tearing and
compression of nerve roots. Batten and Collier found such changes in 20
of 29 cases. The cervical cord was chiefly affected, the condition was espe-
cially common with cerebellar tumors, and the chief symptom was loss of
knee-jerks.

(d) Meningeal complications consist chiefly in local or diffuse invasion
by the tumor process. While very pronounced conditions of this type belong
to pial melanoma and rare forms of pial sarcoma, Verdun was able to
collect 28 cases of more or less extensive invasion of the pia by various types
of tumors. In one glioma of the pons he observed extensive pial thrombo-
phlebitis.

(e) Changes in the skull. The bones of the skull may suffer absorption
from local pressure or thinning from general cerebral pressure. Bony changes
are most common with tumors of the base and in children, and by means of
the #-ray they form an important class of localizing symptoms. Up to the
age of puberty intracranial growths may separate the cranial sutures as does
hydrocephalus. Perforation of the skull is observed with hypophyseal
growths, which may discharge into the nares, and with sarcomas which pene-
trate the orbit or pharynx.

Anatomical Classification. — Of the numerous pathological conditions
which fall in the clinical group of brain tumors several may for the present

384 NEOPLASTIC DISEASES

purpose be eliminated from the category of intracranial neoplasms. Such are
the solitary tubercle, gummas, echinococcus cysts, and simple hydropic
cysts. The remaining list of true tumors includes:

f Astrocj'toma,
Glioma \ Gliosarcoma,

[ Neuro-epithelioma.

Sarcoma, derived from blood-vessels.

Endothelioma and psammoma, derived from endothelial structures of
the meninges.

Papilloma and carcinoma of the ventricles and choroid plexus.

Neurofibroma, arising from cranial nerve-trunks.

Melanoma derived from misplaced or wandering chroma tophores.

Fibroma and myxoma, derived from the dural connective tissue or repre-
senting acellular forms of glioma, or endothelioma.

Osteoma.

Lipoma.

Cholesteatoma.

Finally, there are specific tumors of the pineal gland and the hypophysis.

The plan adopted for the discussion of these tumors recognizes the fact
that some, especially the benign tumors, are of rare occurrence in the brain
and are of more general interest. Fibroma, osteoma, lipoma, endothelioma
and melanoma are therefore included with similar growths in other situations.

Tumors of the pineal gland and hypophysis are treated as specific diseases
of these organs. There remain as true tumors belonging to the brain, glioma,
sarcoma, and tumors of the ventricles. Glioma, the chief cerebral tumor,
occurs in other situations and its various types and locations will be con-
sidered together.

GLIOMA

Glioma is the characteristic tumor of the central nervous system and
consists of neoplastic neuro-epithelium or its adult derivative the glia-cell.
Three structural forms of this tumor may be distinguished:

1. Astrocytoma, typical adult glioma.

2. Gliosarcoma, anaplastic, cellular.

3. Neuro-epithelioma, embryonal.

The typical glioma occurs in the brain, spinal cord, and roots of cranial
nerves while atypical forms arise both in these organs and in the eye and in
teratomas. The adult form of glioma consists of well-developed glia-tissue
but in many embryonal tumors undifferentiated neural epithelium appears
and the tumors are called neuro-epithelioma. There are considerable varia-
tions in the proportions of glia-cells and glia fibers giving rise to the terms
" glioma molle" and "durum7' and the great predominance of round or spindle
glia-cells deficient in fibrils produces cellular tumors called gliosarcoma.
Some would limit the term gliosarcoma to mixed tumors derived from glia-
tissue and from mesoblastic elements in nervous tissue but it is doubtful
if such tumors exist, and in a morphological sense the term gliosarcoma is
admissible for cellular and malignant gliomas. Scaffidi argues for the meso-
blastic origin of a portion of the glia-cells. Glia tumor-cells often grow to
large dimensions and resemble ganglion-cells in tumors which may be called
glioma ganglionare, or ganglio cellular e.

Gross Anatomy.— Gliomas appear as irregular or rounded segments of nerv-
ous tissue of greater or less density than the normal tissue but often without
definite enlargement of the affected part. They are usually more opaque

TUMORS OF BRAIN 385

than normal brain tissue and the blood content is increased so that the color
is bluish. Hemorrhage or excessive development of blood-vessels, glioma
telangiectaticum, may render them especially conspicuous. Yet the borders
grade insensibly into the surrounding tissue so that it is often difficult to
determine the limits or even the existence of a glioma from the naked-eye
inspection. Gliomas obliterate the normal markings of the brain, some
are distinctly nodular and quite firm; they may cause flat protrusions of
the pia and a diffuse thickening is often produced. Ependymal gliomas
occur in the form of projecting nodules or larger masses which may become
pedunculated (Virchow, Linck). In Bielschowski's case and in Pfeiffer's
the tumors were multiple and the ventricles dilated. In size gliomas^vary

FIG. 138. — Glioma cerebri,

from a small focus to a diffuse involvement of nearly a whole hemisphere,
with distinct widening of the convolutions. They are seldom multiple, and
local metastases are rare. Retinal gliomas differ from the cerebral in
producing bulky fungating tumors. In the spinal cord the tumors may be
localized but usually they arise in the region of the central canal into which
they extend in the form of long cords, destroying the gray matter, and sheathed
by the white tissue. A dilated central canal may persist and the condition
resembles syringomyelia (Miura, Saxer, Schlesinger). Neuro-epitheliomas
frequently grow to large size and produce metastases.

Secondary degenerations in gliomas are relatively frequent. Hemor-
rhages, old with formation of cysts and deposit of pigment, or recent and
diffuse, belong to the natural course, especially of the cerebral tumors. Necro-
sis of large central areas is common. Hyaline degeneration may affect
the vessels and calcification may appear in such vessels or in old necrotic

386

N EOF LA STIC DISEASES

areas. Globular myelin droplets may be very numerous and may become
calcined. Soft gliomas may be extensively edematous, strands of tissue
being widely separated by collections of fluid. Myxomatoid changes follow
edema and have led to the use of the term myxoglioma. Cysts form from
absorbed necrotic areas, from extensive edema, areas of hemorrhage, and
dilated canals.

The structure of glioma presents glia-cells and glia fibers in their various
forms and in varying proportions. In many cases the typical spider cell
(astrocyte) is predominant. This cell has a small compact nucleus, and
scanty cytoplasm from which radiate very numerous comparatively short
fibers. Golgi believed that the cells with short fibers characterize tumors

Ci-vs-s-srw

of the outer cortex (astromas), while cells with long fibers are found chiefly
in the deeper or central gliomas, but this relation appears to be inconstant.
In other cases the cells are larger and the fibers less numerous and much
longer.

In certain tumors the large glia-cells possess cytoplasmic processes,
large nuclei, with multiple nucleoli, and closely resemble ganglion-cells.
Stroebe finds such cells most frequently about the edges of spaces lined
by neuro-epithelium, but they are not limited to such situations and in some
tumors all the cells may be of this type (Borst). Occasionally the cells
contain multiple nuclei, so that Stroebe speaks of giant-cell glioma. The
significance of these ganglionic glia-cells has generally been interpreted
as an expression of the normal developmental tendency of the originating cells
of the tumor, both glia- and ganglion-cells being derived from neural epithe-
lium. Even in normal brain tissue Golgi and v. Kolliker finds glia-cells

TUMORS OF BRAIN

387

approaching the form of ganglion-cells, and Renaut's view that glia-cells
functionate as conducting nerve cells is being regarded with increasing favor.

FIG. 140. — Detailed structure of glioma (astrocytoma). (After Stroete.)

FIG. 141. — Details of structure of a glioma. Astrocytes, round-cells, and cavities lined
by neuro-epithelium. Muller's fluid. Mallory's hematoxylon. (After Stroebe.)

Renaut described axis-cylinder processes in the large cells of glioma, but
Storch finds by means of Weigert's neuroglia stain that these processes have

388

NEOPLASTIC DISEASES

the brush-like ends of glia fibers and often terminate in the adventitia of
blood-vessels. Mallory finds that the cells in many gliomas contain from
2 or 30 of the glia granules described by Weigert in ependymal cells, and
that these granules form a valuable diagnostic sign of glioma. Pig-
mented astrocytomas of optic thalamus and lateral ventricle with ependymitis
granularis occurred in a case described by E. J. Kraus.

Finally, the cells in glioma may assume a spindle-form and when they
are numerous the tumor resembles a spindle-cell sarcoma. From the poles
of such spindle-cells the radiating fibers may usually be demonstrated, and
portions of such tumors may show more typical glia structure.

The glia fibers are the most characteristic element in glioma. Although
Ranvier and Weigert claimed that the fibers are disconnected from the cells,
Golgi, Kolliker, Lenhossek and many later observers using specific staining

FIG. 142. — Large cell glioma of brain cortex.

methods have shown that the fibers emanate from the cells and under ordi-
nary conditions retain their cellular connection. In normal tissue the great
length which the fibers attain, reaching ioooju (Kolliker) renders very
difficult the determination of their origin, and in glioses where fibers increase
and predominate over cells, solution of continuity may doubtless occur.
The study of gliomas emphasizes the essential connection of fibers and the
growing glia-cells into which they are readily traced (Stroebe, Storch, Borst).
That occasional separation of fibers from cells may occur and that this
condition is prominent in hard acellular gliomas can at the same time be
admitted (Aschoff). Ribberts holds that the relation of glia fibers and cells
is much the same as that between fibroblastic fibers and cells.

TUMORS OF BRAIN 389

The glia fibers are very numerous, fine and short (astrocytes) or fewer,
thicker and longer, while from the large glioma-cells there may pass only a
few coarse, irregular, protoplasmic processes which later assume the characters
of glia fibers and break up into a terminal brush. Anastomoses with other
fibers or connections with other cells are not observed. Buchholz and
Storch noted a striking accumulation of fibrils about the walls of blood-
vessels, but this feature is not invariable. Mallory finds that glia fibrils
may fuse together in a sort of membrane where they meet connective tissue
structures. Degenerating fibrils become varicose, fragmented, and granular.
The proportion of fibers varies extremely, the hard gliomas exhibiting a
predominance of them, while in certain round- and spindle-cell tumors they
may be difficult to demonstrate. Stroebe claims that neuroglia fibers may
always be demonstrated in gliomas, but this criterion cannot be demanded
for retinal gliomas and it is supplied with difficulty for some gliosarcomas.
Special stains are required for their complete demonstration, the best of which
are Weigert's neuroglia stain and especially Mallory's phosphotungstic
acid-hematoxylon .

In a somewhat peculiar form of cerebral glioma the detritus of the invaded
tissue becomes inclosed in large phagocytic tumor-cells in the form of homo-
geneous globules and much of the affected area is composed of such cells.
Between them lie many small cells with compact nuclei and scanty glia
fibrils besides which are many large multinucleated cells of uncertain origin.
On the edges of the tumor it seems possible to trace the ganglion-cells of the
invaded cortex which become hypertrophied with hyperchromatic nuclei
and are gradually lost among the numerous tumor-cells. Their ultimate
fate is uncertain but they seem to participate in the very diffuse tumor
process.

In many gliomas there are canals lined by small cuboidal cells which
resemble ependymal epithelium. The lumen is minute or of considerable
dimensions and the contents are watery fluid or granular detritus. The
external borders of the cells merge insensibly into the surrounding tissue,
and glia fibrils are scanty or missing. Canals of this character are to be
distinguished from rosettes of embryonal and often cylindrical neuro-epithe-
lium which inclose minute spaces and form large cysts in neuro-epitheliomas.
The significance of the ependyma-like canals has been variously interpreted.
Buchholz believed that glia-cells of the tumor became transformed into
ependyma-like cells with which they are genetically related. Stroebe and
many others have concluded that the canals arise from sprouts and misplaced
groups of ependymal cells and this view is suggested especially by the abun-
dance of such structures in tumors of the basal ganglia and spinal cord.
Misplaced islands of ependymal epithelium have been found by Arnold
in a deformed hemicephalic brain, by Miura in syringomyelia, and by
Aschoff in ependymitis granularis. A third origin has been suggested from
spaces lined by endothelium. In my own cases it has been possible to trace
the glia-cells of the tumor into cubical epithelium lining canals and spaces
usually of considerable size, and in these cases the cubical cells are of neo-
plastic type. In other cases canals lined by cubical epithelium not of neo-
plastic type have appeared on the outer portions of the tumor and these I
believe result from transformations of glia-cells of the invaded tissue. Similar
changes may be seen in other pathological conditions. Borst describes
them both in glioma and in multiple sclerosis. In central and spinal gliomas
the inclusion of groups of ependymal epithelium probably accounts for some
of the canals. The participation of endothelial cells in this process seems
very doubtful, and the presence of the canals does not require an ependymal

390 NEOPLASTIC DISEASES

element in the tumor anlage, as urged by Stroebe, since any of the glia-cells
may apparently produce the cubical cells in the formation of the canals.

Neuro-epithelioma. — In a numerous group of cases the cells greatly
exceed the fibrils, they assume a polyhedral or spindle form, rosettes of
low cubical or high cylindrical cells surround central points or canals, and
from its predominant cellular element the tumor is designated as neuro-epithe-
lioma or neurocytoma. In this group one has to deal with a more embryonal
form of glioma in which the cells develop but slightly from the original form
of embryonal neural epithelium. The essentially gliomatous character of these
tumors appears in the presence of very many well-formed neuroglia fibrils,
which with specific stains are nearly always demonstrable and often form a
very prominent structural feature. In edematous, degenerating and spindle-
cell growths the fibrils, which are a highly important diagnostic feature,
may be scanty and difficult to identify.

4rt£iEBfi?V'* ' . "*"

;i.V:

FIG. 143. — Structure of neurocytoma. (After Landau.)

Neuro-epitheliomas are of wide distribution, occurring in the cortex,
basal ganglia, arachnoid, eye, spinal cord, abdominal sympathetic, adrenal,
and in teratomas in many situations. The retinal gliomas are often of this
type. Many of them are very cellular and in this class fall most of the tumors
to which the term gliosarcoma has been applied. It is probable that the
gliomatous nature of many sarcomas connected with the nervous system has
been overlooked.

The blood-vessels in gliomas are usually abundant. They appear as
medium-sized arterioles with well-developed walls, or as capacious venules
with thin walls, or as large sinuses. Areas of cavernous blood-vessels may
displace the tumor-tissue, and varicosities are common. The walls may
undergo a peculiar thickening and hyalinosis which may terminate in occlu-
sion and formation of lamellated homogeneous, or partly calcified masses.
Proliferation of the cells in the walls of vessels may be considerable but a

TUMORS OF BRAIN 391

true neoplastic character I have not observed in this process. The capacity
of the blood-vessels is very great and the blood content is subject to wide
variations. Hence the course of glioma is marked by intermittent symptoms
dependent on variations in the blood content, and hemorrhage with apo-
plectic symptoms is frequent. Several observers have noted an accumulation
of glia fibrils about the blood-vessels, a feature which I have seen, especially
in neuro-epithelioma. Small vessels may form the nodal points of neuro-
epithelial rosettes and the entire tumor may consist of thick perivascular
cell sheaths, an arrangement determined by the demands for nutrition.

The growth of gliomas is one of the best examples of tumors of the infil-
trative type. The edge of the tumor often merges insensibly into the sur-
rounding tissue and usually fails of demarcation by vascular reaction or
cellular exudate or signs of compression. Yet the hard gliomas and the
neuro-epitheliomas may be sharply circumscribed from the surrounding tissue
by virtue of expansive growth. Pressure symptoms are slowly established
with all varieties of glioma, infiltrative or expansive, but these symptoms

FIG. 144. — Detail of fibril formation in a neurocytoma. (After Landau.)

are partly dependent on the blood content and may therefore be intermittent.
Flattening of convolutions often occurs and demonstrates the existence of a
permanent mechanical element in the pressure symptoms. On the edges of
infiltrating tumors one finds a zone of round-cells with few or no fibrils, and
Ribbert points out that it is only such cells without fibrils which are capable of
explaining the infiltration. Just within the growing edge the cells develop
fibrils which permanently fix their location. Hence the growth of typical
glioma is slow. Cell-division by mitosis, symmetrical or multipolar, and by
amitosis, has repeatedly been observed.

The fate of the invaded tissue is gradual atrophy and absorption, but
ganglion-cells may persist for some time on the edges of the tumor, and
Stroebe finds in all cerebral gliomas traces of medullated or naked nerve-
fibers derived from the original tissue. Large vacuolated phagocytic cells
containing fatty detritus and pigment may appear on the edges of the tumor
or throughout its substance.

The possibility that the normal glia-cells are partly transformed into
tumor-cells, while actively opposed by Ribbert, is considered as uncertain
by Stroebe and others. It is not yet clear what relation is borne by certain
structural anomalies observed in the central nervous system and the

392 N EOF LA STIC DISEASES

occurrence of very diffuse forms of glioma and the uncertain criteria which
separate glioma from certain glioses render somewhat hazardous a definite
opinion on this point. In a peculiar form of diffuse cerebral glioma, I
find that the ganglion-cells seem to become hypertrophied, they acquire
multiple pyknotic nuclei, and become merged with the numerous glia-cells of
the tumor.

Resistant structures offer a rather firm barrier to the advance of glioma
even to the most cellular varieties. The pia mater terminates the extension
of most cortical gliomas but is itself often split up by strands of cells which
fill the natural spaces of this membrane, leading to adhesions but not to
metastases. The retinal tumors, however, infiltrate the perivascular sheaths.
Spinal tumors also may extensively infiltrate the pia and subdural space.

The differential diagnosis of glioma from sarcoma may offer difficulties,
especially with the small round- or spindle-cell tumors. According to
Stroebe the small glia-cells show very scanty cell body but some fine fibrils
are always attached to the cells. The margin of the glioma shows infiltra-
tion by tumor-cells but lacks the sharp demarcation and reactive inflam-
mation often observed with sarcoma. The glia-cells are of uniform character
throughout the tumor and fragments of medullated nerve-fibers or myelin
droplets are always present. Gliomas do not infiltrate the vessel sheaths
and they either stop at the pia, or if infiltrating its layers, do not destroy this
structure and cause its fusion with the tumor. Yet Pels-Leusden saw very
extensive infiltration of the pia up to the medulla from a lumbar glioma.
A fibrin network is said to closely simulate glia fibrils but fibrin fibrils radiate
from nodal points and are not connected with cells but exhibit numerous
anastomoses.

Sarcoma-cells may possess fibrils but they are less numerous and more
granular than glia fibers. Glioma without fibrils probably occurs in rare
cases, but cellular tumors of this character almost always prove to be sar-
comas. The existence of glioma with sarcoma of the vessels of the central
nervous system has not been satisfactorily demonstrated. In some cases
the diagnosis may remain in doubt. Borst studied two sarcomas of the
brain which showed all the gliomatous characters except abundant fibrils,
and Stroebe claims to have observed a primary infiltrating round-cell
sarcoma of the supramarginal gyrus with fatal hemorrhage. Such tumors
suggest the existence of glioma without fibrils. In a tumor of the lumbar
cord Thiele saw cellular glioma in the upper portion changing to spindle-cell
sarcoma below. Henneberg also found purely sarcomatous areas without
fibrils in a glioma of the brain. It is therefore highly probable that anaplastic
gliomas occur in which no trace of fibrils may be demonstrable. Gowers
and Bruns both concluded that glioma-cells frequently resemble sarcoma-cells
and may exhibit no signs of specific fibrils, but Borst is inclined to exclude
uncertain cases from the category of glioma. It is probable that the careful
use of modern staining methods will greatly limit the number of doubtful
cases.

Etiology of Glioma. — Although occurring at any age, the predominance
of gliomas in early life, their frequency in childhood, and the occurrence
of bilateral congenital gliomas of the retina, indicate that the tumor
usually results from an embryogenic disturbance in the structure of the
nervous system, v. Rindfleisch assumed the existence of superfluous embry-
onal tissue distributed in the glia structures as furnishing the cells of origin
of gliomas. Lenhossek conceived that these embryonal cells must take
the form of indifferent round-cells without fibers, but mitotic figures have
been observed in adult glia-cells in forms of gliosis, and multiplication of

,. TUMORS OF BRAIN . 393

glia-cells and especially of fibers occurs in chronic sclerosis. It is quite clear
that these highly differentiated and firmly bound cells are by no means devoid
of regenerative power.

The association of glioma with various gross deformities is further
evidence of the embryonal origin. Schule observed multiple glioma of the
cord with fissure of the medulla. Schmidt interpreted a glioma of the nasal
sinus as a form of encephalocele and referred to several other cases of the
same nature. Hildebrand collected a series of cases of glioma associated
with gross abnormalities in the central nervous system.

Heterotopia or local malformations of the cortex have been observed
which suggest a probable origin for some cerebral gliomas. Ernst described
misplacement of circumscribed foci of cerebellar tissue which exhibited
some of the characters of incipient glioma. Baumann observed multiple
thickened areas of cerebral gyri in which there were groups of hypertrophic
ganglion cells. Hartdegen found a dozen very hard areas in several convo-
lutions in a newborn infant with spina bifida. These areas contained numer-
ous groups of large polygonal cells resembling large ganglion-cells. In the
ventricles projected several nodular swellings of the same structure.

Schultze observed reduplication of the central canal with glioma of cere-
bellum and gliosis of the cord. In cases of congenital hydrocephalus there
may appear multiple nodular outgrowths in the cortex which resemble
tumors. They consist of glia-tissue rich in fibers and of ganglion-cells and
they are associated with focal sclerosis and hypertrophies (Lubarsch, Borst).
Small gliomas probably of this class are described by Simon and Meschede.

The embryonal character and eccentric position of the neuro-epitheliomas
indicate their derivation from embryonal and misplaced cells, and this
origin becomes certain in the numerous group of gliomatous teratomas in
which the structure is usually that of neuro-epithelioma.

On the other hand the embryogenic disturbance becomes less prominent
and less essential with the slowly growing and diffuse gliomas of the brain
which may exhibit a very wide distribution. Such cases have suggested to
Rindfleisch and many others that here the glioma is not a true tumor but a
chronic proliferation of glia-tissue resulting from a disturbance of nutrition.
Stroebe was much impressed with this view and even went so far as to describe
protozoon-like structures in the cells of old gliomas. In the cord the chronic
gliosis associated with syringomyelia passes through many gradations up to
true glioma with central softening (Saxer, Schlesinger), and Miura finds
it difficult to distinguish between central gliosis and glioma. Meyer and
Beyer describe focal lesions in the brain, the inflammatory or neoplastic
nature of which they find it difficult to determine. Heterotopia of ependy-
mal epithelium seems to favor both the gliosis of syringomyelia and ependymal
glioma, and Schultze and Hoffmann expressed the view that both processes
arise in superfluous tissue about the ventricles and central canal.

In a study of seven cases of ependymal gliomatosis Margulis found
the lesion distributed over the ventricles, especially the lateral, and affecting
also the subcortical tissues. It was often associated with other proliferative
processes affecting the glia-tissue but inflammatory changes in the vessels
were missing. Many stages of the progress terminating in sclerosis may
usually be observed in the same case. He interprets the condition as a
local or general response of the glia-tissue to infectious or toxic irritation.
The symptomatology was variable and not specific.

Pf eif er found the entire ventricular system covered with projecting nodules
from which extended a diffuse infiltration of the surrounding brain tissue.
The nodules consisted of small polymorphous cells with fine, short processes

394

• NEOPLASTIC DISEASES

but true astrocytes were scanty. Roccavilla demonstrated diffuse glioma-
tosis of brain and medulla in a child with spina bifida and reduplication of
the central canal of the cord. He regarded the gliosis as the result of prolifera-
tion of congenitally superfluous glia-cells.

All of these observations form a rather broad bas's for the conception of an
anatomical predisposition as an essential factor in the etiology of glioma.
The formative influence of misplaced epithelium may be a factor of impor-
tance in such cases, and the etiological inquiry leads back to the influences
which cause the misplacement. Here structural abnormalities, chronic
inflammation, and possibly trauma, all claim attention (Henneberg).

FIG. 145. — Early multiple extramedullary cylindrical cell tumors of ependyma and spinal
arachnoid. Section of cauda equina. (Pfeiffer's case, Z. N. 5.)

Thus the etiology of glioma reveals in this group of tumors many grades
of neoplastic growth, from processes which are difficult to distinguish from
replacement or slightly formative glioses, up to highly embryonal tumors.

The relation to trauma has already been discussed.

Clinical Types of Gliomas.-— (a) Cerebral gliomas have been chiefly
considered in the foregoing general discussion. These tumors are usually
soft and hemorrhagic, ill-defined or rarely firm and nodular, and their
position is subpial, intermediate, or central. Multiple flat or nodular growths
of variable structure project into the ventricle. The cerebellum, basal
ganglia and medulla and pons furnish the majority of cerebral cases. The
centrum ovale is a favorite seat. In structure the great majority of cerebral
gliomas fall in the class of astrocytomas with small cells richly provided

TUMORS OF BRAIN 395

with fibrils, but gliomas with large ganglionic cells are not infrequently
observed, and there are many other variations in structure.

The histological classification includes the following varieties of intra-
cranial gliomas:

1. Embryonal heterotopias of small segments of gray and white matter,
with slight hypertrophy and hyperplasia of cells and fibers.

2. Hard gliomas approaching in structure simple gliosis.

3. Typical astrocytomas with or without canals lined with low or high
epithelium.

4. Astrocytomas with many large ganglionic glia-cells.

5. Neuro-epithelioma.

6. Diffuse atypical glioma, with many imperfect astrocytes and formation
of many large multinucleated cells and phagocytic cells distended with myelin.

7. Gliosarcomas, round- or spindle-cell tumors with partial or complete
loss of glia fibrils.

(b) Nasal Glioma. — A peculiar form of cerebral glioma appears in children
as a swelling at the base or tip of the nose or in the nasal sinus (Schmidt).
They arise as a form of encephalocele and Reid and Muhr traced the origin
through the foramen cecum, Meyer through the cribriform plate. In
two cases of Clark's large ganglionic glia-cells were well represented, but other
cases have shown only glia-tissue with scanty evidence of progressive growth.

(c) Glioma of the spinal cord appears in several widely different forms
dependent upon the origin, location, and varying grade of the neoplastic
character of the process.

1. Solid central glioma is a common form of the spinal tumor of which
Schlesinger has collected 18 cases. The growth forms a cylindrical mass
inclosing or obliterating the central canal and surrounded by a sheath of
the distended white matter which in places may be entirely destroyed. It
extends over several segments in any portion of the cord or involves almost
the entire organ (Daxenberger, Miura). A tumor limited to the filum termi-
nale was observed by Lachmann, and an irregularly distributed growth
yielding Brown-Sequard's syndrome was studied by Volkmann. The tumor
seldom reaches the pia but this structure may become involved and in a case
described by Pels-Leusden the arachnoid was diffusely infiltrated from cauda
to medulla. Grund collected several similar cases.

The structure of the tumors varies considerably. Not a few belong
in the group of neuro-epithelioma with the predominance of polyhedral or
spindle-cells with spaces lined by high epithelium and comparatively few
astrocytes and glia fibers. Such tumors exhibit expansive growth, but
Ribbert has observed both types of growth in the same tumor. In others the
structure is that of the usual type of cellular glioma. Astrocytes and glia
fibrils are abundant. Large glia-cells are also present but the adult characters
are prominent, the tumors grow slowly and they infiltrate the surrounding
tissue. Canals and spaces lined by ependyma-like cells and compact
groups of such cells are present. The majoity of spinal gliomas fall in this
latter class.

2. In a group of cases a definite gliomatous process is associated with
syringomyelia at one or both poles of the tumor, which itself may exhibit
elongated canals lined by cubical cells. A typical case is that of Rosenthal in
which the tumor was composed largely of a series of canals lined by embryonal
ependymal cells lying in a cellular glioma with many astrocytes. Other cases
of this class have been collected by Miura. The associated syringomyelia
has been referred by some to disturbance in circulation caused by the tumor,
while^ others regard the tumor as an advanced stage of a process depend-

396

N EOF LAST 1C DISEASES

ent on developmental anomalies which lead also to the syringomyelia. There
can be little doubt that the chief factor in the softening which produces
the canal is the presence of fluid under pressure. Saxer describes a central
glioma with syringomyelia extending far beyond the ends of the tumor. In
the central portions of the tumor the canal was lined by neoplastic epithe-
lium, extensions of which formed a part of the growth. Elsewhere in the
tumor the canal was walled by softened tumor-tissue. Above and below the
tumor the canal lay in an area of simple gliosis which Saxer refers to dis-
turbances in circulation caused by the tumor. In a case studied by Strauss
in this laboratory the canal extended from the cauda to the pons. It was

V ->"*

FIG. 146. — Miliary glioma of spinal gray matter. (From a specimen of Dr. I. Strauss.)

surrounded by a well-circumscribed zone of dense gliosis, beyond which the
cord was compressed or soft, edematous, and contained many granule cells.
The proportion of glia fibrils and cells varied at different levels, fibrils
greatly predominating, but ganglionic glia cells were occasionally found.
Ependymal epithelium was entirely missing and all stages of central softening
of the tumor could be seen. Here was a low grade but definite tumor process
leading to syringomyelia by central softening. This case supports Saxer's
view that no embryonal anomaly is needed for the development of central
glioma with syringomyelia, and that there is no essential connection between \
these cases of glioma and the central canal or its epithelium.

•• TUMORS OF BRAIN 397

3. In an important group of cases a pronounced central gliosis is asso-
ciated with extensive syringomyelia. The new glia-tissue is comparatively
acellular but its dimensions are considerable and the tracts are displaced
and the cord deformed. Definite histological features of neoplastic growth
are lacking but not more so than in some slowly growing diffuse gliomas of
the brain. The central space is wide and an epithelial lining may be wanting,
in which case the canal seems to be formed by progressive softening of the
new tissue. Or the canal may be lined by epithelium which may show numer-
ous invaginations extending into the new tissue. In some cases the canal
may be compressed by a bulky overgrowth of rather cellular glia-tissue
(Hoffmann).

The significance of these cases of syringomyelia with overgrowth of
glia-tissue has been the subject of much discussion by observers whose
views are summarized by Saxer. Some regard the process as a true neoplasm
while others consider it as a form of inflammatory gliosis. In favor of the
neoplastic theory is the congenital character of some cases in which the
syringomyelia follows hydromyelia with extensive gliosis and secondary
degeneration (Saxer, Schlesinger). Lateral invaginations of epithelium
occur with hydromyelia and may favor the gliosis. In certain cases without
hydromyelia the presence of outlying groups of epithelial cells about the
central canal suggests the deposit of superfluous material in this locality.
Hence Hoffmann, who finds considerable proliferation of cells in the new tissue,
regards the process as neoplastic. Storck having observed angiomatous
glioma in the upper cervical cord combined with syringomyelia below, in-
clines to the same view. There is no doubt also that pronounced glioma is
occasionally associated with extensive cavity formation, as in the cases of
Pels-Leusden, Saxer, Strauss, etc. On the other hand it is clear that syringo-
myelia may result from many processes not connected with tumor growth,
as in myelitis, meningomyelitis, hematomyelia, simple regressive tissue
atrophy (Chiari), lymph or blood stasis (Langhans, Storck) and various
chronic inflammatory processes (Saxer). The softening and solution of
tissue about the central canal may be referable to changes in the blood-
vessels to which this region is prone, and the outgrowth of epithelium is
probably often a natural extension of the lining cells of the canal in the
attempt to cover defects thus created (Mliller, Meder, Miura). Finally,
the symptoms of genuine tumors of the cord are pronounced and progressive,
while those of the present group of syringomyelia are suppressed or mild,
or of very slow progress (Baumler, Simon).

It seems necessary therefore to exclude most of the present group of
cases from the class of true glioma, and to regard them as representing
that common type of process which falls into an intermediate position between
neoplasms and inflammatory or simple tissue hyperplasia. Syringomyelia
occurs in the course of central glioma but unless the structure of the process
is clearly gliomatous the case should not be classed in that category.

(d) Pial glioma occurs as a secondary invasion of this structure from
central tumors (Pels-Leusden, Grund), or as a primary tumor arising from
misplaced glia-tissue. Inglis reports a pial glioma composed of scanty
astrocytes and many fibrils, originating from the root of the seventh dorsal
nerve and forming a small elongated intradural tumor. In the numerous cases
of extradural tumors collected by Leyden, Goldscheider, Grund and others, it
does not appear that any uniform effort was made to recognize glioma, so that
the frequency of extradural glioma cannot at present be stated. Thus in
two cases recorded by Spiller as sarcoma, the author later states his impres-

398 NEOPLASTIC DISEASES

sion that they were gliomatous. That many supposed multiple gliomas of
the cord are artefacts was shown by Van Giesen.

(e) Neurocytoma. — Under this term Wright has collected a series of tumors ,
chiefly of the adrenal with metastases in the liver, but also occurring in
the cranium and elsewhere. They have the structure of embryonal neuro-
epithelioma. In some the cells exhibit abundant fibrils, in others cells
greatly predominate over fibrils and assume the rosette arrangement. Wright
believes that certain tumors reported as sarcoma, lymphoma and lympho-
sarcoma are in reality highly embryonal forms of neuro-epithelioma, as in the
cases of Pepper, Tileston and Wolbach, and Hutchinson. For the so-called
congenital sarcomas of the adrenal and liver Kretz has expressed the view
that they arise from the formative cells of the sympathetic.

(f) Teratomatous Glioma. — Nervous tissue occurs in a considerable
proportion of teratomas. In teratoma testis, besides portions of brain,.

FIG. 147. — Neurocytoma. (From a section of Symmers' case.)

retina, ganglia, and ependyma, neuro-epithelial cells frequently occur and
may occasionally form a considerable portion of the tumor (Ohkubo, Lit.).
In ovarian teratoma nervous structures are rare.

From the sacral region Mallory has described a large neuro-epithelioma
presenting the structure of carcinoma but exhibiting an extensive develop-
ment of neurofibrils. The origin of the tumor he referred to remnants of
the neural canal (Fig. 148).

TUMORS OF THE CHOROID PLEXUS AND EPENDYMA

A considerable variety of pathological processes occur in the choroid
plexus and ependyma, many of which have a relation to tumors of these
structures.

Pigmentation, and calcine, fatty, and amyloid degeneration are frequently
observed in the choroid plexus and have been described in detail by E.
Hackel. Common structural changes include varicosity and overgrowth

TUMORS OF BRAIN

399

of blood-vessels, thickening, induration and mucoid degeneration of the
stroma. Calcine changes in the vessel-walls may lead to the formation of
angioliths, which are commonly observed in subjects over 50 years. A diffuse
overgrowth of stroma and lining cells with well-marked squamous meta-
plasia may result from chronic inflammation (Delamarre, Merle). Cysts
arising from mucoid degeneration of the stroma occurred in 15 of 23 cases
studied by Loeper. Rarely such cysts reach a large size, and in the case of
an infant observed by Cayley and Brown there was protrusion of the parietal
bone by a very large cyst. In the infant the choroid plexus is very highly
developed and the abundance of lipoids, pigment, and glycogen have led to
the assumption that it possesses a secretory function. Petit and Girard

•'•7

FIG. 148. — Sacral neurocytoma, with rich development of fibrils. (Mallory's specimen

and stain.)

class this structure with the hypophysis and other glands of internal
secretion.

The ependymal epithelium is also capable of marked proliferation with
changes in form and size in acute and chronic simple and specific inflam-
mations (Ependymitis granularis). In several conditions but chiefly
in tumors, close relations are revealed between ependymal and glia-cells,
the one readily becoming transformed into the other. Thus in inflamed
and edematous brain tissue, polyhedral cells often inclosing lumina appear in
multiple foci, by a type of embryonal reversion of glia-cells. In many gliomas
alveoli, spaces, and cysts form with a lining of cubical or cylindrical cells
of ependymal form (Saxer, Muthmann, Sauerbeck, Lit.). In certain multiple
ependymal gliomas the ependymal and the modified glia-cells are richly
commingled and one type of cell passes into the other (Linck). With both

400

NEOPLASTIC DISEASES

ependymal and plexus epithelium nutritional and inflammatory changes
seem to pass through many gradations into tumor processes.

The excessive pigmentation observed by Virchow in the pia-arachnoid,
with tumor-like proliferation of cells, appears in exaggerated form in the
melanomas arising from these cells (Pick, Esser, Thorel). Extensive calci-
fication of the plexus may apparently lead to the rare osteoma of the ventricle
(Bonnet). The common angioliths appear frequently in cellular tumors of
the plexus. Myxomas and angiomas recall the mucoid stroma and varicosi-
ties of the chronically inflamed plexus. Hypertrophy of the plexus may

lead to extensive overgrowth of this
structure, and Bruchanow interpreted
his large papillary tumor as a simple
hypertrophy and hyperplasia. Ependy-
mitis granularis involves both epithe-
lium and subepithelial glia-tissue, and
seems to present a frequent preliminary
to multiple ependymal gliomas of the
ventricles (Jeremias, Saltykow).

General Etiology. — Tumors of this
entire group are comparatively rare.
Boudet and Clunet found 32 cases on
which to base their study, but their list
does not include many recent cases.
The majority of subjects are children or
young adults. A history of typhoid
fever, or coincident tuberculosis, has
frequently been noted. In several cases
trauma had recently preceded the out-
break of symptoms (Muthmann, Sauer-
beck, Linck, Saxer).

The chief seats are the fourth, the
lateral and the third ventricles, n, n,
and 7 cases respectively being located
in these situations by Boudet and
Clunet. Four cases were extracerebral
and in the region of the chiasm. Cornil
described two papillary tumors within
cortical tissue. Marchand's tumor was
attached to the oculomotor nerve.
Fauret finds that tumors of the fourth
ventricle are chiefly observed in chil-
dren and often appear to follow trauma.
They are chiefly astrocytomas or
He collected 12 gliomas, i gliosarcoma, 3 sarcomas,

5 papillary tumors of the plexus and 4 cysts, all involving the fourth ventricle.
Hunt describes two congenital cystic tumors projecting into the fourth ven-
tricle. Weisenburg collected 30 tumors of the third ventricle with autopsy,
and points out that the symptoms in these cases are caused by pressure or
by hydrocephalus. The syndrome is ill-defined but presents ocular paral-
yses, impaired reaction of pupils, exophthalmos, and cerebellar ataxia.
Bassoe reports 6 ependymal gliomas of third and fourth ventricles.

A congenital anatomical predisposition has often been assumed to favor
the development of tumors of the plexus and ependyma, but there is little

FIG. 149. — Papillary carcinoma of
choroid plexus distending lateral ventricle.
(After Boudet and Clunet.}

ependymal gliomas.

TUMORS OF BRAIN

401

evidence in favor of this view. Saxer's large congenital tridermal teratoma
attached to the plexus is an unique observation.

FIG. 150. — Structure of papillary carcinoma of choroid plexus in lateral ventricle. (After

Boudet and Clund.)

FIG. 151. — Papillary adenocarcinoma of choroid plexus in third ventricle.

Gross Appearance.- — The tumor is usually single except in the case of the
ependymal glioma, which is regularly multiple. While several small growths
have given rise to perplexing cerebral symptoms, the tumors frequently

402

NEOPLASTIC DISEASES

reach the size of an egg or an orange and produce definite focal symptoms.
While usually circumscribed they may invade the brain tissue. The ven-
tricles are frequently distended. The papillary conformation predominates
but some growths are spongy or polycystic, a few resemble thyroid gland
tissue (Mackay, Bruce), and nearly all are highly vascular.

Structure. — Tumors of the ependymal epithelium vary from the peri-
vascular neuro-epithelioma toward the true glioma (astrocytoma) with
spider cells and glia fibrils, while tumors of the plexus retain a papillary
adenocarcinomatous type and may show squamous metaplasia. Von Wilier
points out that the ependymal epithelium is ciliated at birth and long re-
tains the condensed border and intracellular fibrils of ciliated cells, whereas

FIG. 152. — Structure of a papillary carcinoma of choroid plexus in the third ventricle.

the plexus epithelium is granular, reticulated and secretory in type. These
original characters may assist in the separation of the two types of tumors.

Three main structural types are observed (i) Papillary adenocarcinoma
(2) Pavement-cell carcinoma, and (3) Ependymal glioma.

i. Papillary adenocarcinoma is the usual form of tumor of the choroid,
plexus. The papillary axis contains a well-developed blood-vessel supported
by scanty connective tissue which often undergoes mucoid degeneration.
Rare fibromyxomas probably represent a predominance of this structure.
The blood-vessels are thin walled, often varicose, and subject to hemorrhage.
Calcification of the walls often leads to complete occlusion by angioliths.
The lining cells present one or more rows, the first usually cylindrical,
the others cubical. Numerous capillary blood-vessels surrounded by a single
layer of cubical cells are a common picture. In cellular growths adjoining
papillae fuse, the epithelium may grow diffusely, and an angiosarcomatous

TUMORS OF BRAIN

403

structure may result. In one case I found all the cells very small, cubical,
consisting chiefly of nuclei, and suggesting a gliomatous tendency (cf.
Boudet). Cysts form by mucous degeneration of the stroma and they
are usually bounded by palisade cells.

Malignant tumors yielding multiple metastases in the pia or brain
tissue have been observed. Spat found a primary tumor of the plexus or
ependyma of the lateral ventricle with small multiple metastases in the brain
substance. Bielschowsky and linger describe a large vascular papillary
growth arising from the plexus of the lateral ventricle. A second tumor
developed in the lateral horn of the fourth ventricle and 14 metastatic nodules
appeared in the pia over both hemispheres. The structure presented capil-
lary vessels surrounded by radiating high cylindrical cells. E. Meyer found
a tumor in the third ventricle composed of numerous hyaline blood-vessels
surrounded by small closely packed round cells, while two small nodules of
similar structure appeared in the fourth ventricle. Although this tumor was

\ ^j$i ^«S"- / JT ,-;*:? ^

l|8Sk,-'fp f;^,f £f.si

FIG. 153. — Papillary adenocarcinoma of choroid plexus. A specific tumor of ependymal

cells. (From Saxer.)

described as a sarcoma a relation to the small-cell epithelial tumors of epen-
dyma or plexus is suggested. Kaufmann also pictures round-cell sarcoma of
the pia with hyaline blood-vessels.

2. Squamous-cell carcinoma is the type presented by certain tumors
of the choroid plexus. Occurring in the third ventricle they may be dim-
cult to distinguish from acanthoma of the hypophyseal duct, but similar
growths are observed in the fourth and lateral ventricles and without rela-
tion to the hypophysis (Cornil, Boudet, Clunet).

The structure is essentially a duplicate of the adenocarcinoma. The
squamous-cells appear in scanty groups or diffusely and they form pearls
or diffuse sheets usually surrounded by cylindrical cells.

Boudet and Clunet collected seven cases in which keratinization was present, but the
origin of some of their cases is doubtful. Mott and Barrat in a tumor attached to the

404

N EOF LA STIC DISEASES

choroid plexus observed intercellular bridges between flat cells. E. Wagner described a
villous papillary tumor near the chiasm without involvement of the hypophysis. It was
covered externally with many long papillae lined in places by cylindrical cells in other places
by flat stratified cells. Selke's case has been variously interpreted. It was a large
tumor of the third ventricle passing by the foramen of Monro into the lateral ventricles.
The hypophysis was intact. The ependyma about the base of the papillary tumor was
represented by layers of squamous cells lying on connective tissue and the entire tumor
contained flat stratified cells. Selke regarded the growth as originating from the ependyma
of the third ventricle, while Erdheim considers it a cystic tumor of the hypophyseal duct.
Saxer has described a papillary tumor of the choroid plexus of the third ventricle, a com-
pact papillary adenocarcinoma of the fourth ventricle and a papillary squamous cell-growth
from the hypophyseal duct, all of which form in structure comparative types of these
tumors.

3. Ependymal glioma is a rare but well-defined tumor. Linck collected
six fully described cases and to these may be added those of Saxer (Wun-
scheim), and Mallory. Cimbal refers to many fragmentary reports. Its
chief seat is in the fourth ventricle, where it commonly produces a bulky,
solid, rather firm but vascular tumor which produces marked pressure symp-
toms. Cimbal's tumor showed extensive central necrosis and Henneberg

FIG. 154. — Characteristic fibrils and granules of ependymal cells. (After Mallory.}

described a gelatinous growth as large as a hen's egg. The ependyma of the
ventricle is usually the seat of multiple or diffuse, granular or papillary out-
growths, and from such lesions the tumors probably originate. The structure
varies chiefly in the relative proportions of ependymal epithelium and astro-
cytes with their fibers. At one extreme the tumors approach the ependymal
adenocarcinomas (Saxer's case), and at the other they may be chiefly glio-
matous (Linck's case). Alveolar groups of neural epithelium are regu-
larly present in the form of cubical or cylindrical cells inclosing ill-defined
lumina or surrounding capillary blood-vessels. In some cases the cells
are very long and cylindrical. By suitable stains (Mallory) neuroglia
fibrils derived from the cells may be demonstrated. In very cellular tumors
the cells become more numerous, of small size, round or spindle, the fibrils
diminish and a picture resembling round-cell sarcoma may result. That
gliosarcoma in the vicinity of the ventricles may develop in this way may
safely be assumed. The prominence of blood-vessels may suggest an angio-

TUMORS OF BRA IX 405

sarcoma, or very cellular sheaths about blood-vessels may yield a perithe-
liomatous structure.

The origin of these tumors has been traced satisfactorily to the ependymal
epithelium and the underlying glia tissue. In ependymitis granularis the
erosion of segments of ependymal cells permits minute extrusions of the
underlying glia layer, forming the characteristic granules of ependymitis
(Jeremias). Proliferation of the glia tissue and the neighboring ependymal
cells follows and the tumor develops with varying proportions of these ele-
ments (Linck). A transformation of ependymal cells into astrocytes probably
occurs in some tumors but mitotic figures are limited to the rounded or cubical
epithelium (Saxer).

Tumors of the Infundibular Ependyma.— The hypophyseal region and
the third ventricle are the seat of a group of papillary cystic tumors which
strongly suggest an origin from ependymal epithelium. These tumors lie
outside of the brain tissue, but within the dura. In advanced cases it may
be difficult to determine their original relations. They are composed of a
loose edematous meshwork of connective tissue covered by one or more layers
of small cubical epithelium which may be gathered into broad sheets or
thrown up into papillary projections. The great vascularity and the
perivascular arrangement of the cells often recalls the structure of the
choroid plexus. Saxer, Hart, and others have attributed such tumors to
the ependymal epithelium and their occurrence largely beneath the base of
the brain and in close relation to the pedicle of the hypophysis indicates that
they may arise from the ependymal prolongation of the infundibulum. I
have studied such a tumor in a young girl with a long history of cerebral
compression. The growth was cystic, 4 cm. in diameter, lay above the hypo-
physeal lobes, had destroyed the pedicle, was separated by a thin partition
from the distended ventricle and the structure resembled Saxer 's (Case i)
ependymal carcinoma. A somewhat similar case is described by Mullaly.

GLIOMA OF RETINA

Characteristic clinical behavior and peculiar structure render glioma
retina one of the most striking examples of a specific tumor process. Many
of the old cases of fungus hematodes described by Wardrop wrere probably
of this nature. The first histological descriptions were given by Robin in
1854, since which time the interpretation of the tumor has been the subject of
very extensiye study and speculation, which have not yet reached a final
conclusion (Parsons, Lit.).

These tumors are soft and bluish in early stages, but soon become milky
or gray from fatty degeneration and focal calification. They are very sub-
ject to necrosis, and are often hemorrhagic. Twenty-three per cent, are bi-
lateral. They arise chiefly from the ciliary portion or from the posterior seg-
ment of the retina. According to Wintersteiner the origin is often multiple
and chiefly from the posterior pole. The origin has been traced in different
cases with considerable certainty to the internal granular layer (Knapp,
Hirschberg), from the inner side of external granular layer (Delafield),
from the external granular layer (Schweiger, Flexner), from the fibrillar
layer (Iwanoff). The early anatomical and ophthalmoscopic appearances
are tabulated by Eisenlohr. The tumors grow expansively, splitting the
retina and stripping it from the choroid or covering it with a mass of tissue
which encircles the vitreous or penetrates it in dendritic masses. Invading
the choroid at the papilla it may form a discoid mass in this structure, and
traveling within the optic nerve it reaches the base of the brain (Knapp).

406 NEOPLASTIC DISEASES

In the eyeball it later replaces the vitreous, invades all portions of the
bulb, perforates the sclerotic or cornea by way of the vessels, invades the
orbit, from which in advanced cases it protrudes as a vascular necrosing
tumor of large dimensions. Metastases are late or absent but recurrence is
common, and secondary growths appear in brain, skull, spinal cord, regional
lymph-nodes, and internal organs. Most cases have proven fatal (66 per cent.
Wintersteiner), but Collins reports four recoveries (?) from bilateral tumors
after double enucleation. In a group of cases glioma retinae is said to have
shown temporary regression, leading even to complete atrophia bulbi. Yet
the nature of these cases is open to doubt (Lagrange, Parsons).

The structure of glioma retinae was recognized by Virchow as recalling
that of many cerebral gliomas. The tumor is composed of small round-cells
appearing often as naked compact nuclei but exhibiting a scanty cytoplasm
from which as a rule no definite fibrils can be traced. The cells lie usually

FIG. 155. — Glioma of retina.

in perivascular groups between which there may be diffuse cellular tissue
or more often necrotic detritus. Besides the perivascular groups two
other features are revealed on close inspection.

(i) The cells may assume a low cuboidal form and be arranged in small
alveoli or rosettes after the manner of neuro-epithelial rosettes (Flexner,
Becker). Such structures were observed in n of 32 cases by Wintersteiner,
and in several cases I have found them the predominating feature. By
means of serial sections Steinhaus showed that these rosettes are spheroidal
and not tubular bodies. On account of this structure Flexner applied
the term neuro-epithelioma retinae. Eisenlohr also described occasional
very minute canals lined by a thin membrane but not bounded by cylindrical
cells.

The inner border of the typical rosettes is lined by a thin membrane which
has been interpreted as a reproduction of the membrana limitans externa,
while the cells of the rosettes are believed to be derivatives of the rods
and cones. Similar structures have been found in malformed eyes and in
inflammatory conditions (Parsons, Lit.).

2. Even when the rosettes are not prominent the small cells are not

TUMORS OF BRAIN 407

diffusely distributed but are arranged in rows or indistinct circles which
indicate traces of the same tendency which produces the complete rosettes.
This appearance is observed even in the perivascular cell mantles but in
old tumors it is gradually obliterated (Steinhaus). In the local extensions
of the tumor through the choroid, in the orbit or into the brain, all traces
of structure are commonly missing and the tumor is composed of small round-
or spindle-cells which tend to travel along the perivascular lymph sheaths.
Yet Greef found that in extrabulbar extensions the tumor-cells might show
more of the characters of ordinary glioma cells.

The demonstration of glia fibrils in retinal glioma requires special technic.
Ordinary staining methods usually fail to reveal any trace of fibrils and
Scaffidi and others have been unsuccessful with Weigert's and Mallory's
stains. Greef, however, using the Golgi-Cajal silver impregnation found
many cells with scanty fibrils, resembling the embryonal spider cells of the
optic nerve, and in some areas these fibrils were very numerous. Borst
pictures the fibers as short and rudimentary and he finds them only on the
cylindrical cells forming rosettes. Greef also demonstrated larger ganglionic
cells with many branching processes and more numerous medium-sized
tripolar cells. These observations have been verified by Hertel, de Gama
Pinto, and others. Yet Scaffidi believes that these large cells are persistent
remnants of the original retina. It may be urged that the silver method is
not a reliable means of distinguishing ganglion-cells from large multipolar
glia-cells.

From the descriptions of many authors it is evident that the structure
varies considerably. In one group of cases the perivascular arrangement is
most prominent, in another the rosettes are the most striking feature, and
in still others the tumors are diffuse and large and small glia-cells are demon-
strable. These variations do not warrant the assumption that the tumors
may be of different nature, but they have formed the basis of much difference
of interpretation.

Etiology. — Glioma of the retina appears almost exclusively in infants and
two-thirds of the cases occur before the fourth year. The congenital char-
acter is most remarkable. Newton reports a family of 16 children 10 of
whom died of retinal glioma, in seven of which the disease was bilateral.
Wilson saw eight children in one family affected and several other similar
reports have been collected by Williams. An hereditary element may pos-
sibly be traced in the cases of Steinhaus and of Feinstein in which several
first cousins were victims of the disease.

The tumor has several times been associated with ocular deformities,
as microphthalmos (Helfreich, Ginzberg, Salzmann), or persistent embryonal
vessels in the lens (Eisenlohr). The embryonal structure accords with the
congenital origin. Although there has been much discussion as to the nature
of the growth, the general resemblance to other gliomas in which fibrils are
demonstrated with difficulty and the demonstration of spindle-cells by Greef
and others, are satisfactory evidence of the embryonal gliomatous nature.
The exact nature of the embryogenic disturbance can only be surmised, while
its cause is entirely obscure. The tumor bears a strong resemblance to the
outer granule layer of the retina to which its early stages have been traced,
so that one may assume the existence in this locality of superfluous or
misplaced tissue material. Wintersteiner concludes that the tumor arises
from misplaced elements of the outer retinal layers which have been found
as rosettes in a series of malformed inflamed eyes. He assumes that the
disturbance must occur late in the development of the retina, but the highly
embryonal structure of the growth and its association with gross abnormali-

408 NEOPtASTIC DISEASES

ties, favor an earlier origin (Greef, Axenfeld, Emanuel). Trauma has been
held responsible for the outbreak of many cases but usually on uncertain
evidence.

SARCOMA OF BRAIN AND MENINGES

The only well-defined form of sarcoma of the brain and meninges is
derived from the walls of blood-vessels and since these tumors are often
quite vascular they may be regarded as essentially angiosarcomas. Very
cellular tumors composed of round-cells arise from the glia-tissue and are best
designated as gliosarcomas or malignant gliomas. Cellular endotheliomas
also present many features of spindle-cell sarcoma, but in all but rare in-
stances they may be identified on minute structural features, such as the
presence of areas of flat cells and a concentric arrangement around small
canals. Owing to the general similarity of structure it is probable that the
sarcomas recorded in the literature include tumors of each of the three above
groups. There has been much controversy over the use of the term glio-
sarcoma. Strictly speaking this word signifies a mixed tumor of glia-cells
and some mesodermal cell. It is not clear that any such mixed tumor exists,
although Stroebe describes a rare growth with commingling of glia and
mesodermal cells, and Merzbacher saw reactive proliferation of glia about
invading pial sarcoma. Wohlwill also describes as true gliosarcoma a
tumor composed of glia-cells in one portion and mesoblastic cells in another.
Entirely separate glioma and sarcoma in the same brain are recorded by
Hanel.

Gross Anatomy. — (i) Sarcoma arises chiefly from the dura and pia and
probably some deeply placed tumors develop from the blood-vessels of the
brain. Their position is therefore extra- or intracerebral, and about equally
frequent in all parts of the brain. They produce firm or soft opaque cellular
well-circumscribed tumors which may attain large dimensions. Putnam
describes one case in which the tumor replaced nearly one-half of the cere-
brum. It was successfully removed but recurred after some months.
Henschen's series includes a large cystic sarcoma replacing a parietal lobe,
one involving vertex, dura, and base, one arising from the occipital portion
of the falx, and one involving both hemispheres. Stern saw the entire
corpus callosum destroyed, while a very large tumor of chronic course oc-
cupied most of the frontal region. Many of the large tumors are soft,
cystic or hemorrhagic. Arising from the membranes they at first displace
but eventually tend to invade the brain tissue. At all times they are
rather sharply defined from the surrounding brain tissue, occasionally by a
capsule.

Perforating dural sarcomas are rarely observed and most of these tumors
probably arise from the bone. In certain instances an intradural tumor
has forced its way through the dura, eroded the skull and appeared beneath
or even on the scalp (Bruns).

Arising from the outer side of the dura they may perforate the bone and
appear externally, or most of the growth may remain in the skull at the
expense of the brain tissue. Weisewange has collected a series of perforating
tumors, a few with the structure of alveolar sarcoma, which he traces to
dura, diploe, or periosteum. The typical osteosarcomas of bone also per-
forate the skull in either direction.

Osteochrondrosarcoma arising within the cerebellum and extending
into the spinal canal is described by Jacobson and Jamane.

2. Diffuse Sarcoma of Cerebral Meninges. — While local invasion of the
meninges by malignant tumors is not uncommon, a widespread extension

TUMORS OF BRAIN 409

over meninges, ependyma, nerve roots, and down the spinal cord, is observed
in a limited number of characteristic cases which include glioma, sarcoma, en-
dothelioma, melanoma, and one tumor of the pituitary gland (Schlesinger's).
Verdun has collected 28 cases of this group of sarcomas, to which may be
added several others from the reports of Nonne and M. Rindfleisch, as well as
recent cases of Markus and Almecrona. The same condition usually in-
volves both brain and spinal cord, but in many cases only one of the regions
was examined. Occasionally the brain alone or the cord alone is affected.

The anatomical conditions vary. In some cases there is a large primary
tumor from which the diffuse invasion spreads through the arachnoid space
(Weaver). Or small multiple tumors may appear at several points connected
by diffuse invasion of the pia. This condition is observed chiefly with sub-
ependymal gliomas of the ventricles (Martens, Seiffer, Verdun).

No definite tumor mass may be present anywhere, but the meninges
exhibit a moderate diffuse opacity. To this form Orth's term, pachymen-
ingitis interna sarcomatosa, best applies. In such a case Marcus found the
changes to consist of proliferation of large hyperchromatic cells in the walls of
blood-vessels occluding the lumen. Almecrona described a very similar
case as endothelioma. It was complicated by invasion of the brain tissue
and metastases in the liver.

In other cases of this group the structure has been described as large
round-cell sarcoma (Weaver), spindle-cell sarcoma (Carnot-Bougle), glio-
sarcoma (Fischer), ependymal glioma (Verdun).

While it is thus evident that diffusion in the pia is not peculiar to any
one form of sarcoma, yet the cases without any localized tumor stand out
from the others as a disease sui generis for which a special etiology must
probably be found. Many of the patients are young. The clinical course
is that of chronic meningitis.

Structure. — The structure of the typical angiosarcoma of the brain is
often an exact duplicate of that observed for this tumor in other regions.
There are many blood-vessels lined by endothelium and supported by a thin
layer of connective tissue, beyond which lies a broad sheath of polyhedral,
rounded, or spindle-cells. The unit of the vessel and its cell sheath is very
prominent. The vessels may be widened, the walls imperfect, and the
tissue infiltrated with blood. Areas of necrosis and cyst formation may
greatly alter the appearance. Oppenheim describes pigmentation of these
and of less vascular sarcomas. In fact not a few diffuse melanomas of the
pia closely resemble the non-pigmented sarcomas, differing chiefly in the
presence of pigment. A possible relation between these processes may well
be considered. Berblinger found perithelial sarcoma associated with
diffuse melanoma, but he regarded the two processes as distinct.

Very cellular forms of this tumor probably give rise to diffuse large
round-cell or giant-cell sarcoma. Coste and Levy describe both these
structures in the rapidly growing recurrence of an original typical perithe-
lioma which was possibly of traumatic origin. In another group of cases
the abundant sheaths of perithelial cells are not prominent, the vessels are
more numerous and smaller, and the tumor-cells are arranged concentrically
about the vessel, forming a thickened wall lined by tumor-cells or a single
layer of endothelium. These tumors resemble very cellular granulation
tissue. With increasing proliferation of tumor-cells and loss of vessels they
pass into spindle-cell sarcoma. Such tumors develop both in the pia and in
the substance of the brain. The great difference in the structure of these two
forms of sarcoma suggests a difference in origin. One is embryonal or ana-

410 N EOF LA STIC DISEASES

plastic in type, the other more adult. In neither case has the origin been
traced.

Myxomatous changes occur in vascular sarcomas as well as in glioma
and endothelioma, and the exact origin of the growths which are largely
myxomatous is not clear. Oppenheim described a calcified chondromyxo-
angioma as large as the fist developing in the frontal region of a boy of 16
years, eight years after trauma.

The malignancy of most brain sarcomas is considerable and some show
extremely active growth, especially after operative interference. The
perithelioma of Coste and Levy recurred promptly and reached a very large
size with a change to a diffuse structure. Putnam's large tumor recurred
only after an interval of several months. Boettiger examined the site of a
sarcoma 10 years after its removal and found only a cyst and a scar, but he
failed to describe the original growth. Not a few of the successful operative
results appear to be with angiosarcoma or perithelioma. The prolonged
course (Stern) as well as the successful removal of some of these tumors
indicate that the prognosis may not be entirely unfavorable. Yet their
natural tendency is to grow rapidly and steadily until within a few months
there is extensive destruction of brain tissue, and a fatal outcome is assured.
General metastases are not observed.

CHAPTER XXIII
TUMORS OF NERVE TRUNKS

Neuroma. — Neuroma is a tumor composed of nerve-cells and nerve-
fibers, in which form it is usually designated as neuroma ganglionare or
ganglionic neuroma. Extensive overgrowth of nerve-fibers, medullated and
non-medullated, occurs without participation of ganglion-cells and this
process is termed neuroma myelinicum or amyelinicum.

Although ganglion-cells and their process stand as the most highly dif-
ferentiated and immutable of the soft tissues, yet both cells and processes
occasionally reveal surprising powers of growth, the cells yielding genuine
neoplasms, and the fibers multiplying or sprouting to an extent which closely
approaches the nature of a neoplasm.

Intermediate grades of proliferation of nerve-fibers which do not consti-
tute genuine tumors are rather numerous.

Traumatic Neuroma. — In amputation stumps and after severe injuries
to peripheral nerves the fibers may exhibit protracted and excessive pro-
liferation, giving local thickenings which resemble tumors. The connective
tissue of the severed nerve bundles first proliferates and forms a mass of
cellular tissue into which the nerve-fibers push their way. The axis-cylin-
ders elongate, divide, and sprout into the surrounding tissue in the form
of twisted bundles in which medullary sheaths are present or absent. The
nuclei of the medullary sheaths multiply and provide new sheaths for the
axis-cylinders. The result is a marked thickening of the ends of the nerves
and when several masses join with each other and with the thickened fasciae
and scar tissue a nodular tumor of considerable size is produced. Since
very similar changes occur in the simple regeneration of nerve- trunks (Bunger)
the amputation neuroma must be regarded as a form regenerative over-
growth comparable to proud flesh (Thoma). Yet Ziegler holds that the proc-
ess may exhibit certain neoplastic characters.

Plexiform Neuroma.- — While in most cases of neurofibromatosis the
nerve-fibers are passive and gradually atrophy there are rare forms of over-
growth of nerve-trunks and ganglia in which the nervous elements take part
in the hyperplasia. In certain plexiform neuromas of neck, back, eyelid
and face, the elongated, nodular and contorted nerve-trunks show preser-
vation of nerve-fibers, and Ziegler, Birch-Hirschfeld, and Klebs believe there
may be an active newgrowth of nerve-fibers (Bruns, Lit.).

In the cirsoid neuroma, which consists of a congeries of elongated and
irregularly thickened nerve-trunks, Ziegler points out that the bulk of
nerve-tissue is greatly in excess of that normally provided for the affected
part. These processes seem to stand in an intermediate position between
genuine neuroma and neurofibroma. Thoma describes neuroma of the
Pacinian bodies of the skin, producing small painful tumors which are chiefly
fibrous but may show overgrowth of nerve-fibers.

True Fibroneuroma.— Virchow divided tumors of nerve-trunks into true
and false neuromas. The false neuromas arise by proliferation of connective
tissue and endothelium of the nerve-trunks with passive atrophy of nerve-
fibers, and this group is numerously represented in the multiple neurofibroma

411

412 N EOF LA STIC DISEASES

of Recklinghausen. Since his work true neuroma of peripheral nerve- trunks
has nearly disappeared from the literature. Yet Virchow gave a full de-
scription of tumors of outlying tissues in which he recognized newgrowth of
nerve-fibers with, and more often without, myelin sheaths. The tumor is
composed of masses of long, straight running, branching and anastomosing
nerve-fibers in which lie many long oval nuclei. These fibers he identified
as naked nerve-fibers, and in some tumors he traced them into fibers possess-
ing myelin-sheaths. The amyelinic tumors he regarded as an undeveloped
form of the myelinic. Virchow collected a series of cases of this class in

FIG. 156. — Multiple neuromata of the peripheral nerves. A, Nerves of the right arm;
B, the left sciatic with its branches; C, the left anterior crural with its branches. (Prud-
den's case.)

all of which there seemed to be a newgrowth of atypical nerve-fibers. In
recent literature this group of tumors seems to have been divided among the
neurofibromas on the one hand and the ganglionic neuromas on the other.
The existence of true fibroneuroma has been emphasized anew by Knauss,
but his tumor was a ganglignic neuroma.

Borst and Ribbert are quite convinced that a neoplastic growth of nerve-
fibers apart from ganglion-cells does not exist, but this conclusion does not
dispose of the possibility of marked overgrowth of peripheral nerve-fibers
without corresponding multiplication of ganglion-cells. I have^seen several
tumors of this type, of small size, and occurring beneath the skin.

TUMORS OF NERVE TRUNKS

413

FIG. 157. — Structure of a true neuroma with well-formed medullated nerve fibers.

FIG. 158. — Nerve fibrils in a true neuroma. (Stained by Weigert's method.)

414

NEOPLASTIC DISEASES

Bruce and Dawson in an elaborate study of a remarkable case of multiple
miliary myelinic neuromas of medulla, cord and pia, have fully disposed of
the theory that medullated nerve-fibers cannot develop without the trophic
or functional influence of ganglion-cells. In this case the very numerous
neuromas developed from indifferent widely scattered cells which the
authors regarded as embryonic residue. They clearly traced the origin of
medullated nerve-fibers in chains of peripheral cells of the above type. It is
interesting to note that these cells and the resulting fibers in the tumors
showed a notable tendency to develop in the adventitia of blood-vessels.
These observations may have an important bearing on the histogenesis of
various more cellular tumors of the nervous system, in which myelinization
does not occur, especially the sarcomas of nerve-trunks and pia mater.

Ganglionic Neuroma.- — Tumors composed of ganglion-cells and nerve-
fibers, while rare outside of the central nervous system, have occurred in a

FIG. 159. — Structure of myelinic neuroma. (Bruce and Dawson.}

small group of cases and present rather notable characteristics. They form
small, nodular and multiple growths, or bulky, single tumors located beneath
the skin or more often in the course of large nerve-trunks or plexuses, in the
adrenal, gastro-intestinal tract, retroperitoneal region, skin, and about the
cerebral and spinal dura. They seem to be chiefly or exclusively derived
from the sympathetic system (Knauss, Falk, Lit.), arising usually from the
thoracic and abdominal sympathetic trunks and ganglia and from the per-
ipheral circumvascular sympathetic plexuses. These tumors may be regarded
as the counterpart of the ganglionic gliomas of the central nervous system.

In the gross the tumors resemble soft fibromas, with radiating markings
which correspond to the bundles of nerve-fibers. Their position may suggest
their relation to the sympathetic. The microscopical structure shows bun-
dles of nerve-fibers coursing among ganglion-cells and supported by connec-
tive tissue and blood-vessels. Fat-cells may also be present. The fibers

TUMORS OF NERVE TRUNKS

415

may be chiefly medullated or wholly non-medullated. The ganglion-cells
are of ordinary characters or hypertrophied to giant size but deficient in
chromatic substance, or they may be very numerous and approach the form
of large round-cells. Falk believes that the connective tissue participates in
the growth and that the neoplasms are mixed tumors. They differ in com-
position from the neuro-epithelioma or neurocytoma which Wright described
as arising from the sympathetic. The true ganglionic neuroma may be
difficult to distinguish from fibroma of ganglionic nerve-trunks, in which both
cells and fibers may long persist. In the multiple neurofibroma of stomach
and intestine the tumors are probably derived from sympathetic nerves and
ganglia and ganglion-cells may long persist (Askanazy). The ganglion may
become greatly distended with myelin-like material. Beneke describes
mitoses, and many forms of degeneration and atypical cell-growth.

FIG. 160. — Structure of medullated nerve fibers in myelinic neuroma. (Bruce and Dawson.)

The adrenal is the chief seat of ganglionic neuroma, where tumors from
the size of a cherry to that of a man's fist have been observed by Weichsel-
baum, Bruchanow, and Ribbert. In a case of Schmidt's the tumor lay
between kidney and adrenal, yet the suprarenal plexus was normal. A
combination of suprarenal tumor with multiple growths on the surface of the
cerebellum, cerebrum, spinal cord, in the cauda equina, spinal ganglia, audi-
tory nerve roots, and axillary plexus, and sciatic nerve occurred in a remarka-
ble case described by Soyka. In the thorax Loretz and Borst have described
subpleural tumors lying near the spinal column and doubtless derived from
the thoracic plexus. Multiple subcutaneous tumors probably originating
from perivascular plexuses, recurrent or associated with internal tumors, are
recorded by Soyka and by Knauss. In Kredel's case, scores of small and
large tumors were scattered over the body of a five-year-old child. Chiari,
Busse and Beneke found unusually large tumors arising from the abdominal
or pelvic plexuses.

Malignant neuroma occurred in a remarkable case of Beneke 's.

416 NEOPLASTIC DISEASES

In a child of 10 years a tumor the size of a man's head, of seven years' duration originat-
ing in the region of the celiac axis, was found to consist largely of typical ganglionic neu-
roma, but in some wide areas the ganglionic-cells could be traced into smaller rounded
cells without processes and arranged in the form of alveolar sarcoma, which structure also
appeared in much enlarged lymph-nodes. A much less cellular tumor with secondary
growths in neighboring lymph-nodes is described by Miller. These cases form a transition
group between ganglionic neuroma and malignant neuroblastoma, which will be described
under the tumors of the adrenal, from which organ they chiefly arise. The entire group
has been systematically discussed by Wahl, and by Dunn.

In the etiology of ganglionic neuroma one must assume an embryonal
disturbance of the structure of the sympathetic nervous system with the
presence of superfluous un differentiated tissue in localities giving origin to
the tumors. This view is favored by the congenital or early appearance of
the tumors, by the undeveloped character of their component structures,

*''.;

y.s<;

FIG. 161. — Advancing edge of infiltrating neurofibrosarcoma.

by their wide and multiple distribution. As to the nature and cause of this
disturbance nothing is known, but congenital variations in the size of various
nerve-trunks and ganglia have frequently been observed (Virchow).

Acoustic Neurofibroma. — Intracranial tumors of the nerve-trunks affect
chiefly the acoustic, rarely the trigeminus nerves, and form a relatively fre-
quent and characteristic group of brain tumors (Henneburg and Koch)
(Fraenkel and Hunt, Lit.). They are usually single, rarely bilateral and may
form a part of general neurofibromatosis. Neuromas of the other cranial
nerves are regularly extracranial. The condition was reported by Forster
in 1862 and fully described by Monakow in 1900.

The tumors occur usually before the $oth year, and often in young per-
sons. They may be associated with other abnormalities of the brain, as
hyperplasia and hypertrophy of the glia-cells of the cortex (Henneberg,
Koch), endothelioma and psammoma of the dura, sarcoma of brain, multiple

TUMORS OF NERVE TRUNKS

417

hernias of brain tissue through the dura (Fraenkel, Hunt). These abnor-
malities suggest an underlying anatomical predisposition to tumor growth.
In one of Henneberg's cases there were neuroma of the acoustic, fibroma of
the falx, fibrosarcoma in right ventricle, three small tumors in the medulla,
and multiple psammomas of pia and dura. The comparative frequency with
which isolated brain tumors, fibroma, sarcoma, and glioma are observed with
peripheral neurofibroma has an obvious bearing on the origin of many solitary
intracranial neoplasms.

The tumors begin in a portion or involve the whole of the nerve-trunk,
producing a fusiform or round swelling which has been encountered when as
small as a cherry or as large as a hen's egg. They are firm, lobulated and
encapsulated, but often adherent. They compress the cerebellum, medulla,
and adjoining nerves. The diffuse swelling of the nerve may penetrate the
internal auditory meatus.

FIG. 162. — Structure of a malignant neurosarcoma.

The structure is usually that of simple neurofibroma, but some very
cellular growths approach the type of neurosarcoma. Glia-tissue has several
times been demonstrated and from this element a sarcomatous process may
be derived. Regressive changes include fibrosis and cyst formation.

Sternberg points out that the trigeminus, acoustic, facial, glossopharyngeal
and vagus arise from the neural ridge which appears at an early date when
the tissues are comparatively undifferentiated, while the other cranial
nerves develop from the cerebral vesicles. Hence the former nerves may
readily include embryonal cell groups which explain the complex structure
of their tumors.

The clinical course is of a slowly growing tumor of the posterior fossa,
preceded by symptoms referable to the fifth or eighth nerves. The slow
course and encapsulation place them among the operable cases, but the inac-

418 NEOPLASTIC DISEASES

cessibility, adhesions, destruction of neighboring vital tissues, and occasional
malignancy yield an unfavorable prognosis.

Optic Neurofibroma.— The optic nerve is the seat of a characteristic neuro-
fibroma or neuromyxoma which has been described by Collins and Marshall,
and others. Through the kindness of Dr. Arnold Knapp I have had oppor-
tunity of studying his tumor. It occurred in a boy of eight years, was of
slow growth, had involved and destroyed the entire optic nerve but had not
invaded the eyeball or cranium. It formed a soft, elastic, vascular fusiform
swelling of ^the entire nerve, and was enucleated without disturbing the eye-
ball. The central portions were almost diffluent. The structure presented
numerous small cells of the type of glia-cells without fibrils, lying in
compact groups or singly in a mucinous matrix. Numerous small vessels
coursed through this tissue which was limited chiefly to the periphery of the
tumor and appeared to have developed chiefly from the sheath. Remnants
of degenerating nerve-fibers were abundant in the mucoid material. The
structure approached that observed in some soft peripheral neurofibromas
in which modified derivatives of neuro-epithelium are probably concerned.

In another case, the tumor, removed by Dr. Ernest Krug and placed at
my disposal, gave the same history, but the structure was more cellular.
In both these cases the bulk of the tumors was composed of new blood-vessels,
edema, collections of mucus, and degenerating remnants of the nerve-trunk,
while neoplastic elements were scanty.

Tumors of the Gasserian ganglion are of considerable surgical interest,
and form a definite pathological basis in one type of trigeminal neuralgia,
which is their chief clinical symptom. Sachs collected 21 cases, and the
conditions have been reviewed in detail by Spiller and by Giana. The
pain in these cases usually becomes continuous, the results of surgical treat-
ment have been very unfavorable, and the disease terminates fatally in
one to three years. The tumors involve and destroy the ganglion or arise
in the capsule and compress the ganglion. They reach the size of a marble
or pigeon egg. Several cases appear to have had an inflammatory origin
and were associated with tuberculosis (Giana), or extensive plasma-cell
overgrowth (Hoffmeister, Meyer). The structure has varied from fibrous
to very cellular growths, the latter presenting alveoli surrounded by several
layers of polyhedral cells. In some the structure resembles perivascular
endothelioma. In others gliomatous features were noted. Marchand
believed that they represented various types of neurocytoma. Others
have derived their tumors from the pericellular lymph-sheaths.

CHAPTER XXIV
TUMORS OF SPINAL CORD AND MEMBRANES

General Etiology. — All tumors of the spinal cord or membranes that
compress the cord fall in a single clinical group which can be differentiated
only after complete study. They include gummas, tubercle, and parasitic
cysts, as well as neoplasms.

Statistical studies of Schlesinger give 151 such tumors among 35,000
autopsies at Vienna (0.43 per cent.). Of 400 cases collected by this author
302 were intradural and 88 extradural. The sarcomas head the list with
107 cases; followed by tubercle, 64; echinococcus, 44; neurofibroma, 37;
gumma, 28; glioma and gliosarcoma, 27; psammoma, 18; myxoma and
lipoma, each, n; endothelioma, 6. Excluding 144 cases of tubercle, gumma,
and parasitic cysts, the proportion of sarcomas becomes even more
prominent.

Practically, the spinal tumors are chiefly sarcomas, of which a considerable
proportion are extradural, 31 of 107 cases; glicma and gliosarcoma, which
are always intradural, 27 cases; neurofibroma, 37 cases; and psammoma
with its congener endothelioma, 24 cases. Lipoma and myxoma are distinctly
rare, and some of the latter are probably degenerating forms of growths
originating in glia-tissue or nerve-trunks.

It is of interest to note that tumors of the spinal column in the Vienna
series of 35,000 autopsies were far more frequetit than in the meninges and
cord (107 cases to 44); while brain-tumors of all types were six times as
common (994 cases) as the spinal cord growths (151 cases). Primary tumors
of the spinal meninges were twice as common as the secondary metastatic
growths. During this same period 427 cases of tuberculous spondylitis
were observed.

Trauma. — Less frequently than in the brain, severe trauma has appeared
to be the direct exciting cause of spinal cord tumors, usually of the gliomatous
type. Severe injury capable of reaching the meninges and followed by
symptoms continuing until the existence of a tumor at the injured point
was established, occurred in the gliomas of Silberkuhl, Wichmann, Schuppel,
Schlapp, and others.

Sarcomas appeared to develop on a traumatic basis in reports of Traube,
Forster, Ollivier, Hunt and Woolsey, and myxomas in the cases of Gowers,
Bruce, and Mott. Very similar histories have appeared in cases of fibroma
(Marshall) and psammoma (Oustaniol). Gaupp's angiofibroma appeared
many years after a severe spinal injury.

In many instances symptoms proven to result from tubercle, gumma,
or echinococcus cyst have followed immediately or soon after trauma
(Schlesinger, Lit.).

It thus appears that trauma may be the direct exciting factor, or may
accelerate the growth, or reveal or intensify the symptoms of spinal tumors,
or may have no connection whatever with an accidentally associated lesion.

Hereditary influences have been suggested in some interesting cases.
Two sisters of Huppel's patient with multiple sarcoma suffered from the
same symptoms. A brother of Hunt's case of traumatic sarcoma died of
the same lesion, also of traumatic onset.

419

420

NEOPLASTIC DISEASES
AGE INCIDENCE OF 187 SPINAL CORD TUMORS

barcoma

Years

Intradural

Extradural

Diffuse

1-9

10-19

20-29

30-39

40-49

50-59

60-69

The above table includes 81 cases tabulated by Schlesinger in 1898,
many of the cases collected by Collins, and some recent reports up to 1915.

The main conclusions from these data are as follows: Solitary sarcoma
occurs chiefly in young adults between 20 and 40 years. Diffuse sarcomas
are practically limited to children or young adults under 30 years of age.
Gliomas are well distributed in the age periods. Psammoma is not reported
under 30 years. Among extremes are Anderseck's sarcoma of the cord
in a newborn infant and Duseberg's angiosarcoma in a man of 79 years.

The great majority of lipomas occur in children under five years.
Neurofibromas occur at all ages.

In children under 10 years a spinal cord tumor is in order of frequency
a solitary tubercle, a diffuse or unfavorable form of sarcoma, or rarely a
lipoma. After 40 years the benign tumors and favorable forms of circum-
scribed sarcomas become more frequent. Tubercle is distributed over all
periods, but gummas are rare before 30 years.

While customary subdivisions of spinal tumors are numerous it is proba-
ble that they arise from three main structures, (i) glia-cells and neural
epithelium, (2) blood- and lymph-vessels and their endothelial lining, and
(3) the nerve-trunks. From this histogenetic standpoint they may be
classified as follows:

Glia-tissue — Glioma, Gliosarcoma.

Neural epithelium — Neuro-epithelioma. Some so-called angiosarcomas.

Blood-vessels — Angioma, angiosarcoma, sarcoma.

Lymphatics— Lymphangioma, Endothelioma, Psammoma, Sarcoma.

Nerve-trunks — Neurofibroma, Fibroma, Myxoma.

Spinal fat tissue — Lipoma.

Only the spinal sarcomas will here be considered in detail, the others
being considered elsewhere.

Sarcoma of Cord and Meninges. — Sarcoma of the cord or meninges
occurs in several anatomical forms:

1. A solitary tumor.

2. Multiple, large, small, or miliary tumors.
This form merges into

3. A diffuse infiltration which results from: (a) Extension from a single
large primary meningeal growth, or (b) as a diffuse infiltration without local-
ized primary tumor, and (c) as a secondary invasion from extramedullary
growths.

Extradural tumors of a variety of types arising from the bone, connective
tissue, fat-tissue, and nerve-trunks are commonly included in this clinical
group. Of 6 1 sarcomas in the vertebral canal Schlesinger found 18 extra-

TUMORS OF SPINAL CORD AND MEMBRANES 421

dural. Of 42 primary intradural sarcomas 16 arose from the dura, 14 from
pia, 6 from arachnoid, 4 from nerve roots, and 2 from the ligamentum
denticulatum.

1. The solitary sarcoma is a relatively frequent form of cerebral and
spinal tumor. It arises from the dura, pia, or nerve roots, and extends
in elongated form along the cord with local compression if firm and encapsu-
lated or adapting itself to the spinal canal if soft. The hard tumors remain
permanently encapsulated or become pedunculated and do not invade the
cord. They are composed of closely packed spindle-cells, with few vessels
which escape the calcification of psammoma. They are probably related
in origin to the neurofibromas and neurosarcomas but lack the specific
structure of these tumors.

Myxosarcoma is a rare but characteristic form of spinal tumor of which
Oustaniol collected nine cases. The cauda is a favorite site. They are
occasionally extradural and here the frequent admixture with fat indicates
an origin from misplaced mesodermal tissue. Berthelot and Merklen
described multiple myxomas of the cord.

Round-cell sarcomas form soft, vascular growths which are prone to
hemorrhage and cystic degeneration and while long remaining encapsu-
lated they may eventually invade the cord or produce metastases. Their
sources have not been traced. The great abundance of blood-vessels in
certain cases suggests a perivascular origin (Schlesinger, 30). As a rule the
cellular tumors are difficult to distinguish from endotheliomas, and when the
cells are quite round and very numerous the separation from gliosarcoma
is required.

2, 3. Multiple and Di/tise Sarcomatosis of Meninges. — This remarkable
and highly specific neoplasm appears in the form of multiple nodules or
plates or a diffuse infiltration of the pia-arachnoid. It may extend over
many segments of the cord, or over the entire cord from medulla to cauda,
or may cover the cerebral pia over the base and even extend into the ventricles
(Nonne, Schroder). The nervous tissue usually escapes infiltration but
may be involved in the later stages. A localized primary tumor of the
meninges is occasionally present and rarely the tumor appears to originate
in the nervous tissue or its sulci.

The alteration in the exposed cord may be so slight as to escape the
naked eye (Nonne), but usually there is a nodular or diffuse thickening or
opacity from grayish red tumor-tissue which appears first on the post rior
aspect of the cord, encircles it more or less completely, and passes along the
nerve roots.

In R. Schulz' case the entire cord was surrounded by a layer of new tissue
H cm. in thickness, and in the cases of Schataloff and Nikoforoff the investing
layer was i cm. deep. Bausch found a uniform tumor sheath extending from
cauda to brain, irregularly over the cerebral pia, and into the ventricles
along the choroid plexus. When a localized primary tumor appears as the
source of the diffuse infiltration it usually lies in the cerebellum or base
(Hippel, Nonne), or in the substance of the cord (Westphal). Of 18 cases
collected by Schlesinger, 14 were associated with large tumors, 12 of the
cerebellum and three of the medulla. The occurrence of miliary nodules
over the peripheral areas indicates that the tumor advances by transfer of
cell groups along the arachnoid, but in many cases the advancing edge
merges gradually into healthy tissue. Cerebral involvement often leads to
hydrocephalus.

The structure of the diffuse sarcoma is somewhat uniform but owing to
the activity of growth the exact origin of the tumor has never been satis-

422

N EOF LA STIC DISEASES

factorily determined and in fact the exact nature of the process in some cases
is obscure.

In most cases the tumors contain many fine blood-vessels sheathed by
round or polyhedral or spindle-cells. When the vessels are very numerous

the tumor has been called angiosarcoma
or perithelioma (Nonne, Busch). Hya-
line changes in the vessel walls led
Kramer to designate his tumor as
cylindroma. In two cases W. Rind-
fleisch found the vessels overgrown or
obliterated by a diffuse growth of large
and small round-cells. Lenz analyzes
the process as an angioblastic sarcoma
to which is added a marked prolifera-
tion of the pial endothelium, yielding
many^large cells in alveolar arrange-
ment. In his case a cerebral extension
was purely sarcomatous and failed to
show the secondary endothelial over-
growth. Other cases of this type are
the original observation of Ollivier,
two cases of Coupland, and that of
Westphal. Cramer and Lowenfeld de-
scribed multiple nodules of the same
structure which probably represent an
early stage of the process. Marked re-
gressive changes were observed by Cra-
mer and Ganguillet.

The main histological features in
this group point to an origin from the
adventitial cells of the blood-vessels,
so that the recognition of a specific
form of diffuse angioblastic meningeal
sarcoma seems warranted.

In a second group of cases endo-
thelial characters are more prominent
and the tumor appears as an alveolar
sarcoma. Schulz' bulky growth con-
tained large endothelial cells in alveolar
arrangement.

Di/use melanoma of the meninges
has been observed in a considerable
series of cases. In many of these the
perivascular arrangement of the cells
was prominent (Schopper, Lua).

The clinical course of diffuse men-
ingeal sarcoma presents certain features

,& . , . J

of special interest. Most cases occur
in children or young adults, but Rind-
fleisch reports the condition at 49 years. When there is a large primary
tumor the symptoms are usually dominated by local pressure phenomena, while
the infiltration reveals its course by increasing spinal disturbance.
Rindfleisch established a diagnosis during life by the presence of many large
cells in the spinal fluid. Many cases_are very acute and resemble tuber-

„ ....

FIG. 163. — Diffuse sarcoma of spinal pia

mater. (After Schuize. A. p. 16.)

TUMORS OF SPINAL CORD AND MEMBRANES 423

culous or syphilitic meningitis. In fact it is not always possible to dis-
tinguish the disease from cellular meningitis. Thus, Grund found rather
•typical gross lesions of tuberculous meningitis with miliary tubercles in
liver and kidney in a child of n years, with a duration of four months.
Under such conditions his diagnosis of multiple miliary gliosarcoma suggests
at least that a tuberculous element was concerned in the meningeal process.
Central spinal sarcoma has occurred in a series of cases of which
Schlesinger has collected thirteen. Gliomas and gliosarcomas are much
more frequent in this region. The upper portions of the cord are chiefly
involved and in three cases the entire cord was affected (Forster, Glaser,
Schultze). The tumor mass forms a narrow cylinder or an irregular mass
Y^ to i cm. in thickness. Schiff found a minute spindle-cell sarcoma in
the anterior horn. Elongated cavities filled with serum or bloody fluid may

FIG. 164. — Central glioma of spinal cord with syringomyelia. fa, Anterior fissure; ca,
anterior horn; g, tumor. (After Saxer.)

form within the tumor (Glaser, Seebohm). The central canal is usually
obliterated but in some cases beyond or within the tumor mass the canal
may be dilated and the wall softened and eroded. Sharp encapsulation
from the compressed nerve tissue is usually noted (Fenger, Adamkiewicz).
The gliosarcomas, on the contrary, begin with central gliosis and gradually
invade the cord with central softening. The structure of the more specific
forms of these tumors is that of round- or spindle-cell angiosarcoma. They
are not always clearly distinguishable from glioma or neurofibroma, which
are often highly vascular. Nonne noted the resemblance of his round-cell
tumors to gliomyxosarcomas, from which he separates them chiefly on gross
characters. In "Glazer's case the structure resembled neuro-epithelioma.
The true sarcomas appear to originate exclusively from the vessels of the
gray matter.

Psammoma arises from the spinal dura or arachnoid and usually pro-
duces a single, firm, well-encapsulated growth compressing the cord. Its
progress is slow and several years are commonly required to reach rather

424 NEOPLASTIC DISEASES

limited dimensions which seldom exceed 2X4 cm. Pressure on the cord
begins early, motor and sensory symptoms are prominent, and extensive
secondary degenerations are commonly established. In Steudener's case
the cord was completely severed in the course of two years' growth. The
tumors usually lie on the dorsal and lateral aspects of the cord, and chiefly
in the lower half. The structure presents either a cellular and vascular
form of sarcoma or a less cellular sclerosed tumor with much calcification.
In the cellular forms there are many small canals surrounded by concentric
layers of spindle- or polygonal cells. Calcification of the walls of these small
vessels may appear early when the tumors are cellular, yielding the sarcome
angiolithique of Cornil and Ranvier. Very cellular forms of this tumor differ
from the common spindle-cell sarcoma, chiefly in the presence of these calcine
vessels. In late forms the growth may be largely composed of calcine
granules and hyaline tissue.

Multiple neurofibroma of the spinal cord is relatively frequent. Schles-
inger collected 15 cases of which 10 were intradural, while 7 sprang from
the membranes and 3 from the nerve roots. All portions of the cord are
about equally affected but the cauda is a somewhat favorite seat. They
are frequently a part of general neurofibromatosis (Hunt), and in Vast's
case both cerebral and spinal nerve-trunks were involved. Schlesinger
observed three large tumors compressing the medulla and very numerous
small nodules throughout cerebral and spinal meninges and in the cauda.

The solitary fibroma is probably in most cases a hard neurofibroma.
While usually appearing as small, hard masses attached to dura or pia, they
are occasionally cystic, and at times rather cellular and vascular.
Merzbacher found a trilobed cervical intradural fibroma 1 1 cm. in length
and of 1 8 years' duration in a man of 55 years. Heurtaux traced to an
intraspinal origin a very large congenital fibroma projecting from the neck.

Endothelioma of the spinal meninges appears in the form of a large
solitary tumor or as multiple nodules.

Spinal lipoma occurs in solitary, multiple and diffuse forms. It is usually
extradural, and extravertebral tumors may grow between the vertebrae
into the canal (Holmes, Temoin); or an extradural growth may perforate
the dura (Johnson); while others originate in the arachnoid (Obre). The
extravertebral forms may be connected with spina bifida. Braubach's
intradural tumor in a child of 5 years extended from the fourth cervical
to fourth dorsal segment. Multiple lipomas extending over much of the
lower dura and the posterior nerve sheaths are described by K. Hoffmann.
Multiple angiolipoma is described by Berenbuch, and multiple malignant
myxolipoma by Virchow Wolbach reports diffuse lipomatosis of the cord
in an infant. Gowers saw striated muscle-fibers in caudal lipoma.

Spinal angiomas present a benign illustration of the proliferative capacity
of the meningeal blood- and lymph- vessels. They show many gradations up
to angioblastic sarcoma and endothelioma. Gaupp pictures a cavernous
angioma of the pia, and a cellular capillary angioma, occurring in the same
cord with central glioma and two fibromas. Barenbruch found 12 cm. of
the cord partly replaced by a coarse angiomatous structure. Angiomatous
tumors of the cauda have been described as cylindroma, owing to the hyaline
degeneration of the vessel-walls (Ganguillet). Cobb collected several
cases of cavernous angioma of spinal meninges and cord, and points out
the association with cutaneous nevi in the same regions.

Zanda describes multiple osteomas arising from the calcified walls of
blood-vessels. Cavernous and cystic lymphangiomas are reported by Laquer
and by Taube. A dermoid cyst of the dorsal cord is reported by H. White.

TUMORS OF SPINAL CORD AND MEMBRANES

425

Trachtenberg has described a remarkable case of multiple dermoids of
cerebral and spinal meninges.

Metastatic sarcoma may extend over considerable segments of the
cerebral or spinal meninges. Such cases are reported with renal sarcoma by
L. Muller and after ovarian sarcoma by Hensen. The entire spinal meninges
was found microscopically to be diffusely infiltrated
from a primary intestinal lymphosarcoma, in a case
described by Stursberg. Schlesinger describes a
glioma and endothelioma of the pituitary gland
with diffuse infiltration of the spinal meninges.

Secondary changes in the cord, meninges,
and canal, following tumor growth, are of much
practical importance.

Simple compression without destruction of
nerve-tissue may greatly narrow the cord directly
opposite the tumor. About the compressed area
the cord is swollen and hyperemic and there may
be much accumulation of fluid in the central canal,
in the arachnoid, or in a cystic compartment which
often forms about the tumor. Upon removal of
the tumor all the changes may rapidly disappear,
even during the operation (Kummel). Func-
tional recovery may be almost immediate. That
long-standing compression is not necessarily ac-
companied by irreparable damage is shown by
the recovery from complete paralysis after such
duration as eight months (Lichtheim), thirteen
months (Schultze), eighteen months (Macewen).
Eventually there may be complete atrophy of
nerve tissue and fusion of the envelopes in a
fibrous cord to which the tumor may adhere.
Acute degenerative changes may supervene in
the course of the compression and seem to be
referable not merely to pressure but also to an
inflammatory process accompanying the growth.
These changes may appear suddenly in the course
of benign, slowly growing tumors, as psammoma,
and are especially frequent when the pia is invaded
by locally aggressive tumors. The nervous tissue
is then found infiltrated with blood, softened,
and diffluent. The hemorrhage may extend far
from the tumor along the tracts or canal and the
myelin sheaths of the fibers are swollen and de-
generated. Above and below the main lesion
Schlesinger describes focal areas of swollen axis-
cylinders and myelin sheaths which he refers to a local inflammatory proc-
ess. Following the early lesions the usual forms of secondary degeneration
of the tracts become established but in very variable degree.

The spinal column itself may suffer from local absorption of vertebral
bodies and at the weakened point scoliosis and sharp kyphosis may develop.

The changes in the lumbar spinal fluid have been extensively pursued.
The presence of increased albumen in a fluid of distinctly yellowish tinge
(xanthochromia) is frequently observed in spinal cord tumors but is by no
means pathognomonic (Froin, Nonne). The yellowish color is probably de-

FIG. 165. — Multiple der-
moids of spinal meninges.
(Trachtenbergs case. V. A.
I54-)

426 N EOF LA STIC DISEASES

rived from altered blood-pigment. The onset of meningitis is indicated by
admixture of fibrin and many round-cells. Rindfleisch found many tumor-
cells in the aspirated fluid.

Meningeal Pseudoneoplasms. — Aside from parasitic cysts, meningeal
neoplasms may be simulated, in both clinical and anatomical features, by
tuberculous, syphilitic, and traumatic meningitis.

Spinal tuberculosis occurs in several forms which resemble extra- or in-
tradural tumors with or without bone involvement. It produces grayish,
vascular or partly necrotic plates or masses extending over several seg-
ments on either side of dura or in the pia-arachnoid. The structure is that of
hyperplastic granulation tissue in which the overgrowth of endothelial cells
in and about the vessels is very marked. Giant-cells may be absent and
lymphocytes abundant, so that the tissue may resemble round-cell sarcoma.
Fungous masses of tuberculous granulation tissue arising from carious bone
foci may penetrate the subdural space in much the same manner as sarcoma
(Schlesinger). The nerve roots in the lumbar and cauda region have been
found agglutinated by tuberculous tissue in a tumor-like mass (Schamaschin,
Fischer, Schlesinger).

Meningitis (arachnitis) serosa circumscripta in both brain and cord may
give rise to cystic accumulations of serous or milky fluid which cause symptoms
of tumors (Adler, Spiller, Lit.). The cysts form in the thickened arachnoid,
extend over a segment J^ cm., incompletely encircling the cord, distending
the dura and effectively compressing the cord or convolutions. The ad-
joining meninges may be normal or adhesions may extend over a wide area.
The hydrops may involve also the central canal and in Schwartz' case there
were cavities in the anterior horns, and considerable myelomalacia. Sec-
ondary degenerations emanating from the central lesion may be extensive.
The disease occurs at all ages, chiefly in middle life, and many of the subjects
are luetic or tuberculous. Trauma, infectious diseases, and vertebral caries
have been charged with other cases. It is relatively frequent, having occur-
red in 6 of 21 laminectomies by Oppenheim and Krause for supposed spinal
tumor. Quincke has described cerebral cases. The symptoms are those
of a mildly progressive tumor (Horsley).

Hodgkirfs granuloma may produce well-circumscribed tumors in or about
the meninges. A supposed dural sarcoma recently submitted to me proved
to be of this nature and mediastinal and cervical tumors developed
later. In Welch's case of Hodgkin's disease terminating in sarcoma a para-
plegia of many months' duration was found at autopsy to have resulted from
a large intradural mass, Nonne also mentions a case of spinal granuloma
malignum.

P achy meningitis cervicalis hypertrophica, often of luetic origin, produces
a diffuse thickening of the spinal envelops which may approach the character
of an angiofibroma but apart from the abundance of vessels the structure is
quite different from any tumor (Charcot, Koeppen, Wieting). While ordi-
nary gummas are readily distinguished from tumors, the scope of struc-
tures in tertiary lesions of the meninges is as yet imperfectly defined.

Trauma following spinal fracture in one case and sharp scoliosis in two
cases led to diffuse fibromatoid growths, as reported by MacEwen.

Symptomatology of Spinal Cord Tumors. — Elaborate analysis of the
symptoms of spinal cord tumors has been required as a guide to the surgical
treatment of these growths (Bruns, Starr, Malaise, Nonne). Its main fea-
tures may be briefly outlined.

Level of the Tumor. — Bruns formulated the law that root pains should
be referred to the segment from which the root arises and not to pressure on

TUMORS OF SPINAL CORD AND MEMBRANES 427

the root in its intraspinal course. They may persist for years before medul-
lary symptoms appear or may fail entirely, especially in ventral growths.
They are usually very severe and persistent, continue for a long period,
especially in extradural growths, but may eventually disappear when the
nerve- trunks are destroyed. Widely disseminated pains point to a medullary
lesion. A zone of hyperesthesia extending somewhat above the tumor is often
present in both meningeal and medullary growths. Vertebral symptoms,
pain and tenderness, are more characteristic of vertebral than of cord tumors
but may be present in both. Sharp kyphosis has once followed bone ab-
sorption by dural growths. Girdle sensations have little localizing value,
and Hunt finds the root symptoms more reliable than local tenderness.
Motor paresis or paralysis appear later than the pains, and a more extensive
lesion involving two or three roots is required before paralysis occurs. Pain-
ful cramps may denote the onset of anterior root or horn lesions. Brown-
Sequard's paralysis, usually continuing for a limited period only, may result
from unilateral pressure and is rather more frequent in extramedullary
tumors, especially in the dorsal region, yet it occurs also with intramedullary
growths. The location of the tumor is generally found to be two to four
inches above the level of the anesthesia. This rule is based on the fact that
with small tumors the pains, anesthesia, and pareses may be due not to root
pressure but to compression of cord well below the roots adjacent to the
tumor.

Relation to Cord, Membranes, and Vertebra. — A spinal tumor may be in-
tramedullary, intradural, extradural, or vertebral, and a somewhat different
prognosis attaches to each location.

Intramedullary tumors, usually gliomas, present as cardinal symptoms,
loss of pain and temperature sense with preservation of tactile sense due to
destruction of the intermediate gray matter and the commissure. Yet this
symptom-complex occurs usually in unilateral and transitory form in com-
pression of the cord from without (Schlesinger). Invasion of the posterior
horns eventually destroys the tactile sense. An initial neuralgic period is
usually wanting, or brief and mild, while bilateral motor paresis appears
early. Irregularities in course, remissions, and eventually a wide extent
of the symptoms accord with the cellular nature of gliomas. Yet meningitis
may give pronounced root pains, and Kurtz observed continuous neuralgia for
three years with multiple gliomas of the cord. Vasomotor and atrophic
disturbances frequently occur, and spinal deformity without pain or tender-
ness is sometimes observed. In many cases the symptoms are those of trans-
verse myelitis.

Extramedullary tumors almost always begin with neuralgic pains. Ma-
laise found them absent in only 5 per cent, of the cases. Absence of pain may
be due to a location away from the roots, to the resistance of the roots to
pressure from soft sarcomas or to compression of cord above the involved
roots (Schultze). The posterior roots have been found incased in tumor but
without pain (Quensel, Sailer). Neuralgia was the only symptom for
eight years in a case of Schultze, and for 18 months in Sach's caudal sar-
coma. Following the neuralgic period come progressive motor disturbances.

An extradural position is indicated especially by long-continued Brown-
Sequard's paralysis with unilateral root symptoms, followed by unilateral
medullary symptoms (Malaise) . Because of the elongated form of many extra-
dural tumors muscular cramps and paralysis are relatively commoner than
with intradural growths, but owing to the protection of the dura, medullary
symptoms may be long delayed.

Vertebral tumors are suggested by diffuse or local spinal pain and ten-

428 NEOPLASTIC DISEASES

derness and by sharp kyphosis or marked degrees of vertebral disturbance
which may be determined by the radiograph.

The duration of spinal tumors varies widely. Malignant vertebral
tumors are the most rapid (average 8.5 months) ; 20 extradural sarcomas gave
an average duration of 12.7 months; 10 intramedullary sarcomas, 16.8
months; 18 intramedullary gliomas, 23 months; and 30 intradural sarcomas,
24.2 months (Schlesinger). The extremes for tumors diagnosed as sarcoma
vary from one month to 25 years. Of prognostic import is the rule that a
tumor of more than three years' duration is usually intradural. The slowest
courses are those of the benign fibroma (31-38 months) and psammoma (30-
36 months). Yet the duration of symptoms in psammoma has varied from
a few weeks to 14 years. The diffuse sarcomas may clinically resemble men-
ingitis. Tubercle and gummas progress slowly (4-6 years).

CHAPTER XXV

GENERAL PATHOLOGY OF EPITHELIAL TUMORS

PAPILLOMA; ADENOMA; CARCINOMA

PAPILLOMA

From cutaneous, mucous, and serous surfaces local outgrowths of tissue
composed of lining cells and subjacent connective tissue occur in many por-
tions of the body, and in a wide variety of forms, to which the general term
papilloma is applied.

A papillary structure is often observed in tumors of glandular organs
which pursue the course of adenoma or carcinoma of these organs and are

FIG. 166. — Topography of a fibro-epithelial papilloma of nares.

therefore properly designated as papillary adenoma or carcinoma. They
usually develop in cysts of these organs where the conditions nearly duplicate
those obtaining on free surfaces. Pronounced papillary tendencies appear in
papillary adenoma of the ovary and in papillary fibroma of the breast, etc.,
which, however, are conveniently discussed with other adenomas and fibromas
of these organs.

429

430

NEOPLASTIC DISEASES

In certain cases, a somewhat specific structure, a characteristic clinical
course and well-defined etiological factors combine to render these processes
more or less distinctive diseases and demand for them special considera-
tion. Otherwise the term papilloma might well be abandoned or replaced
by the adjective papillary attached to the particular inflammatory or tumor-
process concerned.

The form of the papilloma is chiefly determined by the local conditions
surrounding the tumor. Outward growth of hyperplastic cells is in the line
of least mechanical resistance. Irritation leading to overgrowth of surface
epithelium, hyperemia, dilatation and elongation of blood-vessels, and cel-
lular or fluid exudate, give rise to a large series of inflammatory polyps, es-
pecially in mucous membranes and these lesions pass not infrequently into
true tumors.

With the papillomas of true neoplastic type it has long been questioned
whether the initial process affects epithelium or connective tissue. No
single factor covers all cases. Growing epithelium reacts on the underlying

FIG. 167. — Malignant papillary epidermoid carcinoma of larynx.

connective tissue; projecting masses of stroma demand increase of epithe-
lium for their covering; mechanical torsion gradually elongates an originally
flat wart; and inflammatory changes modify the contained blood- and lymph-
vessels. Each of these elements becomes prominent in different papillomas,
and several of them are so often combined that the bulk of a papilloma is
usually far greater than would ordinarily result from any neoplastic element
that may reside in it. In most neoplastic papillomas both epithelium and
connective tissue exhibit the tumor tendency.

While the majority of specific papillomas affect cutaneous and mucous
surfaces the same processes appear in the ducts and parenchyma of glands
and here the same caution must be exercised in judging of their nature.

The clinical course of papilloma is usually benign, and in most instances
the growth capacities are limited. Exceptions to this rule result from per-
sistence of exciting factors, progressive development of new tumors, and ma-
lignant changes. The natural history varies with each locality. In the

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 431

skin the common wart has a transitory life, papillomas of the bladder and
intestine are usually multiple, and in the larynx the papilloma is often ma-
lignant from its inception.

The development of clinical signs of malignancy is probably much more
frequent than a corresponding change in the growth capacities of the tumor.
Such a change may be simulated when an original carcinoma is associated
with secondary simple papillomas on the surface or in the vicinity which mask
the malignant character, or an originally malignant process may for a time
present a simple papillomatous appearance. The first two conditions are
exhibited in papillomatosis of the intestine and the last in some malignant
papillomas of the larynx. Nevertheless the gradual transformation of a be-
nign papilloma into a malignant tumor has been fully demonstrated in the
cervix uteri, bladder, larynx, and other locations, and has usually followed
the trauma of incomplete operation, or prolonged chronic inflammation.

In structure the papillary tumor may fall in one of four groups: (i)
An inflammatory hyperplasia of epithelium, connective tissue, vessels, and
tissue cells, which belongs in the field of chronic productive inflammation
(nasal and uterine polyps, condyloma latum); (2) a simple overgrowth of
histologically normal tissues, for which a congenital origin is probable;
(3) overgrowth of atypical tissues of the type of adenoma (polypoid adenoma
of mucous membranes); (4) distinctly atypical and malignant epithelial
overgrowth with supporting stroma which is normal or neoplastic (papillary
carcinoma of bladder, malignant papilloma of larynx).

All papillomas do not fall readily into these classes. It may be extremely
difficult to determine whether a mucous polyp is purely inflammatory or
partly neoplastic. Vesical papilloma often appears to be dependent upon
chronic irritation, as of uric-acid crystals or of excretory products in anilin
workers, but the resulting polyp is usually distinctly neoplastic. Hence
the study of etiology may or may not assist in the classification. The bulk of
a condyloma latum surpasses that of many papillary epidermoid carcinomas,
and the hyperplastic epithelium of cervical polyps may exhibit every gra-
dation from normal to adenomatous or carcinomatous cell types. In many
instances the transformation of clinically benign into malignant growth
is attended with few demonstrable changes except a softening of the under-
lying tissue and a downward heterotopia of exactly the same type of cell
which formed the polyp. Abundant mitoses and a change in the type of the
misplaced cells are to be regarded as suspicious features. Induration and
fixation of the base are early signs of the desmoplastic process that accom-
panies beginning carcinoma.

Cutaneous Warts. — Verruca vulgaris, the common wart of the skin
is to be distinguished from papillary fibroma of the skin and from the pap-
illary nevus. It is a specific form of epithelial overgrowth, is probably of
inflammatory origin, and any neoplastic element it may possess reveals
itself in ways peculiar to this process.

It occurs on exposed regions of the skin, especially on fingers, hands and
face. The duration is very variable, some disappearing after a few weeks,
others persisting for years. A tendency to recurrence is often noted. The
characteristic single discrete wart may become multiple, conglomerate,
and occasionally bulky. Rarely, elongated forms develop with numerous
thin papillae. In young subjects very numerous small flat warts may appear
on the backs of both hands (Verruca plana juvenilis).

The structure exhibits an overgrowth of the entire Malpighian layer
with folds and projections into which extend thin strands of stroma. In

432

N EOF LA STIC DISEASES

some cases there is considerable increase of blood-vessels approaching the

type of the papillary nevus, and for these a congenital origin is probable.

There are numerous clinical observations suggesting the contagiousness

of warts but on analysis they can be dismissed as examples of the transfer

FIG. 168. — Topography of an epithelial papilloma with beginning epidermoid carcinoma.

of peculiar chemical irritants, or exposure to the same irritant, 01 the actual
transfer of proliferating epithelial cells. Payne saw three warts develop
under the nail of his thumb which he had used to separate a wart from its

FIG. 169. — Structure of a malignant wart. The lesion was covered with many long papil-
las and exfoliated many scales.

base. In many instances warts have developed on the skin of opposed sur-
faces. Lanz implanted a series of warts on the back of his gardener's hand by
inserting the comminuted fragments under the epidermis. From 74 in-

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 433

oculations from warts in four adults Judassohn secured in two to six months 33
warts. Leale successfully employed sections of warts to promote healing of
ulcerated surfaces. The etiological importance of chemical irritants appears
in the cases where warts develop after contact with irritating substances.
Many of the observations suggesting the contagiousness of cutaneous warts
have been duplicated with gonorrheal condyloma and papilloma of the larynx.

Occasionally warts become soft, scaly and inflamed, they develop atypical
cell changes, numerous fine pearls form, invasion of the derma follows, and
the process proves malignant.

Cornu cutaneum is a peculiar form of cutaneous wart marked by excessive
and progressive keratosis. The cutaneous horn occurs chiefly on the scalp,
but also on the face, eyelids, buttock, penis, and scrotum. Lebert collected
104 cases of general distribution. Wilson analyzed 90 cases. Pick reported
10 cases of horns on the penis. Botge observed six horns on the face of one
patient. Multiple horny growths approach the character of the diffuse
ichthyoses. They may reach a length of several inches. Rodriquez reported
a horn of the scalp 14 in. in circumference.

The growth is slow but variable, and the course when uninterrupted con-
tinues for many years. Lebert found that carcinoma developed in 12 per
cent, of his cases.

The growth begins as a wart on the normal skin or in scars. Some horns
take origin in the epithelium of sebaceous cysts, a fact which suggests that the
originating cells have a peculiar functional tendency to hornification. The
structure presents elongated papillae of the derma covered by lamellae com-
posed chiefly of hornified epithelium. The persistence of blood-vessels in
very fine papillae coursing through the horny material accounts for the ex-
tensive development of the greatly elongated forms. The chief oncological
interest centers in the excessive development and persistence of the function
of keratosis. The process may be interpreted as a tumor of horny substance.
(Dubreuilh).

Condyloma Acuminatum. — The pointed moist venereal wart occurs chiefly
about the genitals but also on the thighs and abdomen, while similar growths
are occasionally seen in the axillae and on the face. They are single, mul-
tiple or conglomerate, and while usually elongated, some multiple forms are
small and low. They are composed of few or many villous projections or
tufts which commonly spring from a single pedicle. They are usually moist
and bathed in rancid, serous or mucinous fluid, the irritation of which is be-
lieved to be the cause of the overgrowth. Yet similar warts occur in posi-
tions which are free from moisture. While commonly associated with gonor-
rhea they occur in children, and the aged. In the irritating fluid many
bacteria are found, among which are spirochaetae sometimes in enormous
numbers. The growth may be very rapid, especially in pregnancy, but they
persist for long periods, and may reach a large size or cover a widening area.
Hyde mentions a compound venereal wart of the penis in a negro which was
as large as an orange. Contagiousness is often observed and must be re-
ferred to the transfer of peculiar irritating secretions and of the microorgan-
isms which find in such fluids a suitable habitat.

The structure presents a central core which is more vascular than in
other warts, and is covered by a variable thickness of epithelium in which
hornification is imperfect or absent. Kuhneman finds the chief peculiarity
in a thickening of the granular layer and an imperfect hornification which
leaves the epithelial nuclei still visible in the superficial cells. Through
this loose epithelial covering there is a slight constant exudation of serum.
Tn the core of acuminate condylomas Herxheimer found varicose nerve-fibers.

434

N EOF LAST 1C DISEASES

Condyloma latum is the broad, flat-wart of syphilis and occurs about
the genitals, and especially about the anus. This orifice may be surrounded
and partially occluded by a luxuriant fungating mass several inches in
diameter and markedly protuberant. The lesion may advance within the
external sphincter and over a considerable portion of the buttock. It is
subject to fissuring, infection, and ulceration, and in some cases a destructive
form of carcinoma develops from it.

The structure shows an extensive overgrowth of the entire Malpighian
layer which becomes greatly thickened and much convoluted. The cells are
hypertrophic but otherwise typical. Hornification may be defective. The
connective-tissue papillae are thickened, moderately elongated and bifurcated,
and present the characteristic changes of secondary syphilis.

Molluscum contagiosum is a peculiar, contagious, and possibly infectious
disease of the skin which produces multiple, wart-like, projecting nodules

FIG. 170. — Intracellular bodies of molluscum contagiosum.

distributed over the hands, face, neck or over much of the body. The dis-
ease appears chiefly in children, continues for months or years but eventually
subsides. A somewhat similar condition is observed in chickens.

The nodules are single or conglomerate, wax-like, or almost transparent,
as large as a pea or bean, and usually present a central depression. On
section they exhibit a series of swollen rete pegs composed of a moderately
increased number of markedly hypertrophic swollen epithelial cells which
produce convolution and projection of the Malpighian layer. Many of
the lesions develop in the hair or sebaceous follicles of the skin (Kaposi).
Between opposed layers there is considerable exfoliation of epithelium. The
structure of the cells is quite peculiar. The cytoreticulum becomes thickened
and coarse at the expense of material from the nucleus, and a large portion
of the cytoplasm thus becomes converted into a well-defined reticulated struc-

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 435

ture imperfectly separated from nucleus and cell-membrane and appearing
as a foreign body. The nucleus eventually shrinks to one side of the cell. The
variations in the minute structure of these molluscum bodies are quite nu-
merous. They appear to form in much the same manner as the vaccine bodies
of variola, or as the psorosperms of Darier, and similar structures appear in
ordinary hyperkeratosis (Petersen). Lubarsch finds them in warts, secon-
dary papillomas, and in various forms of epithelial hypertrophy. Many
have assumed that the bodies are parasitic, but their minute analysis has
failed to support this view (Kromayer). Juliusberg reports that the virus
of human molluscum is filterable.

Papilloma of Tongue. — The lingual and buccal mucosa is frequently
the seat of papillomas, which present peculiarities in structure, origin and
clinical course.

The papillomas occur on any portion of the tongue, affecting the lateral
borders, under surface, and dorsum. The median raphe of the dorsum is a
frequent site. Many are of congenital origin. Butlin mentions multiple
papillomas of the fungiform papillae, and bulky, warty outgrowths of the
dorsum of tongue in infants. Riga's disease refers to multiple papillomas
on either side of the frenum caused by irritation of coughing in pertussis.
In adults papilloma arises in the middle line of the dorsum from a congenital
basis, from leukoplakia and other forms of syphilis, from simple glossitis
due to tobacco, and irritation of bad teeth. The etiology, therefore, almost
exactly duplicates that of lingual carcinoma. The form is either acuminate
or flat, and while some remain single and small, others become bulky or mul-
tiple. They may be painful and bleed, but ulceration points to a malignant
process. In some cases a large portion of the tongue and floor of mouth may
be covered by papillomatous growths and from various points multiple car-
cinomas may develop (diffuse buccal papillomatosis).

Lymphatic varicosity affecting the papillae may produce a bulky, papil-
lomatous growth of tongue or buccal mucosa (Robin-Leredde, Kaufmann,
Rehn).

While some papillomas long remain benign and enjoy a limited growth
there is a strong tendency toward malignant change which is indicated by
increasing growth, induration and fixation of the base, and ulceration. A
large proportion of lingual carcinomas exhibits a brief preliminary papillo-
matous stage, and the more pronounced this character as a rule the slower the
progress of the disease.

The chief interest in lingual and buccal papilloma lies in the differential
diagnosis from carcinoma. The former readily responds to radium or to
simple excision of the lesion, and many successful operations for lingual
carcinoma refer to simple papilloma or papilloma with precancerous or minia-
ture carcinomatous changes. A careful microscopical study is therefore in-
dicated before operation.

ADENOMA

Adenoma is an organoid tumor which reproduces the structure of a gland.

The attempt to further define this neoplasm meets at once with limita-
tions. A complete and typical adenoma reproduces epithelial alveoli, gland
ducts, membrana propria, stroma and vessels, in a somewhat orderly and
functionating organ, as in mamma and thyroid. More atypical adenomas are
devoid of definite function, of differentiated ducts, of specific stroma, and
of membrana propria, these features being lost in the order named.

Langhans and Lubarsch find a definite membrana propria in most ade-
nomas but not in all. Dreyfuss could find it only. in traces in mammary

436

NEOPLASTIC DISEASES

adenoma, but he describes a proliferation of the cells of the membrana in
certain cases, in which it is difficult to distinguish between sustentacular
epithelium and stroma-cells. Hyaline thickening of the membrana is also
observed.

In adenoma malignum the hyperplastic and hypertrophic cells main-
tain their polarity so that orderly but giant alveoli and glands constitute the
tumor unit. Such a tumor is still an adenoma, preserving the gland type, and
the common suggestion to abandon the term malignant adenoma seems
ill-advised.

In gross appearance the adenomas are usually well circumscribed or
encapsulated tumors which do not infiltrate the surrounding tissue as do
carcinomas. They are well nourished by blood-vessels running in a sufficient

FIG. 171. — Adenoma of axillary sweat glands.

stroma and are therefore not prone to necrosis. On superficial surfaces they
often produce polypoid tumors, and in the organs they frequently assume a
cystic or papillary character. While some are of miliary size and multiple,
others are single and large, while a few by virtue of good nutrition or cyst for-
mation reach voluminous dimensions.

Clinically true adenomas are usually slow of development and of limited
growth capacity. Their disturbance of the organism is chiefly mechanical.
The occurrence of metastases would lead many to separate the tumor from
the group of adenomas, while others would classify such growths as a form
of malignant adenoma. Most metastasizing simple adenomas exhibit areas
of adenocarcinoma in some portions of the tumor.

Even in the benign metastasizing thyroid struma, which is the best ex-
ample of simple adenoma yielding secondary tumors, many have claimed that
the morphology is that of adenocarcinoma. The peculiar relations of thy-
roid and adrenal alveoli to the blood-vessels are exceptionally favorable
for cell emboli from these growths. Encapsulation is a strong barrier against
malignant change so that adenomas of embryonal origin long retain their

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 437

type, while those arising on a basis of diffuse chronic inflammation or on
mucous or serous surfaces more readily become malignant.

In judging of the probable course of an adenoma it is important to consider
which organ is affected. Simple adenomas of the thyroid and stomach are
frequently malignant, those of the rectum rarely.

While the study of single sections of an adenoma may fail to yield a cor-
rect estimate of malignancy, the finer histological details are usually of dis-
tinct prognostic significance. Uniformly atypical cell forms, nuclear hyper-
chromatism, abundance of mitoses, and reduplication of cell layers are
commonly associated with dangerous types of adenomas but the significance
of these signs must be learned for each organ.

Functional capacity is retained by many adenomas, occasionally it is much
increased, and probably in all cases the product is abnormal. Fatty material

FIG. 172. — Structure of a thyroid tumor of frontal bone. Subject, male, 65 years. Thy-
roid gland apparently normal.

appears in adenoma sebaceum (Barlow) and in tumors of the breast. T have
found rudimentary hairs in adenoma of the hair follicles. Overproduction
of mucus is excessive in some ovarian tumors, but Schmidt regards this as a
pathological activity not shared by the cells of origin, which do not secrete
mucus. In gelatinous adenoma malignum of the colon the production of
mucus may be enormous, even destroying portions of the tumor. Bile is
often seen in adenoma of the liver (Schmidt, Lit.), and Marckwald found the
secretion excessive. Thyroid adenomas occasionally contain colloid, both in
the main tumor and in hetero topic and metastatic growths ( Wolfler) . Schmidt
points out that the structure of adenoma or adenocarcinoma is regularly
assumed in functionating malignant tumors of thyroid and liver. Early
adrenal adenomas contain much lipoid material, but the formation of adrenalin
in such growths has not, I believe, been demonstrated. Yet some adrenal
adenomas are extensively pigmented, and in a well-known group remarkable

438 N EOF LA STIC DISEASES

hirsuties and sexual precocity point to disturbed or excessive functional
activity.

Contrasted with this group of functionating adenomas stands another,
chiefly of embryonal origin, in which there is a sharp suppression of function.
Hence it appears that function in adenomas represents an acquired character
of the cells of origin and that it is not an essential feature of this tumor group.

Mode of Growth. — In adenoma the neoplastic process resides either in
the gland-cells alone or in both cells and stroma. In the former case highly
cellular tumors develop, in the latter fibro-adenomas. The original impulse
is probably always located in the epithelium which exerts a formative in-
fluence over the connective-tissue structures. Yet in some adenomas the
growth appears to begin in both elements simultaneously, and occasionally
the stroma overgrows the glands. The vessels may also become extremely
prominent. The key to the morphology of most adenomas is to be sought in
the course of the normal embryonal development of the gland, which is re-
peated in the tumor (Ribbert). Yet many secondary factors, as mechanical
pressure, retention of secretion, and overgrowth of stroma modify or dominate
the structure.

Tubular adenoma results chiefly from elongation of the affected gland,
as in the colon, but the same process may give rise to an alveolar appearance
in cross-sections of folded and twisted glands. White cut serial sections of a
lobule of mammary a denoma, finding that all the alveoli represented a single
tubule entering the lobule from the main tumor. Saccular or follicular ade-
noma results from the formation of lateral sacculi from original glands. This
process occurs in many organs, but it best seen in some adenomas of the breast
and thyroid. In serial sections of a rectal polypoid adenoma White found
lateral sacculi, communications between adjoining acini, and multiplication
of surface openings.

Papillary cystic adenoma is a form assumed by many adenomas in which
with or without retained secretion the original alveoli are distended by fluid
or by papillary outgrowths of epithelium and connective tissue. There has
been much discussion of the mechanism which causes the distention in cystic
adenoma (Dreyfuss, Lit.). Both retention of secretion and primary over-
growth of epithelium and connective tissue with secondary enlargement of
the alveolus are concerned in the result. Fusion of neighboring alveoli
is also a factor, while serous and bloody exudates and extravasations may
cause rapid enlargements of cystic tumors. Paget divided cystic tumors
according to the prominence of these processes. Rokitansky regarded the
true cystic adenoma as a structure tending essentially to grow in cystic form,
and Dreyfuss emphasizes the importance of proliferation of the membrana
cells as leading to a widened lumen. He found the ducts patent in some cystic
adenomas of the breast and the smaller alveoli empty. It has often been
urged that pressure alone causes atrophy rather than overgrowth of lining
cells.

Structure. — -Adenoma malignum maintains the alveolar structure, and
the polarity of the lining cells, but early loses ducts and specific membrana
propria, while the stroma is deficient or absent. The alveolar structure may
be rigidly maintained even in metastases, but the cells are usually hyper-
trophic and atypical, and the nuclei hyperchromatic. In this form the tumor
has infiltrative capacity and produces metastases. Adenoma malignum
often passes into adenocarcinoma.

Morphological distinctions between benign adenoma and adenoma
malignum vary in different organs. Adenoma of the thyroid may yield
metastases of quite typical form. In an interscapular metastasis of gastric

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 439

adenoma I found regular alveoli lined by a single row of normal-sized cu-
boidal cells with slight nuclear hyperchromatism. In a splenic metastasis
from adenoma of the corpus uteri the alveoli were more typical than in the
uterus, but the cells were twice as large as the columnar cervical epithelium.
Hence the statement is correct, that the alveoli of adenoma malignum may
not differ from those of ordinary adenoma or of glandular hyperplasia. As a
rule, however, the alveoli of adenoma malignum are atypical, the cells larger,
the nuclei more hyperchromatic, the cell layers are multiplied, secondary
alveoli form, quite atypical cells begin to appear, and there is an entire ab-
sence of membrana propria. For each organ a special standard is needed
in estimating the grade of anaplasia and malignancy. The relation of glands
and stroma is also of much importance. Borst emphasizes the promiscuous
distribution of glands and stroma in malignant adenoma.

Adenocarcinoma is a tumor of gland-cells resembling adenoma but failing
to completely preserve any of the normal features of the gland. The or-
derly alveolus is the essential element of an adenoma, but in adenocarcinoma
even the alveolus is imperfectly formed and the epithelial cells begin to lose
their polarity. Markedly atypical cell morphology and extensive over-
growth are also characters of adenocarcinoma, and this tumor may lose all
adenomatous characters and pass into carcinoma. Yet many infiltrating
and highly malignant tumors exhibit numerous traces of alveolar formation.

The attempt to classify adenomas on purely morphological features is
quite unsatisfactory. In many cases tumors which show simple adenoma-
tous structures in one portion exhibit adenocarcinomatous areas in another,
and pure carcinomatous infiltration in still other areas. This instability of
the adenomatous structure is more notable in some organs than in others but
is a rather general characteristic of many adenomas.

While the tendency is usually toward greater anaplasia with continued
growth, occasionally the metastases of an adenocarcinoma are more dis-
tinctly adenomatous than the original tumor. Apolant was able to trans-
form an adenocarcinoma of the mouse into an adenoma by transplantation
in partially immune animals. The study of many adenocarcinomas indi-
cates that the pure adenomatous structure may represent an intermediate
or transitory stage in the evolution of the tumor process which is rapidly
traversed and soon passes into a more atypical carcinomatous phase.

There may be considerable or pronounced variation in the structural
type of the adenoma in the same tumor. Thus in an adenocarcinoma of the
prostate I have found hypertrophied alveoli recalling adenoma malignum;
many small alveoli resembling simple tubular adenoma; distended tubules
filled with neoplastic papillary ingrowths; as well as fibrocarcinoma. Clin-
ically this tumor pursued the course of carcinoma.

Accordingly, if the term adenoma is to enjoy any great pathological sig-
nificance, its application must be made with due reference to the gross ana-
tomical and the clinical features of the disease. From this standpoint
there are still many tumors which tend to maintain the morphology of ade-
noma, with some persistence of the function of the originating gland, and pur-
sue a clinical course which is less malignant and destructive than that of
carcinomas of the same organ.

Examples of this true adenoma in the general biological sense are those
of the cutaneous glands, fibro-adenoma of the breast, follicular adenoma of
thyroid, adrenal adenoma, the adenoma of the islands of Langerhans, Kauf-
mann's adenoma of the testis, and some adenomas, chiefly papillary, of dif-
ferent organs. All of these tumors arise under somewhat peculiar conditions,

440 NEOPLASTIC DISEASES

exhibit little morphological variation, and run a uniform and commonly
benign clinical course.

Physiological Conception. — When one considers the great variety of con-
ditions in which an adenomatous morphology is presented and analyzes
their physiological and clinical significance, the conclusion must be reached
that adenoma is rarely a distinct morphological entity but is rather to be
regarded as a series of structures which tissues assume in response to various
forms of irritation, functional activity, and overgrowth. It is chiefly, if
not exclusively, the adenomas of embryonal origin which fail to show this
complex significance. It were better therefore in most instances to avoid
the rigid morphological conception of adenoma and to regard the diseases
marked by adenomatous hyperplasia as specific clinical and pathological
entities. The justification of this view will appear in dealing with some of
the many forms of adenomatoid and adenomatous hyperplasia.

Most authors distinguish sharply between true adenoma and adenomatous
hyperplasia of organs and tissues. It is highly desirable that the distinction
should be made wherever possible, but it cannot always be accomplished on
morphological data alone. It is usually necessary to consider the conditions
under which the abnormal process develops and its clinical course. In the
extensive group of adenomatoid hyperplasias it is often impossible to dis-
tinguish the morphology from that of adenoma of other types but reference
to the clinical data reveals that the process is dependent on chronic inflamma-
tion and tends to run a self-limiting course. In the thyroid and hypophysis
adenomatoid changes result from functional hyperplasia. In many situa-
tions adenomatoid hyperplasia becomes progressive and passes into a neo-
plastic process and when this stage is reached the conditions exhibit the same
potentialities as other adenomas. In intestinal polyposis different portions
of the intestine exhibit peculiar inflammatory overgrowth, adenomatoid
hyperplasia, adenoma, and even carcinoma.

The adenoma arising under such conditions may differ in some respects
from other adenomas but still deserves recognition as a neoplasm. All of these
considerations, which apply equally to adenoma and carcinoma, urge the
necessity of regarding these tumors from the biological or clinical standpoint
rather than from the morphological side alone.

On physiological analysis adenomas are found to represent several dif-
ferent processes and from this standpoint the interpretation of the mode of
origin, structure, and significance is most satisfactory.

Thus some adenomas are traceable to a localized inflammatory over-
growth. Others represent chiefly an excessive response to functional stimulus.
Some appear to owe their existence to minor anatomical disturbances
in the blood-supply or configuration of the organ. Many true adenomas
represent pronounced neoplastic growth of definitely misplaced and em-
bryonal portions of gland tissue. Probably more than one of these factors
may be combined in origin of the same adenoma.

Inflammatory adenomatoid hyperplasia is of widespread occurrence.

In the mucous membranes of the gastro-intestinal tract, uterus, and nares,
it produces diffuse overgrowth or single or multiple polypoid excrescences
which constitute definite clinical entities, and it is a feature of the late
stages of chronic catarrhal inflammation of these tissues. The process
affects both glands and stroma. The glands become hypertrophic or cystic
and the lining cells are increased in size and number. There is usually
increased and abnormal secretion. The stroma shows new and tortuous
blood- and lymph-vessels, multiplication of stroma-cells, atrophy of lymph-
follicles and perivascular infiltration by lymphocytes. The process tends

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 441

first to produce a diffuse thickening but focal overgrowth of the tissue,
edema, venous stasis, and mechanical traction lead to papillary and polypoid
outgrowths which may become numerous and bulky. In this condition there
is a tendency to further overgrowth of the predominating element, glands,
stroma or vessels. In the nares the mucous polyps show wide variations
in structure, some being glandular, others myxomatoid, other angiomatous,
but the tendency to true tumor growth is slight.

In gastritis polyposa the development of polypoid outgrowths may
reach an astonishing grade, covering most of the mucosa and leading to
dilatation of the organ.

In colitis polyposa the entire colon from cecum to anus may be the seat
of myriads of small or pedunculated outgrowths, the pedicle may be elongated
and ruptured and the polyp discharged through the anus. The ileum or
jejunum is rarely affected, but Kaufmann and Hauser saw involvement of
the entire mucosa from cardia and pylorus to anus, and lesions in duodenum,
jejunum and ileum are reported by Lubarsch, Niemarck and Petrow. Pe-
culiar catarrhal symptoms mark the onset of the disease, and hemorrhage,
anemia, and emaciation, intussusception and prolapse occur in advanced
cases (Virchow, Luschka, Hauser, Schwab, Smoler). The condition affects
both old and young subjects and exhibits an hereditary, individual, and local
predisposition (Cripps, Smith, Bickerstedt, Port, Verse). In the early
stages I find one of the earliest changes is a pronounced hypertrophy of
the epithelial cells, a tendency which Verse regarded as the sole element in
the local predisposition. Although many cases maintain their inflammatory
character throughout there is a striking tendency toward the development
of malignant adenoma and carcinoma. According to Quenu and Landel
about half the cases are associated with carcinoma, while Hauser found this
combination as the rule, and Doering who analyzed 50 cases found 37 fatali-
ties, 31 from carcinoma. There is probably no other tissue which illustrates
so clearly the transition of an inflammatory overgrowth into a malignant
tumor.

Hypertrophic Endometritis, — Fungous or glandular endometritis.

In a somewhat limited group of cases associated with myoma, carcinoma,
misplacement of the uterus, or disease of the adnexa, the uterine mucosa
becomes much thickened (0.5-1 cm.), very vascular, prone to hemorrhage,
cystic, and covered with papillary or polypoid projections. There is exten-
sive overgrowth of large, irregular, compact or dilated glands. Infoldings
of the cell lining may yield one or two epithelial rings within the lumina
on section. The cells are considerably enlarged, nuclei hypertrophic
and often in mitosis, and the layers may be multiple. In a series of cases
every gradation may be observed from normal glands to those of adenoma
malignum, and one often finds single glands outstripping the others in this
transition. New growth of interstitial tissue, with large flat decidua-like
cells, lymphocytes and plasma-cells may appear, especially in the polypoid
projections (E. interstitialis). Hitschman and Adler have shown that
many cases of so-called glandular endometritis represent merely the cyclic
changes of menstruation and they deny the existence of any but an inter-
stitial endometritis. Yet the occasional occurrence of definite conditions
of the type described is fully attested and the origin must be attributed
to the usual factors connected with chronic productive inflammation of
mucous membranes, to which is here added the influence of tumors and
inflammations in the uterus and adjoining tissues (Weishaupt-Schickele).

That chronic glandular endometritis may pass into adenoma is strongly
indicated J^y its frequent occurrence with myoma which nearly always

442 N EOF LA STIC DISEASES

shows glandular hypertrophy and often adenoma, and by the histological
evidence of the transition. The malignant change seems to occur suddenly
and affects first single glands, or larger areas. It is marked by striking
increase in the size of the epithelial cells, pronounced hyperchromatism,
atypical mitoses, multiplication of cell layers, and reduction of stroma.
These changes are pronounced and unequivocal when the diagnosis of
adenoma is justified, and it is only in rare instances that the decision remains
doubtful. When the adenoma is sufficiently established to reach the surgeon
all traces of the original hyperplasia may, as Heurlin found, be obliterated.

Prostatic Hypertrophy. — In the prostate inflammatory overgrowth is
responsible for the great majority of cases of chronic prostatic enlargement
(q.v.). Here the results are peculiar, depending on the structure and func-
tions of the organ and the changes must be referred not exclusively to the
inflammatory factors but also to secondary disturbances of nutrition and
function. In fact, a primary disturbance in the function of the prostate
may possibly prove to be an essential factor in the causation of hypertrophy,
since most cases of active prostatitis tend toward atrophy of the organ.
The inflammatory process begins about the ducts, retains a periductal
character throughout, and causes more or less new growth of fibromuscular
stroma about the systems of alveoli. The nearest parallel to this condition
is seen in chronic mastitis. The overgrowth of epithelium is complicated
by stasis of secretion which may produce small cysts with relatively atrophic
epithelium. Or the epithelium is more active and lateral sacculations and
papillary projections form. Ciechanowski emphasizes the absence of any
new glands in prostatic hypertrophy, but in many cases focal adenomatous
areas appear and the process passes into adenoma or carcinoma. In other
cases the natural tendency is toward fibrosis and atrophy.

Many examples of functional or congenital overgrowth of gland tissue
should be separated from true adenoma although no sharp line divides
these conditions from true tumors and in many instances the one passes
into the other.

(1) Functional Adenomatoid Hyperplasia. — In the breast, hypertrophy,
which is chiefly of functional significance, produces extensive enlargement
of both organs, at first of slight degree, but later, often at puberty, increasing
rapidly until both organs become very bulky (30 kg., Kaufman). The
condition may remain stationary in this stage or may increase during gesta-
tion and enormous amounts of very fatty milk are secreted. The structure
shows uniform increase of cellular connective tissue and of hypertrophied
gland lobules but there are many variations in the proportions of these
elements. In some cases the structure strongly resembles a true fibro-
adenoma. The series of cases analyzed by Voges and by Kirchheim illustrate
many peculiarities of the process, including an hereditary element, involve-
ment of one breast or both, or of one or two supernumerary organs, its
appearance before puberty or in the eighth gestation, after amenorrhea
and with other ovarian disturbances, regression partial or complete after
pregnancy, marked variations in structure, and frequent occurrence of pain
and emaciation. The condition is best interpreted as an excessive response
to physiological, functional and formative stimulus in congenitally pre-
disposed organs.

(2) Congenital hypertrophy of thyroid is a rare condition observed in
infants. The organ is uniformly enlarged to twice or three times its normal
dimensions. The structure shows increase in number of acini and hyper-
trophy of lining cells, with absence of colloid. It may cause early death
by pressure on the trachea and larynx (Kamann, Fabre-Therenot).

GENERAL PATHOLOGY OF EPITHELIAL TUMORS

443

The adult thyroid in Graves' disease presents the most striking example
of adenomatoid functional hyperplasia. The gland .becomes diffusely
enlarged, many new alveoli form, colloid disappears, cysts with papillary
projections develop, and atypical alveoli and giant-cells may form. Yet in
man this condition rarely leads to a true neoplasm. At the acme of the
process the cellular overgrowth reaches a limit and becomes stationary, or
is overtaken by atrophy and by nbrosis of stroma or interstitial thyroiditis
(Ewing, Lit.). In the fish, this form of hyperplasia sometimes results in
infiltrative growth and a true benign or malignant tumor (Gaylord).

Simple goiter presents less pronounced features of adenomatoid hyper-
plasia. In the so-called parenchymatous struma the cellular overgrowth
is extensive but orderly and typical. New follicles form by budding from
the old, following the normal course of growth of the thyroid (Wolfler). A

PIG. 173.

Adenomatoid hyperplasia of thyroid gland in Graves' disease.

somewhat similar picture may be produced experimentally in dogs by
administration of iodin, while a restoration to the normal structure may be
secured by adjusting the diet. This instability of structure and the ready
response to diet and drugs assures that the hyperplasia is in no sense neo-
plastic (Kocher, Marine).

In colloid struma there is abundance or excess of colloid in and about
alveoli and the thyroid may become very large from its accumulation.
Colloid cysts form from the fusion of distended alveoli and hemorrhage may
occur in these cysts. Overdevelopment of blood-vessels is frequently seen.
In the late stages there is fibrosis, softening of cyst contents, atrophy of
alveoli, arteriosclerosis and calcification. All of these changes may occur
in an isolated portion of the thyroid producing a tumor-like enlargement.
These cases suggest an imperfect alignment of a portion of tissue in the gland
with abnormality of blood-supply and possibly retention of embryonal
characters.

444 N EOF LA STIC DISEASES

Nodular hyperplasias of more definite neoplastic character occur in
both simple and Graves' goiter, and it is probable that both conditions favor
the development of true adenoma and carcinoma.

Struma Hypophysis. — Nodular or diffuse hyperplasia of the hypophysis
is frequently observed in subjects over 35 years of age (Lowenstein, Lit.).
Whether these conditions, commonly called adenoma, as well as some of the
more pronounced overgrowths associated with acromegaly, etc., are true
tumors or functional hyperplasias still remains to be determined. It is
probable that many definite adenomas and carcinomas arise from such
hypertrophies.

Struma Adrenalis. — Nodular and diffuse hyperplasia of the adrenal is
frequently observed. Either cortex or medulla or both may be affected.
Between the nodular hypertrophies and true adenomas there appears
to be every transition.

Adenoma Sebaceum. — In the sebaceous glands there is a form of over-
growth attended by oversecretion and marked hypertrophy and multiplica-
tion of glands which may approach a neoplastic grade (Balzer, Menetrier).
The disease occurs chiefly in epileptics and the mentally defective (Crocker)
and is usually limited to the skin of the face. In some cases the long dura-
tion, diffuse distribution, the orderly character of the cell-growth and the
self-limitation indicate a form of functional overgrowth (Caspary's case).
Here there is extensive multiplication of large sebaceous glands and pro-
liferation of the cells of the hair follicles. The epidermis may be thickened
and the small vessels dilated. In other cases there is extensive hyperplasia
of gland-cells and the lesion resembles a reticulated epithelioma, or adenoma
of sebaceous and hair follicles (Barlow). While usually self-limiting these
lesions are doubtless the source of some multiple epitheliomas of the skin.

The liver and kidney are especially susceptible to focal adenomatoid hyper-
plasia as a result of regenerative overgrowth. The process may be localized
or general. It occurs at all ages, in organs which apparently were normal,
in those which were recently the seat of acute degenerative processes, and
in many which are the seat of advanced cirrhosis. The hyperplastic nodules
are multiple and miliary or solitary and bulky. In young subjects nearly
the whole liver may be replaced by adenomatoid nod'ules. While in many
instances the conditions never pass beyond a physiological stage and are
found at death from other causes, a variety of somewhat specific tumors
take origin in the hyperplastic foci. Their relation to tumors will be con-
sidered in detail in connection with the tumors of these organs.

CARCINOMA

Carcinoma is a tumor process characterized by atypical and destructive
proliferation of epithelium.

By emphasizing the atypical morphology this definition separates carcin-
oma from some destructive adenomatous processes, while recognition of the
destructive element sufficiently denotes important physiological and clinical
features. From the structural standpoint emphasis may also be laid on
the equilibrium between epithelium and connective tissue which in papilloma
and adenoma remains more or less intact while in carcinoma it is lost. Better
than any rigid definition is the conception that carcinoma represents more
lawless overgrowth than adenoma and leads to a great variety of neoplastic
structures which show variable but pronounced grades of anaplasia.

Carcinoma shares with sarcoma the full contrast over against inflamma-
tion. This contrast justifies Virchow's general division of tissue changes into

GENERAL PATHOLOGY OF EPITHELIAL TUMORS

445

three groups, normal growth and physiological changes, inflammation, and
neoplasia. Malignant tumors reveal this contrast in the fullest light but
since carcinoma may result from excess of growth energy or from inflam-
matory hyperplasia there is no wide gap between these processes. This
admission does not allow that the processes are essentially the same. With
every addition in quantity there is a change in quality. The rate, vigor,
and extent of epithelial overgrowth may steadily increase over the normal
or over inflammatory hyperplasia, until finally the process expresses itself
as carcinoma. There is no necessary change in the nature of the epithelial
cell. Hence Ribbert states that there is no such thing as a malignant cell
endowed with new biological properties. It is only the process as a whole
and its intensity which are new.

It is necessary to recognize two great groups of carcinomas: (i) those
arising from misplaced portions of embryonal tissue and (2) those arising

FIG. 174. — Mammary cancer. Carcinoma simplex. Fully developed carcinoma. Infil-
trative growth of atypical cells, with desmoplastic properties.

from previously normal and adult cells through the influence of chronic
irritation.

The latter tumors exhibit many points of similarity with chronic inflam-
mation, in that the etiological factors are very diverse, the structural types
very numerous and the clinical courses very different, so that they constitute
so many different diseases which have in common only the fact that the under-
lying tissue change is a malignant neoplasm.

For very few general characters of great significance may be stated of
the cancer process. Chief among these is its progressive and fatal course,
to which there are exceptions. It is much more significant to know the
peculiar conditions under which a carcinoma arises, the particular features
in its gross and microscopical anatomy, its distinguishing clinical signs,
and natural duration. Only in this way can the knowledge of carcinomas
become theoretically sound and practically efficient. Hence one may conceive

446 NEOPLASTIC DISEASES

of carcinoma as a vast group of clinical and pathological entities connected
only as malignant epithelial neoplasms of extremely varied morphology.

Gross Anatomy . — The gross appearance of carcinoma is largely dependent
on the tissue of origin and to a considerable extent on its structure, while
wide variations are observed in the same and in different organs.

The classical appearance of advanced mammary carcinoma with its central
firm mass and many lateral extensions suggested to Galen the resemblance
to a crab and led to the designation as cancer.

Induration of the affected tissue is probably the most constant
and significant single feature of large and even of miniature carcinomas,
and is referable to the desmoplastic property of carcinoma. It is often
of very great diagnostic significance, surpassing at times the indications
drawn from microscopic structure. The induration of carcinoma is a peculiar
physical quality owing to its extreme density, and its presence in suspicious
lesions must stand as a strong indication of carcinoma. It is especially
to be distinguished from the less resistant and more diffuse induration of
chronic productive inflammation.

Associated with certain degenerative changes in the carcinoma cells, as
exposed by section through the tumor, induration and fatty degeneration
become quite specific of carcinoma. In carcinomatous nodules of the
breast, in early carcinoma of lip, tongue, and other mucous membranes,
in stenosing carcinomas of stomach and rectum, a translucent matrix of
new connective tissue streaked with silvery points and lines of fatty
epithelium are absolutely specific of carcinoma. The silvery points lack
the deep yellow color of included fat.

Cross-section also reveals the cicatricial character of many carcinomas.
The surrounding tissue appears to be drawn toward the carcinomatous center,
which may be sharply demarcated from the surrounding tissue, but not
encapsulated.

The nodule or mass is often fringed with fine extensions, or from it pass
many coarse cicatricial bands through which the tumor-cells are advancing.
Induration also marks the beginning of malignant change in the bases of
polypoid tumors which thus become fixed to the supporting tissues. It
marks the beginning of deep infiltration from superficial and ulcerating
carcinomas of mucous membranes.

Induration is a common but alone is not a safe criterion in judging of the
nature of enlargements of lymph-nodes. The encapsulation of these small
organs permits very marked density to be displayed by inflammatory changes
within the nodes. Here fixation is a most important sign of carcinoma.
In scirrhous carcinoma, induration begins early and continues prominent
throughout the process, producing tumor masses of uniform and extreme
density. The lesion is usually cicatricial in character, deforming the affected
organs as in the breast, or causing extreme stenosis as in pylorus or intestine.
Yet in some cases a tendency to hyaline swelling of the fibrous tissue limits
the contraction or even increases the bulk of the tumor. In cancer en
cuirasse a progressive fibrosis accompanies the wide extension of mammary
carcinoma over chest, back, neck, and even abdomen, and surrounds
the body in a rigid encasement which occludes lymph- and blood-vessels
and greatly hampers respiration.

Marked induration usually indicates a slow progress of the local lesion
but very often such quiescent fibrocarcinomas become the source of actively
growing and cellular tumors in the neighborhood or at a distance.

Very cellular carcinomas fail to exhibit marked induration, but appear
as opaque, whitish nodules or masses presenting a rounded or convoluted

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 447

border, a peripheral ring of congestion or hemorrhage marking the growing
edge, a broad intermediate zone of tumor-tissue, and often a central depressed
cicatricial area. Secondary cellular carcinoma of this type may be difficult
to distinguish from massive tuberculosis or syphilis, but the latter lesions
usually exhibit more necrosis and less fibrosis than carcinoma. The terms
encephaloid or medullary cancer are often applied to the soft cellular tumors,
from a fancied resemblance to brain tissue.

Papillary and adenoid carcinomas usually appear as bulky circumscribed
masses which are fragile, crumbly, and of wholly different appearance and
consistence as compared with the involved organ. Minute inspection
frequently reveals specific markings which give a clue to the microscopical
structure. The entire group of papillary carcinomas may usually be
recognized by the circumscribed character of the conglomerate nodules and the
branching opaque cords of cells. Papillary and adenoid carcinomas are
usually vascular and subject to interstitial hemorrhages and necrosis which
often lend characteristic gross features.

Many cystic tumors are of carcinomatous structure. The tumor may
originate by papillary growth into an enlarging gland-duct or alveolus, and
while the tumor remains encapsulated the carcinomatous process remains
confined and comparatively harmless. Or the cysts form in previously
solid tumors by accumulation of secretion, edema, hemorrhage, or lique-
faction necrosis.

Specific degenerative changes are sometimes highly characteristic of cer-
tain glandular carcinomas. Chief among these is the excessive mucus
production of gelatinous carcinoma of the gastro-intestinal tract, perito-
neum, ovary, breast, and other organs, which tends to cause rapid increase
in the bulk of the tumor while actually retarding the proliferation of tumor-
cells. Yet such tumors may prove highly malignant, since the distention
of tissue spaces by the mucus facilitates the dissemination of the surviving
cells. The entire abdominal cavity may be distended with mucinous material
in colloid cancer of the intestine, or the entire stomach wall may be thickened
and honeycombed by such growth. Pseudomyxoma peritonei is a form of
diffuse implantation tumor arising from mucinous ovarian cancer, in which an
originally carcinomatous process becomes greatly altered by a peculiar in-
flammatory process about masses of mucus.

Calcific changes are relatively uncommon and belong chiefly to the
regressive processes. There may be extensive calcification of the pearls of
epidermoid carcinoma, and of atrophic portions of rodent ulcer, or in old
necrosed areas of glandular carcinoma. In psammocarcinoma of the ovary,
parotid, or kidney, actively growing portions of the tumor may present an
enormous number of dense sand grains derived from epithelial concretions
which seem not to inhibit the progress of the growth. In a form of cylin-
droma of the skin, growth terminates in diffuse calcification. In many
cases the walls of blood-vessels and areas of stroma undergo hyaline trans-
formation followed by calcification, and leading to extensive atrophy of the
tumor parenchyma.

Extensive calcine deposits in the organs form a remarkable feature of the
metabolic disturbance in rare cases of carcinoma. Thus in a case of mam-
mary cancer Elser found the walls of the pulmonary air- vesicles calcified over
wide areas.

Miliary carcinosis is a gross anatomical form of the disease presented by
highly malignant and widely disseminated processes. Here the miliary
tumor nodules appear widely scattered over serous membranes, peritoneum,

448 N EOF LA STIC DISEASES

pleura or meninges, or extremely numerous foci appear in skin, muscles, or
organs, having traveled through the lymphatics or blood-vessels.

Ulcerative lesions commonly result when carcinoma affects cutaneous
or mucous surfaces. The characters of the carcinomatous ulcer vary with
the location and form of the disease. When primary they are usually single.
The position is determined by the mucocutaneous junctions or by exposure to
irritation. The base is indurated and eventually fixed to the tissues. The
secretion is scanty, purulent, bloody, subject to increase from infection,
and complicated by hemorrhages from eroded vessels. The edges are
raised, hard, usually not undermined, but rigid and opaque. The vicinity
shows no essential change but may be secondarily invaded. The regional
lymph-nodes are enlarged first by inflammatory changes, later by carcino-
matous invasion.

FIG. 175. — Calcification of walls of pulmonary alveoli in a case of advanced mammary

carcinoma.

Rodent ulcer rarely invades the lymph-nodes. Carcinomatous ulcers
of the buccal or uterine mucosa early reach the first barrier of lymph-nodes
but rarely pass the second chain, while the ulcer will eventually extend to the
invaded nodes and thence laterally until the death of the patient from infec-
tion and hemorrhage. Ulcerating glandular carcinoma as of the stomach or
uterus may produce widespread metastases.

Microscopic Structure. — No single microscopic feature and no combi-
nation of occasional criteria can be claimed as invariably pathognomonic
of the cancer process. The history of the microscopic study of cancer
presents numerous instances of failure to establish this essential character-
istic. The microscopical structure varies so extensively in different organs
and at successive stages as to eliminate the possibility of such rigid cri-
teria. It is sometimes impossible to determine whether a given process

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 449

should be classed as precancerous, as miniature carcinoma, as adenoma or
adenocarcinoma, or as carcinoma. Often several of these phases of the evo-
lution of the process are present in the same lesion, and more frequently
several structural types of true carcinoma are combined in the same tumor.
Hence carcinoma must be regarded not as a uniform structural alteration,
but as a progressive process which has a diverse origin, a variable course, and
an uncertain termination, each phase presenting its own morphology.

Moreover, carcinomas of the various organs and different carcinomas
of the same organs may present their own structural peculiarities. It is
therefore necessary to learn the specific characters of this disease as it occurs
under a great number of conditions. This extremely varied morphology
of carcinoma is the source of much confusion of nomenclature, of much con-
flict of opinion as to what constitutes carcinoma, of great uncertainty re-
garding histogenesis, and it has especially obscured the distinctions between
carcinoma and sarcoma.

Primary Versus Secondary Structure of Carcinoma. — It is highly impor-
tant to distinguish between the primary structure of a tumor, which usually
reflects its original tendencies, and secondary changes in structure which
result from inflammation, hemorrhage, adaptation to mechanical environ-
ment, and interference by surgical procedures. The primary structure often
gives a definite clue to or clearly reveals the origin of the tumor, as in the
various forms of epidermoid carcinoma, adenocarcinoma of uterus, embry-
onal carcinoma of testis, etc. When altered by any of the above influences
all carcinomas tend to assume an indifferent, diffuse or perivascular structure
in which most of the original features are lost, and from which it is usually
hazardous to attempt to reach any conclusions regarding histogenesis. Thus
epidermoid carcinoma may appear as a round- or spindle-cell growth, adeno-
carcinoma of uterus may recur after curettage as perithelioma, and melanoma
may recur as a round-cell, diffuse or perivascular, pigment-free tumor.

Structure. — A detailed analysis of the structure of carcinomas reveals at
least the following features, any one or all of which may be present.

(1) Cellular overgrowth passing beyond that observed in other processes
affecting the same tissue.

Excessive overgrowth indicating abnormal powers of proliferation is a
very notable feature of many carcinomas. Its degree may at once reveal
that the process differs in kind from functional or inflammatory hyperplasia.
It is usually associated with atypical qualities in the cells but in the thyroid
gland, pancreas, and adrenal, the cell type may not differ markedly from that
observed in other forms of hyperplasia. On the other hand excessive over-
growth is not an impressive characteristic of some epidermoid carcinomas;
the bulk of cells in some scirrhus mammary cancers is probably less than that
of the normal breast; while many relatively benign tumors of the gastro-
intestinal tract are more massive than the highly malignant growths in these
tissues.

(2) Atypical Qualities of the Cells. — Although there is no characteristic
morphology of the cancer-cell yet a change in appearance from that of the
originating cell is a nearly constant element in the cancer process. This
change consists chiefly in an increase in the chromatin content of the nucleus,
and signifies increased nutrition and, as the behavior of the cell ordinarily *
shows, increased powers of growth. The nuclear change may be the only
discernible alteration, for such cells may be either larger or smaller than nor-
mal and otherwise unaltered.

In some early multiple carcinomas of the skin described by Janeway,
the lesions consisted exclusively of a slightly increased number of epithelial

450 N EOF LAST 1C DISEASES

cells throughout the Malpighian layer, with very marked hyperchromatism.
Usually such cells show some hypertrophy.

In early flat carcinomas of the larynx the lesion may consist of a thick-
ening of the epithelial layer due to hypertrophy of cells with hyperchromatic
nuclei. Distinct hyperplasia and heterotopia are for a time absent. More
frequently still the altered cells exhibit hyperplasia and heterotopia.

In a large group of carcinomas the altered cells are smaller than normal,
as in some very malignant tumors of prostate, pancreas, liver, adrenal and
other organs. Indeed the small cell carcinomas as a class may be regarded
as particularly malignant.

The whole series of nuclear changes in cancer-cells forms an extensive
chapter in the morphology of cancer which is discussed elsewhere. An abun-
dance of mitoses is observed in many rapidly growing tumors, but is notably
absent in others. The atypical quality of the mitoses may or may not be
prominent and is not essential. An extensive list of degenerative nuclear
and cytoplasmic changes also belongs to the occasional regressive processes
in cancer tissue.

The changes in the type of the cancer-cell are often designated as meta-
plasia, but since this term is more clearly applicable to inflammatory and func-
tional alterations of cells which lack malignant attributes its use in connec-
tion with the cancer process is not wholly desirable. Since these changes go
with destructive proliferation, and signify loss of organization and restraints
to growth, Hansemann's term "anaplasia" appears the more acceptable.

(3) Heterotopia. — The advance of proliferating epithelium beyond its
normal limits is nearly identical, as a feature of carcinoma, with distinct
invasive properties, but there are instances in which heterotopia is not in-
vasive or destructive. Within gland ducts and alveoli malignant prolifera-
tion of epithelium may force the cells into abnormal positions within the
confined space. There is heterotopia without invasion of tissues. In many

Eapillary epidermoid carcinomas islands of epithelium may become displaced
y inflammatory processes or by elongation and twisting of rete pegs before
there is definite invasion of the connective tissue. More pronounced down-
ward growth of surface epithelium is usually preceded by round-cell infiltra-
tion and weakening of the connective tissue. The equilibrium between
epithelium and connective tissue being thus disturbed, the epithelium begins
to pass beyond its normal limits and true cancerous heterotopia is soon
established.

(4) Local Invasive and Destructive Properties.- — Infiltration of tissue-
spaces, lymphatics, and blood-vessels is the criterion of fully developed car-
cinoma. The invasion may be by single cells or cell groups, or by alveoli
of adenocarcinoma. Analysis of the process furnishes ground for the
belief that several factors are concerned. Chief among these is probably
the mechanical pressure of proliferating epithelium. In certain comedo-
carcinomas of the breast the appearances point most directly to the mechan-
ical forcing of cells through hernias and tears in the distended basement
membranes out into the connective tissue, and in many other cases the
shape and position of the cells is best explained as the result of pressure.
The ameboid properties demonstrated in certain cancer-cells may facilitate

' their progress through the invaded tissues, but the evidence in favor of
this view is scanty.

Chemotaxis exerted by agents toward which proliferating cells travel
appears to have been demonstrated in Fischer's experiments with Sudan III,
but in a process which proves not to be carcinoma.

There appears to be no support for the suggestion that tumor-cells secrete

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 451

heterolytic ferments which loosen or dissolve the invaded tissues, but an in-
competent barrier of round-cells, congested and proliferating vessels and
edema, often render the tissues less resistant. In some mucous carcinomas
the wide diffusion of fluid mucus evidently determines the peculiar manner
in which such tumors advance.

Highly malignant carcinomas penetrate the preformed lymphatics and
blood-vessels often like an infection, but when there is much local inflamma-
tion and fibrosis the invasion is more localized, slower, and largely through
new formed spaces created by the tumor-cells. There is abundant support
of the general rule that carcinoma travels by preference through the
lymphatics.

The extent of the lymphatic invasion may be extremely wide. In mam-
mary carcinoma the skin of nearly the whole trunk may be invaded, and
Handley traced continuous permeation through lymphatics from breast to
humerus and femur. Depending apparently on the activity of the process
and the resistance of the organism, lymphatic invasion is attended by peri-
lymphangitis with flbrosis and atrophy of tumor-cells, or by no reaction
whatever.

The invasion of blood-vessels occurs chiefly in organs in which the vas-
cular supply is unusually favorable to this event, as in thyroid, liver, adrenal,
and kidney. It is also relatively frequent in young adults suffering from
highly malignant tumors.

Serous cavities are traversed by permeation through the abundant
subserous lymphatics or by mechanical dissemination of cells discharged into
the cavity. In the peritoneum and especially in the meninges the invasion
may be extremely rapid, simulating an inflammatory process.

The destruction of tissues invaded by carcinoma is a common event.
Pressure atrophy of supporting structures, especially the blood-vessels, is the
chief factor at work and its influence is most evident in metastatic carci-
nomas of internal organs. There is much variation in the resistance of differ-
ent tissues to advancing carcinoma. Arteries and tendons are least affected,
but bone and cartilage are readily absorbed and destroyed.

On exposed surfaces mechanical trauma is added to the pressure atrophy
so that on mucous and cutaneous surfaces carcinoma early tends toward
necrosis and ulceration. In the stomach the gastric juice promptly attacks
the feebly nourished tissues of many early carcinomas converting them into
ulcerating lesions. In Verse's series several early gastric carcinomas were
found with superficial erosion of epithelium which permitted access of infec-
tion with purulent inflammation. In most epidermoid carcinomas infection
becomes established sooner or later, contributes to the destructive process,
and may even dominate the clinical course and anatomical picture of the
disease.

(5) Desmo plastic Properties. — Among the most significant features of the
cancer process is its power of exciting the growth of new cellular connective
tissue. This tissue reaction may be a very prominent and very early element
in carcinoma, so that it deserves important consideration as a diagnostic sign
of malignant disease. In some carcinomas of the prostate it may antedate
characteristic changes in the epithelium, and in carcinoma of the breast it is
often prominent in very early and minute lesions. In true fibrocarcinoma
of breast, or stomach, in linitis plastica, and in peritoneal metastatic nodules,
the bulk of new connective tissue may far exceed that of the tumor-cells,
which may eventually disappear.

That this product has the same significance as the connective tissue of
productive inflammation is shown by the fact that it is often replaced' or

452 N EOF LA STIC DISEASES

preceded by or associated with lympjioid infiltration and commonly termi-
nates in sclerosis. For the same reasons it must be interpreted as a reaction
of immunity on the part of the tissue. In this respect carcinoma exhibits a
parallel with chronic inflammatory processes. According to the activity
and age of the reactive process the new tissue is composed of lymphocytes
and plasma-cells, capillary blood-vessels and endothelium, proliferating
fibroblasts with soft mucinous stroma, or acellular fibrous tissue. Polynu-
clear leukocytes take no part in the uncomplicated reaction to invading
carcinoma. In linitis plastica there is marked proliferation of endothelium
and fibroblasts in the gastric submucosa, and these cells mingled with
scanty tumor-cells present a highly peculiar picture of a process which is
essentially desmoplastic.

(6) Loss of Polarity. — Disturbance in the relation of epithelial cells
to one another belongs chiefly to the advanced phases of carcinoma. Gland
cells normally stand upon a basement membrane and adhere in orderly
fashion to their neighbors, and this arrangement may be assumed as essential
to normal growth and function. Complete loss of these relations is observed
in diffusely growing carcinomas arising from such glands and signifies
advanced anaplasia. Traces of normal polarity may long persist in small
alveolar carcinomas in which a definite lumen appears in the centers of cell
groups. Persistent retention of polarity is a peculiar feature of adenoma
malignum and adenocarcinoma, appearing in the secondary alveoli forming
in distended gland spaces, and reappearing, often in striking distinctness,
in some distant metastases from such tumors. The significance of loss of
polarity as a measure of anaplasia appears in the series of comedo carcinomas
of the breast, some of which produce definite secondary alveoli within the
ducts while in others the cells grow diffusely. The former long spare
the lymph-nodes, 'while the latter rupture the basement membrane and
invade the breast and axillary nodes. Much the same variations may be
traced among the epidermoid and papillary carcinomas.

(7) Metastases. — Apart from the continuous permeation of lymphatics
and tissue spaces it is a highly significant property of carcinoma to give rise
to cell emboli which pass through the blood- or lymph- vessels and originate
distant secondary tumors. While this feature belongs especially to the
actively growing tumors it is also observed in very early stages of the evolu-
tion of carcinoma. In the benign metastasizing thyroid struma extremely
abundant secondary tumors may appear in lungs or bone-marrow in which
the structure closely approaches that of the normal gland. Early adrenal
adenoma may nearly duplicate this phenomenon. In the liver adenoma may
pass easily into the numerous venules of this organ but its cells do not readily
survive in other organs. In vascular tissues as the tongue, upper lip,
stomach, testicle, very small carcinomas may be found to have yielded
metastases. On the other hand some true carcinomas with wide local
extensions, as rodent ulcer, seldom or never invade lymph-nodes. The
property of producing metastases cannot therefore be demanded of all
carcinomas and cannot be regarded as a reliable measure of the degree of
anaplasia. In so far as the embolic cells are able to survive transplantation
and show even accelerated powers of growth, metastases reveal a property
entirely foreign to normal cells.

A survey of the different forms of cancer occurring in various organs
demonstrates that the above microscopical features may be combined in
very different degrees. Many highly malignant and fully developed carci-
nomas exhibit all of them from a very early period in their evolution. In a
large group of tumors the characteristic features are much more pronounced

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 453

in one portion of the growth than in another. It is usually observed that
the recurrence of a carcinoma is more atypical and malignant than the
original tumor. In a series of four recurrences of an epidermoid carcinoma
derived from the enamel organ the tumor exhibited increasing grades of ana-
plasia and finally grew as a diffuse round-cell carcinoma. In the group of
adenocarcinomas some of the characters of fully developed carcinoma are
regularly lacking. Finally, in the beginnings of carcinoma in many organs,
in lesions designated as precancerous, it is sometimes possible to trace the
gradual addition of one after another of the microscopical features of the
fully developed disease.

From these observations several important conclusions follow:

(1) Carcinoma does not necessarily spring fullfledged into being, but is
to be regarded as a process which often exhibits stages of evolution which
gather momentum as they progress.

(2) It is not possible nor advantageous to distinguish sharply between
processes which show more or less of the microscopic characters of carcinoma.
It is necessary to learn by clinical experience the natural history of micro-
scopical structural changes and to class with cancer all those which tend to
progress to the fully developed forms of the disease.

(3) The doctrine of precancerous lesions finds abundant support in the
progressive evolution of processes which from the first have commonly been
classified as carcinoma.

Structural Classification of Carcinoma. — While the structure of carci-
nomas is extremely varied, it is possible to recognize several well-defined
anatomical types.

Adenocarcinoma. — As previously indicated adenocarcinoma is a type in
which the growth reproduces more or less completely the original gland
alveoli from which the tumor springs. It is a partially developed form of
carcinoma in which the arrangement of cells in alveoli with central lumina,
the polarity of the cells, and frequently some trace of their function^ are
partially preserved. In some cases the relation of cells to stroma is main-
tained. The alveoli usually differ, sometimes very notably, from the original
type, but occasionally it may be difficult to distinguish the neoplastic from
the normal alveolus. The reproduction of alveoli does not identify the
tumor with adenoma of the particular organ, for adenocarcinoma lacks the
restrained growth, the orderly proliferation, and more typical reproduction
of alveoli, of adenoma. Adenocarcinoma commonly exhibits a strong
tendency to assume the structure of typical carcinoma in certain portions
of the tumor, so that it is ordinarily invasive and destructive and clinically
malignant. Adenoma malignum is also invasive but tends to maintain
throughout an orderly glandular structure. It also may exhibit the trans-
formation into true carcinoma, in which case it is practically identical with
adenocarcinoma.

The tendency to form acini with central lumina is persistently retained
in many malignant tumors of the organs and it becomes extremely difficult
at times to determine whether the tumor is an adenocarcinoma or a diffusely
infiltrating growth in which the cells appear in small groups.

Papillary Carcinoma. — Is a form of adenocarcinoma arising from glands,
mucous surfaces, and occasionally from cutaneous surfaces. Its relation
to adenocarcinoma is revealed in the partial preservation of cell polarity and
of the supporting stroma. It produces tufts and finger-like branching
projections of exuberant epithelium which may be supported by vascular
strands of connective tissue. The epithelial layer is multiple and the over-
growth, far outstripping the connective tissue, may form thick masses,

454 NEOPLASTIC DISEASES

or convoluted layers which fuse with one another. In this manner the
original polarity of the cells is completely lost and the papillary structure
becomes diffuse. Papillary carcinomas also exhibit malignancy by epithe-
lial invasion of the bases or cores of the papillae. A large proportion of
cystic tumors are papillary adenocarcinomas.

Cystic Carcinoma. — Many glandular carcinomas develop cysts, within
gland alveoli or ducts which become greatly distended by a growth which long
remains confined by the thickened wall of the resulting cyst. The distention
is favored by internal pressure from the epithelial mass, from retained secre-
tion, and from hemorrhage and exudate, while the cyst wall may exhibit
intrinsic powers of growth and participate in the process.

The epithelial growth within the cyst may be papillary or glandular and
is usually of the order of adenocarcinoma. The papillary structures may be
very numerous and low or very long and complex, and present all the features
of other papillary carcinomas. They are especially prone to perforate
the cyst wall and continue their growth in papillary or diffuse form in the
invaded tissues or in adjacent cavities.

Glandular cystadenocarcinoma presents extensive multiplication of
glandular alveoli of the ordinary type of adenocarcinoma.

Certain organs, as ovary and breast, are particularly prone to develop
cystic carcinomas, and the form of the tumor seems dependent upon the
particular conditions under which it develops. In the breast cystic car-
cinoma arises chiefly from the malignant transformation of a previous cyst
or cystadenoma. The tumor perforates the capsule, which lacks muscle-
tissue, before reaching large dimensions. In the ovary carcinoma appears
in very small cysts which by fusion form relatively large tumors. The
capacity of the fibromuscular stroma of the organ to resist pressure as well
as invasion may partly account for the great bulk attained by some malignant
ovarian tumors. Yet perforation of the capsule frequently results at an
early stage.

Secondary cysts form in many carcinomas by liquefaction necrosis,
edema, lymphangiectasis, and hemorrhage.

Fully developed carcinoma appears in a great variety of structural forms
for which there is a wide choice of terms.

Small alveolar carcinoma is a specific term which may properly designate
a carcinomatous structure in which the cells appear in small groups supported
by a moderate amount of connective tissue. The cell groups do not as a
rule surround a central lumen but lie compactly. Yet in many cases the
restoration of a small lumen very readily appears in occasional cell groups
and should not release the tumor from consignment to the anaplastic class
of true carcinoma. Large alveolar carcinoma equally well designates a similar
structure in which the cell groups are larger but still well defined. As these
structures are probably the most frequent histological types of the disease,
they are often described as carcinoma simplex.

Tubular carcinoma refers to the appearance of elongated cords of tumor-
cells, of the type of carcinoma simplex, which may or may not inclose a
lumen. When small lateral cell groups branch off from such central tumor
cords the term acinar carcinoma is sometimes applied.

In different organs many special peculiarities in the structure of carcinoma
appear and some have received special designations as indicated in the
descriptions of these tumors.

The attempt to designate a given carcinomatous tumor by a specific term
meets the difficulty that several structural types may be presented in different
portions of the growth. Not only the most advanced form, but the simplest,

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 455

and the most prominent are of importance in determining the nomenclature,
and in this dilemma the structure is often passed as carcinoma varia.

Diffuse Carcinoma. — In the most malignant and highly anaplastic forms
of carcinoma the cells lose their specific features, all trace of polarity and
capacity to excite connective-tissue reaction, and they grow diffusely, pre-
senting no trace of alveolar formation. Such structures may be designated
as diffuse carcinoma. They are observed in very active or fulminant tumors
of many organs, especially in young subjects, in the breast during gestation, in
certain tumors arising from embryonal structures, and in the accelerated
growth of simpler tumors recurring after operation. In the most pronounced
stages of such growth the structure may be difficult to distinguish from lym-
phosarcoma but the perfectly fixed cells usually remain polyhedral.^Many

FIG. 176. — Atypical diffuse carcinoma of nares.

diffuse carcinomas have figured in the literature as sarcomas, especially of the
testis and adrenal.

Embryonal Carcinoma. — Certain tumors present a structure which
resembles that of the embryonal type of the organ from which they are
derived. They may be adenomatous, adenocarcinomatous, or carcinoma-
tous. Some fall in the structural class of diffuse carcinoma. A typical
example is the epithelial type of Wilms' tumor of the kidney which, even
when composed almost entirely of epithelium, at once declares its embryonal
nature. At the other extreme stands the hornifying epidermoid carcinoma,
which is distinctly adult in type. In nearly all glandular organs are occa-
sionally encountered cellular carcinomas recalling the embryonal structure of
the organ, and many of these, as in the thyroid, are composed of small cells
consisting chiefly of nuclei.

The embryonal nature of a tumor should not be confused with an ana-
plastic character. While many embryonal carcinomas are also highly

456

N EOF LA STIC DISEASES

anaplastic, others are relatively slow in growth and vary little from the cells of
origin. The failure to distinguish between embryonal and anaplastic char-
acters gives rise to much misapprehension regarding the prognosis of cellu-
lar carcinomas, since embryonal carcinomas are very prone to sudden varia-
tions in growth, they often respond to x-ray treatment, and their course is
distinctly less malignant than that of anaplastic carcinoma of corresponding
structure.

Embryonal carcinomas must be conceived as arising from embryonal
structures, often misplaced, and since the cells of origin are imperfectly
developed the tumor reflects this character throughout. The embryonal
character does not signify that there has been any reversion of the originating
cells of the tumor from an adult to an embryonal type. It is possible to
grade the carcinomas of many organs according to this principle, as adult or

FIG. 177. — Mammary cancer.

Embryonal adenocarcinoma producing a bulky, rapidly
growing malignant tumor.

embryonal, and in the kidney especially, it appears that the classification
corresponds with the stage of development which the originating cells have
reached at the time the tumor develops from them.

Fibrocarcinoma. — While most carcinomas excite some connective-tissue
reaction, in some the connective tissue is excessive in amount, it is subject to
hyaline changes, and it compresses the cells so that their growth is impeded.
Fibrocarcinomas are usually of slow growth, of dense consistence, and of cica-
tricial appearance. They are most frequently seen in elderly and resistant
subjects. The peculiar structure may appear from the beginning, as in
mammary scirrhus, or it may develop later in regressing areas. Eventually
the tumor-cells may entirely disappear. Typical examples are observed in

GENERAL PATHOLOGY OF EPITHELIAL TUMORS

457

sclerosing fibrocarcinoma of the pylorus, in metastatic peritoneal nodules, and
especially in cancer en cuirasse.

In most cases the development of fibrocarcinoma appears to depend
chiefly on local conditions, since a localized nbrocarcinoma may develop very
cellular secondary tumors at a distance or even in the same organ.

Epidermoid Carcinoma. — From surfaces lined by squamous-cells, and by
metaplasia of other epithelial cells, develop tumors presenting the characters
of squamous epithelium. The general term "epithelioma" is commonly
applied to this entire group, but should doubtless be displaced in favor of the
designation "epidermoid carcinoma."

FIG. 178. — Mammary cancer. Primary scirrhus or fibrocarcinoma in a young subject.

There are two main groups of epidermoid carcinoma, those presenting
flat squamous-cells and sometimes called acanthoma, and those presenting
smaller cells of the basal type, and called basal-cell carcinoma.

These terms may give a false inference that the one tumor is derived from
the squamous cells of the Malpighian layer, the other from the basal cells.
Yet acanthoma arises from downgrowth of both basal and overlying cells,
which immediately exhibit some of the normal changes into flat cells, often
with intercellular spines. Basal-cell carcinoma arises perhaps exclusively
from basal cells, often from misplaced and embryonal groups of such cells,
but the normal transformation into squamous cells entirely fails.

Many subvarieties of epidermoid carcinoma are observed. Acanthoma
presents adult flat epithelium, with hornification, concentric groups of cells
flattened by pressure (epithelial pearls) and often intercellular fibrils.
Keratohyalin granules may usually be demonstrated by appropriate stains.
The younger cells of such tumors tend to lose their adult characters and
infiltrate the tissues, producing cords of very opaque polyhedral cells (tubular
epidermoid carcinoma).

The squamous cells may become more and more atypical, producing cel-
lular carcinomas of many types, eventually growing diffusely, and even ap-

458 N EOF LA STIC DISEASES

pearing as round-cell or giant-cell carcinoma. Many epidermoid carcinomas,
as in the cervix uteri, reproduce the entire epithelial layer of the originating
structure which becomes convoluted, invaginated into the underlying sub-
mucosa, and appears as a structure which may be designated as plexiform
epithelioma. Others break up early into small groups of cells which rapidly
infiltrate the tissues. They are more malignant than the plexiform type.
An extensive group maintains a papillary structure. Or an original glandular
tendency may appear pronounced in the tumor, as when it arises from the
ducts of cutaneous glands or the enamel organ, and produces a glandular
epidermoid carcinoma. So great is the variety of structures in epidermoid
carcinoma that they must be dealt with separately in the organs in which
they occur.

Squamous metaplasia, affecting the cells before the development of the
tumor, or appearing in the course of glandular carcinoma, or as an element
in teratomas, accounts for the presence of epidermoid carcinoma in unusual
situations.

Precancerous Lesions. — The beginnings of carcinoma have been sought
in most organs without wholly satisfactory results. As a rule the cells of
the smallest established carcinoma appear to be entirely separate from the
normal tissues and to differ essentially from those phases of atypical hyper-
trophy or inflammatory overgrowth which accompany many carcinomas.
These well-established observations have led Ribbert to assert that the cells
of carcinoma are isolated throughout their entire course and hence the cells
of origin must be isolated. This author has affirmed that no one has ever
seen the beginnings of carcinoma of the breast, all true carcinomas of this
organ being so well differentiated from the normal gland that the attempt
to trace the neoplastic from the normal cells invariably fails.

This tenet conveys an important principle in the histogenesis of carcinoma,
namely that the initial proliferation of cancer-cells proceeds rapidly, usually
obliterates any traces of the transformation of normal into tumor-cells and
renders extremely difficult the decision just what form the progenitors of
cancer-cells presented. Is it therefore necessary to regard with caution the
interpretation of many forms of atypical cell-growth as preliminary to the
development of true cancer.

Moreover the comprehensive lists of tissue abnormalities as catalogued
by R. Williams, R. Meyer, and many others, has established on a very broad
basis the theory of Cohnheim that tumors develop from misplaced and
embryonal cell groups which have never enjoyed a normal structure. This
theory must also include structural abnormalities and tissue predispositions
which are not revealed by obvious microscopical changes but which certainly
contribute to the origin of tumors. In all this group of cases the origin
of cancer is from congenitally misplaced or abnormal cells and not from
transformed normal cells.

In another and very extensive group the evidence points to the origin
of carcinoma from previously normal adult cells which pass through a
series of changes induced by chronic irritation and terminating in carcinoma.
This class of tumors has been called the "irritation group," and the prelimi-
nary cell changes have been called "precancerous lesions."

The evidence in support of this view is both clinical and morphological.

Clinical observation has long indicated that the majority of important
tumors are not dependent on congenital abnormalites in tissue structure
but arise from once normal but previously altered tissues, and that various
forms of chronic inflammation are observed to precede the appearance of
most tumors.

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 459

In 1872 Hutchinson termed various manifestations of buccal syphilis
precancerous. Billroth observed that cancer almost never arises in a normal
breast and later studies have shown that chronic mastitis frequently precedes
mammary cancer. V. Bergmann stated that primary cancer of the skin
without previous cutaneous lesions does not exist. In the various organs
it is universally recognized that certain pathological conditions are followed
in a variable but high proportion of cases by carcinoma. For these con-
ditions the term "precancerous diseases" has been employed by Orth, but it
should be emphasized that these diseases possess in themselves no essential
element of the cancer process, and are merely observed to precede and favor
the development of cancer.

The so-called precancerous conditions fall into several distinct classes
but the majority of them, represent specific forms of chronic productive
inflammation.

i. Chronic Inflammation. —In the skin well-known forms of cancer arise
in the cicatrices of burns, tuberculous and syphilitic lesions, and amputation
wounds. A long period usually elapses before cancer appears in scars and
the tumor is often multicentric or diffuse in origin. Lupus carcinoma may
arise in the active tuberculous lesions but in 30 per cent, of the cases it occurs
in the scar tissue (Steinhauser). It develops usually toward the thirtieth
year of the disease and never before the fifth. Ashihara reports several
carcinomas in syphilitic scars. X-ray dermatitis is a remarkable instance
of a destructive and inflammatory process tending to develop cancer. A
period of three to eleven years precedes the malignant process, and is occupied
by necrosis of tissue cells, occlusion of vessels, fibrosis and epithelial over-
growth (Porter, Wolbach).

In glands and mucous membranes chronic inflammation is frequently
followed by cancer. In the gall-bladder cancer was preceded by gall-stones
in 100 per cent, of Janowski's cases and the proportion of cases of cholelithia-
sis developing carcinoma was placed by Slade at 18 per cent. The irritation
of cholesterin seems to have a peculiarly effective influence in inducing
atypical epithelial proliferation.

In the uterus chronic catarrhal endocervicitis precedes cancer in the
majority of cases (34 of 48, Polese). Cervical erosions, leukoplakia of portio
and canal have frequently been traced into carcinoma. For corpus carci-
noma, the hyperemia and endometritis accompanying myoma may be held
responsible for the development of carcinoma. It usually develops opposite
the point of contact of the myoma and the eroded endometrium. Acanthoma
and adenoacanthoma follow leukoplakia of the endometrium (Benckizer).

In routine material I find transition stages from hypertrophic endometritis
to carcinoma rather frequently but clinical observations are still inadequate
to prove the close dependence of the malignant upon the inflammatory
process. In 44 cases of corpus carcinoma Heurlin failed to find any transition
stages, but 29 of his cases were diffuse.

In the urinary bladder most cancers may be traced to previous or coexist-
ent cystitis (Stoerk, Cohen). Specific vesical irritants as in anilin workers
produce many tumors, chiefly at the ureteral orifices, 50 per cent, of which are
malignant (Rehn, Seyberth). In Bilharzia disease the development of
carcinoma on venous and lymph stasis, with cystitis from irritation by ova
and lithiasis, has often been traced in detail. Various forms of balanitis pre-
cede carcinoma of the penis. Demarquay found phimosis in 85 per cent, of
his cases, and Kaufmann observed warty vegetations in 29 of 33 cases.

Buccal and lingual cancer is almost always referable to one or all of three
factors, syphilis, tobacco, or decayed teeth. The syphilitic process usually

460

N EOF LA STIC DISEASES

takes the form of leukoplakia, of which 30 per cent., according to Fournier,
develop carcinoma. In these cases there is hypertrophy and hyperplasia of
epithelium, hyperkeratosis, lymphocytic infiltration of submucosa, papillo-
matous overgrowth, and finally destructive invasion of deep tissues. Darier
finds that the complication of an ulcer or fissure is usually necessary before
leukoplakia becomes cancer. Syphilitic warts, fissures, gummas, and
atrophic glossitis also precede cancer.

Excessive use of tobacco produces the well-known smoker's tongue and
throat, in which there is hyperemia, edema and lymphocytic infiltration of
submucosa, erosion and then downward growth of epithelium. Ragged

FIG. 179. — Atypical adenomatous proliferation in ducts in chronic mastitis.

teeth produce superficial erosions, thickening of regenerating epithelial layer,
lymphocytic infiltration, heterotopia, and then downward growth of atypical
cells.

In all this group of cases it is evident that the carcinoma is only an indirect
result of the irritation, and the long period which precedes the malignant
process, as well as the infrequency of the malignant change, give opportunity
for other local or constitutional factors to come into play. Nevertheless it
is clear, as in Kangri-oven and betel nut cancer of African natives, that local
and general predisposition may be ignored, since the tumor develops wherever
the irritation is effectively applied.

2. Physiological involution of organs and complicating mechanical, nutri-
tional, and inflammatory processes precede the development of cancer

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 461

chiefly in the breast and prostate. Definite neoplastic tendencies in the
"maladie de Reclus" were pointed out by Brissaud and Schimmelbusch.
Reclus, Saar and many others have declared that the step from chronic
mastitis to carcinoma is short. It is especially in that form of chronic mas-
titis in which cysts and epithelial proliferation are prominent from the first
that cancer is observed to develop, but no anatomical form of the disease is
free from the danger of malignant change. Bloodgood prefers to regard the
underlying condition as pure senile involution. The proportion of cases of
chronic mastitis developing cancer has been variously estimated from 10 to
15 per cent. (Tietze, Speese).

In the prostate the chief condition predisposing to cancer is chronic
prostatitis usually with hypertrophy. Whatever the nature of prostatic
hypertrophy may be, it is clear that the influence of physiological involution
is usually concerned. The principle age of incidence of cancer and hyper-
trophy is the seventh decade, in which 68 per cent, of the carcinomas occur.
Notable examples of the development of carcinoma on hypertrophy have been
recorded by many observers, the clinical evidence being a long history of
hypertrophy terminating in cancer. Probably 10 per cent, of prostatic
carcinomas give such a history. The proportion of enlarged prostates after
50 years which prove malignant has been estimated at 13.3-16.5 per cent.
(Freyer, Walker).

Senile degeneration of the skin as observed in seaman's skin and other
disorders often leads to multiple carcinoma. It affects regions exposed to
sunlight, heat, and cold, and often shows an hereditary element. The
changes begin with hyaline degeneration of the derma, sclerosis of vessels
and atrophy of Malpighian layer, followed by keratosis, scaling, papillary
outgrowths, and elongation of deep papillae. Finally the invasive features
of carcinoma are added.

3. Regenerative hypertrophy may be regarded as the predominant under-
lying influence in the development of certain forms of cancer observed
in the liver and in the glands of internal secretion.

In fish, functional overactivity and hypertrophy of the thyroid, observed
in crowded ponds where the animals are fed on meat, leads in a small pro-
portion of cases to a peculiar form of cancer. This condition has been
produced experimentally by Gaylord. Few cases of thyroid carcinoma in
man develop in subjects with entirely normal thyroid history, but many
follow goiter, interstitial thyroiditis, and Graves' disease. Probably many
tumors of the adrenal and hypophysis are of the same nature.

In the liver an important group of primary carcinomas or hepatomas
represents malignant overgrowth of regenerating lobules following injury
with degeneration or cirrhosis (Menetrier).

4. The transformation of benign into malignant tumors is a frequent source
of carcinoma occurring in many organs and has important bearing on the
origin of cancer. Some of these benign tumors appear to originate from
inflammatory processes and the organs may present every gradation between
simple inflammatory overgrowth, adenoma, and carcinoma. The most strik-
ing example is colitis polyposa which exhibits a peculiar overgrowth of epithe-
lium with polypoid adenomas, leading in about half the cases to carcinoma.
In the gastric, intestinal, uterine, and vesical mucosa the transformation of
benign polyps into carcinoma has repeatedly been observed. Menetrier
has shown that gastric ulcer usually leads to cancer through the preliminary
development of polypoid adenomas on the edge of the ulcer. In the solid
glandular organs histological rather than clinical evidence indicates
that the passage from benign to malignant tumors may be readily accom-

462 NEOPLASTIC DISEASES

plished, although as a rule the type of benign adenoma usually remains
constant.

Thus clinical observation reveals several groups of pathological processes
which in a small but notable proportion of cases tend to become malignant.
Such clinical data do not, however, show that there is any essential connection
between the preliminary process and the subsequent cancer. It may be
urged that when carcinoma follows chronic mastitis a new disease has been
grafted upon an entirely different condition. Histological evidence, however,
has fully demonstrated that an extensive series of structural changes takes
place in the precancerous diseases leading up to the fully developed cancer,
the one passing slowly or rapidly but often by insensible gradations into the

FIG. 1 80. — Diffuse hypertrophy of glands in colitis polyposa.

other. The details of these changes will be presented under the various forms
of carcinoma of the organs. It may here be pointed out that precancerous
changes differ in each organ as do also the true carcinomas of those organs.

As a rule considerable time is required in the transformation as is indicated
by the long duration of the preceding disease. Yet in many cases it would
appear that the liberation of the restraints to growth is experienced rapidly
so that the resulting cancer although small is found fully developed and soon
overgrows and obliterates any successive stages which may have occurred.

It is not to be assumed that all carcinomas develop after a preliminary
series of changes in previously normal tissue such as is now under discussion.
In the entire group of tumors arising from misplaced and embryonal cells,
while certain phases of abnormal growth probably precede the appearance

GENERAL PATHOLOGY OF EPITHELIAL TUMORS 463

of the true carcinoma, these changes are of a different nature and morphology
from those occurring in the irritation group of tumors arising from normal
cells. Such changes may be traced in the development of melanoma from
pigmented moles, and with carcinoma from adrenal rests. They indicate
that even here the carcinoma does not spring full-fledged from the cells
of origin but evolves gradually with increasing freedom from the restraints
to growth. Of the factors which incite the malignant growth of embryonal
cells little is known but one may reasonably search for them among the causes
of local hyperemia. Melanoma often develops after mechanical trauma.

Against the theory of precancerous lesions stands the common obser-
vation that many very small cancers cannot be shown to follow such pre-
liminary changes. Verse describes very early gastric carcinomas in which
a limited segment of mucosa exhibited all the criteria of malignant adenoma.
Very small but fully developed mammary carcinomas are observed in chronic
mastitis which cannot be traced to the suspicious forms of atypical cell-
growth so common in mastitis. Clinical studies show that the majority
of cases of chronic mastitis pursue a prolonged but benign course. These
considerations suggest caution in assuming that any given precancerous
lesion will develop cancer, and show that many cancers may be preceded
by little or possibly by none of the precancerous stages, but they seem
not to affect the general validity of the theory that carcinoma as a rule
develops by definite stages both from adult and from embryonal cells.

Mode of Extension of Carcinoma. — The events which follow the establish-
ment of a carcinomatous focus in an organ vary greatly with the mode of
origin of the tumors, the rapidity of growth, and the character of the affected
tissue.

Influence of the Mode of Origin. — Carcinomas arising from misplaced and
embryonal cells are isolated from their inception, probably remain so thjough-
out their history, and illustrate in the purest form the principle that tumors
grow from their own resources and not by the progressive transformation
of normal into tumor-cells. Equally important with this principle, so
strongly urged by Ribbert, is the fact that many carcinomas, during the
period of their inception and for some portion of their early growth, involve
increasing areas of glands or mucous surfaces in their points of origin and thus
extend in part by gradual transformation of previously normal cells. Thus
one may observe epidermoid carcinoma of the glans penis or prepuce covering
a wide area, in different portions of which are presented every gradation from
fully developed infiltrating carcinoma in the central areas, to markedly
hypertrophic, hyperplastic, and atypical epithelium in the peripheral zones.
In very extensive papillary adenocarcinoma of the rectum involving several
inches of the bowel a gradual extension of an originally small lesion must be
assumed. Hauser and Beneke have traced this transformation in intestinal
carcinoma. In carcinomas of multicentric origin the separate foci may
eventually fuse, forming one continuous area of origin. In carcinoma follow-
ing chronic mastitis the malignant process may originate in several foci,
even producing different types of carcinoma, and soon involving the entire
breast. It is therefore not to be assumed that the observed mass of carci-
noma is always the result of local invasion from a single minute focus, but
on the contrary this- mass may depend chiefly on the mode of origin of the
tumor.

The rapidity of growth of a carcinoma determines in many cases its
mode of extension. Rapidly growing tumors soon define their field of origin,
no subsequent additions are made to the originating cells, and the tumor
rapidly extends through preformed and artificial paths, growing from its

464 N EOF LA STIC DISEASES

own resources. Many but not all such carcinomas arise from isolated or
embryonal cells.

The character of the affected tissue influences the mode of extension in
many cases. On mucous membranes ulceration and infection early convert
many carcinomas into ulcerating lesions, in which the inflammatory process
seems at times to retard the lateral extensions of the disease, at other times
to facilitate them. The wide extension of some gastric carcinomas is prob-
ably referable to the contractile movements of the stomach and to a com-
paratively resistant muscular coat. Growing into ducts as in the breast
the extension may long be confined chiefly to these canals as in comedo-
carcinoma, while in the ovary cystic carcinomas may long be confined by
the fibromuscular cyst wall. The whole course of gelatinous carcinoma of
the peritoneum may depend upon the early rupture of a small colloid tumor
into the free peritoneal cavity.

Collateral Hyperplasia. — About the edges of many carcinomas, especially
of the mucous membranes, the neighboring glands commonly exhibit hyper-
trophy, hyperplasia and a somewhat atypical form of the lining cells, which
may approach the appearance of carcinoma. In adenoma malignum of the
rectum the surrounding zone of mucosa exhibits greatly elongated glands
lined by very large cells which strongly suggest a gradual transformation of
hypertrophied into neoplastic glands. These changes are only imperfectly
reproduced in pure inflammatory lesions, for the collateral hyperplasia of
tumors is rather specific. In some cases it is extremely difficult to determine
where the hyperplastic glands cease and the neoplastic begin. Yet the most
careful histological studies indicate that such hyperplastic glands do not
become transformed into neoplastic unless it be in the early stage of the
definition of the tumor focus. Careful study usually discloses that tumor
epithelium grows into the enlarged glands from many sides, gradually replaces
the lining cells and occupies the gland compartments. At the most critical
points the transition between hyperplastic and neoplastic epithelium is
usually sharp, but in some cases it cannot, I think, be denied that it is
impossible to say whether or not a transformation of hypertrophied into
tumor-cells takes place.

Collateral hyperplasia also occurs in many glands invaded by carcino-
matous foci and has led to the unproven assumption that the presence
of foreign tumor-cells may excite a tumor process in an invaded organ. For
example, in the adrenal invaded by carcinoma from the kidney I have seen
adrenal acini assuming a form which strongly suggested neoplastic qualities.
In hepatoma the remaining liver tissue may exhibit extensive hypertrophy
of liver-cells which is not duplicated in simple inflammatory or regenerative
changes of this organ.

Collateral hyperplasia seems to be referable chiefly to overnutrition
of cells in the vicinity of the actively growing tumor. Inflammatory factors
may also contribute a share in the process. Yet the peculiar morphology
suggests that other influences are at work and Beneke assumes that the
proximity of tumor-cells exerts a peculiar trophic action of the neighboring
tissues in addition to ordinary inflammatory, nutritive, and regenerative
effects.

Local Invasion. — The advance of carcinoma from its focus of origin
occurs through the continuous extension of tumor-cells into normal tissues.
The paths pursued are usually those of least resistance and include the
natural channels in glandular organs, lymph-vessels and spaces, blood-
vessels, and nerve-trunks. The ducts of glands become filled with tumor-
cells which replace the original lining cells over wide areas. In the breast

GENERAL PATHOLOGY OF EPITHELIAL TUMORS

465

duct carcinoma may thus invade the entire organ before reaching the
lymph-nodes or penetrating the fascia of the gland. Carcinoma of the
lung may pass along the air passages, filling air vesicles, replacing the des-
quamated alveolar epithelium and consolidating one lobe or a whole lung.
In the liver the bile ducts and in the kidney the glomeruli and tubules often
conduct the proliferating cells. Along mucous surfaces, as of stomach or
uterine cervix, carcinoma may spread laterally by replacing the lining cells
of the glands. In the peritoneum the flat endothelium may be widely re-
placed by cylindrical cells derived from glandular carcinoma of the intestine.
The lymphatics form the main channel of local extension. The cells may
very early penetrate lymph spaces and lymph-vessels and form new spaces

FIG. 181. — Edge of advancing adenoma malignum of rectum. Note sudden transition of
normal to neoplastic epithelium.

in the connective tissue. It is especially the perivascular lymph-channels
which are invaded and from these the route to larger lymph-vessels and
nodes is most direct. The lymphatic endothelium remains passive or suffers
atrophy. Proliferation of these cells cannot, however, be excluded in the
formation of the new connective tissue that often accompanies local invasion.
While the growth in neighboring lymphatics is usually continuous, local
metastases may occur and surround the main tumor with many small
secondary nodules. Yet the fine strands of tumor-cells demonstrable in the
lymphatics connecting the nodules of rodent ulcer suggest that a continuous
permeating cord of cells may be broken by fibrous perilymphangitis. The

466 NEOPLASTIC DISEASES

invasion of lymphatics is greatly retarded or suppressed in favorable cases
by extensive collections of lymphocytes which gather in the vessels and may
even surround the tumor-cells with a rich lymphoid ring. Occasionally the
entire tumor is infiltrated with lymphocytes and in such cases the occurrence
of many degenerating tumor-cells indicates that the lymphoid infiltration is
a phenomenon of immunity.

The lymphatics of nerve-trunks are readily penetrated by many tumor-
cells, especially in epidermoid carcinoma, and through these minute channels
the process may travel over wide areas. It is probable that the spinal
ganglia and meninges are occasionally reached by this method. The nerve
fibers suffer atrophy. Much of the pain of carcinoma as well as pareses,
paresthesias, and the rare attacks of zoster, must be referred to invasion of
nerve-trunks and ganglia.

The paths of access to the local blood-vessels vary much in the different
organs. In the liver, kidney, adrenal, and thyroid, the small vessels are
early penetrated by tumor-cells of otherwise moderate infiltrative capacity.
Hence tumors of these organs may early present bulky intravenous masses
from which vascular emboli are distributed or which completely fill the vena
cava up to and into the right auricle. The intravascular position of the
fetal villi accounts for the extension of chorioma through the uterine vessels.

In many carcinomas the local veins are penetrated by the cells filling
perivascular lymphatics. Goldmann's injections of the veins of carcinoma
show that these vessels are often occluded by tumor-cells and that the local
advance of the growth may be largely through these vessels. Primary
carcinoma of the liver may be rapidly disseminated over the entire organ,
exclusively through the blood-vessels. The formation of granulation tissue
about ulcerating carcinomas often facilitates the local extension, probably
by providing many new capillary channels for invading cells.

The invaded vessel is usually filled by tumor-cells and the lumen occluded,
but in many cases one may observe flat or papillary mural implantations,
or the endothelium may be replaced by a flat layer of tumor-cells while the
lumen remains pervious. Interference with the circulation accounts for
much of the edema in tumors, for the tendency toward central necrosis, for
bulky areas of necrosis from infarction, for hemorrhage, and for the partial
suppression of growth in the centers of carcinomatous areas.

Through these various channels the cells of an originally small carcinoma
gradually involve successive portions of the organ or even pass continuously
from one organ to neighboring structures. The wider dissemination of the
tumor-cells, especially by loosened cell groups, constitutes the process of
metastasis, the complex details of which have been separately considered.

CHAPTER XXVI
EPITHELIAL AND OTHER TUMORS OF THE BREAST

Hypertrophy of Breasts. — Mammary hypertrophy occurs as a rare con-
genital condition in infancy or childhood; it arises most frequently at puberty,
and is seen in adults (Deaver, McFarland, R. Williams, Lit.).

1. Infantile Hypertrophy. — Congenital enlargement is recorded by
Horritt, Hahn and Wilson. Infantile hypertrophy is usually associated with
precocious sexual development, and is more common in the tropics. It is
possibly connected with pituitary disorders, and some of the cases first
observed in infancy seem to have begun at birth (Mallett, Sagra).

2. Diffuse Hypertrophy of Adults. — Most cases arise at puberty, others
occur late in life, and a considerable number is connected with pregnancy.
An hereditary element has been noted in a few cases (Rousseau, Kirchheim).
Delayed onset of menstruation, or suppression of menses frequently precede
the overgrowth. The disease may best be interpreted as an excessive re-
sponse to functional and formative stimuli in congenitally predisposed
organs.

Either one breast or both, or one or more supernumerary organs, are
involved. A partial hypertrophy has been described by Richet and Billroth.
The degree of enlargement may be moderate or very great, Kaufmann
reporting a weight of 30 kg. for both breasts. The structure varies con-
siderably. Lipomatosis and glandular hypertrophy were the chief elements
in the cases of Robert and Warren. Connective- and fat-tissue overgrowth,
with moderate glandular hypertrophy, retention of secretion and marked
vascularity, are observed in a considerable group. Porter described multiple
intracanalicular fibromatous growths with fibrosis, and in many cases the
structure resembles diffuse fibre-adenoma. A low grade of adenomatoid
hypertrophy is frequently seen.

In a well-marked case, age 24, 1 found much excess of fat tissue surround-
ing a greatly hypertrophied breast. The gland presented a structure resem-
bling the lactating organ. The alveoli were greatly increased in number and
while some were compact with narrow lumen others were dilated. Many
ducts were widely dilated. There was a uniform overgrowth of fine cellular
connective tissue between the acini.

Billroth describes very active overgrowth of glands resembling in places
adenocarcinoma. Diffuse carcinoma appears to have followed diffuse
hypertrophy (Billroth, Aitken).

The course is usually active during the first few months and after reaching
certain dimensions a quiescent period is maintained for some years with ex-
acerbations during pregnancy. The tumors often become so large as to
interfere with general health. Inflammation, suppuration, and gangrene
have occurred, or death may result from general exhaustion. Very active
cases are recorded by Billroth and Huston in which the breasts reached a
large size in a few months, while Durston's case was fatal from gangrene
in four months. The tumor may regress after pregnancy and operative
removal is usually successful.

467

468

N EOF LAST 1C DISEASES

Gynecomastism, hypertrophy of the male breast, with and without
changes in the testicles and in the secondary sexual characters, has occurred
in a series of cases collected by R. Williams.

Chronic Productive Mastitis. — From the extensive literature recording
the history of the knowledge of chronic productive inflammation of the
breast it is becoming more and more apparent that the various forms of this
condition are essentially one and the same disease. Some of the variations
depend chiefly on the state of the breast at the time the inflammatory process
occurs, others represent exaggerations of single features of chronic inflamma-
tion, and still others may be explained as different stages of the same process.
Much of the long debate over the inflammatory as against the neoplastic
nature of the processes could have been avoided had it been recognized

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FIG. 182. — Chronic adenomatoid mastitis. A diffuse overgrowth of well-formed lobules.

that chronic productive inflammation may consist in much overgrowth of
connective tissue and glandular epithelium and that inflammatory passes
insensibly into neoplastic hyperplasia. The disease begins as an inflamma-
tion and often ends as a neoplasm. Nevertheless extreme examples of the
different forms of the disease are widely separated.

The importance of the condition is found not only in its frequency, but
especially in its relation to the development of tumors of the breast.

(i) Astley Cooper, 1837, first gave a lucid description of cystic mastitis under the term
"hydatid disease." He described a slow painless increase in the size of the breast affecting
the whole or a portion of the organ, resulting in the appearance of many cysts as large as a
pea or bean, some of which might open externally, giving rise to sinuses. The breast was
not as hard as scirrhus cancer, the axillary nodes were not affected and the general health
remained good. In 1846 Brodie accurately described the same condition in one or both
breasts. In 1883 Reclus gave a full description under the term "maladie kystique."

EPITHELIAL AND OTHER TUMORS OF THE BREAST 469

He emphasized the bilateral distribution and the large number of cysts throughout all
portions of the gland, especially at the periphery.

Brissaud, 1883, found that the formation of cysts was preceded by signs of abnormal
activity of the gland, the structure resembling the fetal breast. Both acini and ducts
became dilated. Upon these appearances, suggesting a neoplastic tendency, he designated
the process as "epitheliome kystique intra-acineux." Phocas, 1886, emphasized the
occurrence of many shotty nodules throughout the organ and employed the term "maladie
noueuse." In Germany, Konig (1875) described the condition in some detail and later
(1893) he followed the successive changes of prolonged cases pointing out many distinc-
tions from a tumor process. Schimmelbusch, however, reached the same conclusions as
Brissaud, that marked activity of the gland preceded the growth of connective tissue and
persisted with the development of cysts, and that the process was essentially neoplastic.
This view has been maintained by many other writers, Cornil, Lecene, Lenormant. The
disease is often referred to as Schimmelbusch's multiple cyst adenoma. This interpreta-
tion has been actively contested by Konig in Germany and Delbet in France, who maintain
that the process is essentially inflammatory. Theile finds it impossible to distinguish
between adenofibroma, a tumor, and "maladie kystique" an inflammatory process, in
the breast, and Delbet admits that the inflammatory process passes into the adenomatous.
La Roy places the condition among the pathological hyperplasias which should be separated
from both inflammatory and neoplastic processes.

(2) A somewhat different form of mastitis was first described by Werner as cirrhosis
mammas, by Velpeau as "induration chronique en masse," and by Virchow as "elephan-
tiasis dura." It is much less frequent than the common cystic disease. Billroth was long
uncertain of its existence but describes a very advanced case with extensive cicatricial
contraction and deformity. Labbe and Coyne described a case in which there was diffuse
growth of very cellular connective tissue infiltrated with round-cells, while a small collec-
tion of pus was found in the axillary border of the gland. Konig recognized a rare form of
diffuse chronic mastitis with a painful onset and a marked tendency to atrophy. R.
Williams collected several cases in both sexes. Many cases of apparently suppurative
mastitis with cicatrization and even calcification (Bryk, Houdoupe) he classifies as cir-
cumscribed chronic mastitis. They should be separated from the non-suppurative diffuse
inflammations. Delbet recognizes the peculiar features of this form of mastitis but on
account of the transitional cases he merges it with the common cystic disease.

(3) Finally it has long been known that senile involution or precocious atrophy of the
breast is often accompanied by irregular overgrowth of stroma and glands with the forma-
tion of cysts, and various authors have assumed that chronic mastitis is essentially an
exaggeration or sequel of the processes concerned in senile involution. R. Williams states
that the new tissue in senile involution is usually free from any signs of inflammation,
although it may be abundant as in cystic disease. Altmann observed much epithelial
proliferation in 34 cases of senile and precocious atrophy. Tietze found marked similarity
between the epithelial changes in about 25 per cent, of senile organs and those of cystic
disease.

Bloodgood finds a close relation between cystic mastitis and senile involution. He
designates the former as senile parenchymatous hypertrophy and traces accurately the
stages of hyperplasia, ectasia and cystic dilatation. He recognizes two types of the disease,
one with small cysts and moderate epithelial hyperplasia and another with larger cysts and
pronounced epithelial overgrowth.

An essential relation between cystic disease and senile involution must, however, be
questioned. Involution is chiefly an atrophic process with slow replacement fibrosis and
often fails to exhibit the cystic and productive changes. When these are added they are
best interpreted as an additional process which may become established in an involuting
breast.

From the above brief review of the literature it is evident that two well-
defined forms of chronic mastitis have been under discussion which may be
designated anatomically as interstitial and glandular, while a third less
prominent group of cases includes those in which normal involution atrophy
is prominent. While accepting the essential identity of all forms of primary
productive inflammation of the breast, as maintained recently by Delbet
and Baumgartner, yet many clinical and anatomical peculiarities seem
to me to warrant the subdivision of the disease into at least three types
interstitial, glandular, and senile.

Etiology. — The various forms of chronic mastitis are comparatively com-
mon, but satisfactory statistical data are unavailable. The increasing atten-

470 NEOPLASTIC DISEASES

tion to the early stages of cancer is bringing under observation a much larger
number of cases of chronic mastitis. Many cases pass as nbro-adenoma,
cystadenoma, and carcinoma. When these conditions develop on chronic
mastitis the condition of the whole breast is commonly overlooked.

The majority of cases are first observed at the menopause but many are
encountered much earlier. Of 67 cysts of the breast Bryant found 4 under
30 years, n between 30 and 40 years, 33 between 40 and 50 years, 16 from
50 to 60 years, and 3 after 60 years. Delbet believes that most cases begin
some years before recognition. Phocas observed a nodular mastitis at 18
years and Baumgartner at 19 years. Rodman finds the condition more
frequent in married women and suggests that a rapid sequence of pregnancies,
or interruptions of gestation, or of the normal functions of the breast, may
lead to nutritional and inflammatory changes.

Delbet considers the disease a bacterial infection, in which the staphy-
lococcus albus is the most common but not the sole agent. He compares
the infection to the infectious mastitis of cattle described by Nocard and
Mollereau and assumes that the microorganism enters through the ]acteal
ducts and penetrates throughout the lobules. The structure in the active
diffuse lesions strongly indicates the presence of an irritant passing out from
the acini but for the more chronic forms this explanation is less satisfactory.

The course of the disease and the structure of the gland vary considerably
in the different anatomical forms.

Senile Involution. — The natural history of the mamma includes a terminal
stage of atrophy. This change is regularly initiated at the menopause,
continues at varying rates and degrees throughout life, and is associated
with decline in the nutrition and function of other sexual organs.

Precocious atrophy is observed with sterility and disuse (Williams,
Reynolds, De Sinety). An atrophic condition of the breasts of Bavarian
women has been attributed by Altmann to a local custom against nursing.
Ovarian disease or extirpation appears to notably affect the breast only
when occurring before the development of secondary sexual characters
(Battey). Yet some observers note pronounced diminution in the size of
the breasts following ovariotomy (Keppler), while others report hyper-
trophy and increased secretion (Baumgartner).

The scope of the changes which may be attributed to simple atrophy
is defined with difficulty, since the process is often complicated by other
disturbances in structure. In many cases the fat, connective and gland
tissue suffer alike and the organ is greatly reduced in size, the cellular con-
nective tissue becomes fibrous and hyaline and the gland lobules are reduced
to a trace, all without reactive processes in any element. The contracted
ducts persist, usually with some desquamation of lining cells and a notable
increase or prominence of smooth muscle-fibers about the walls. That
extreme atrophy may occur without other notable alterations or inflammatory
changes is shown in many of the 34 cases studied by Altmann and it there-
fore seems clear that many structural variations often ascribed to senile
involution are not essentially connected with this condition.

In other cases, especially in obese subjects, the atrophy takes the form of
fat invasion, scanty atrophic lobules and ducts being widely scattered in
much adipose tissue.

In many cases the process is marked by proliferation and desquamation
of lining cells of ducts, the low epithelium may form short lateral outgrowths
or papillary projections, small retention cysts may form, connective tissue
invades the lobules and disturbs their outlines and a low grade of chronic
productive inflammation is established. These changes do not properly

EPITHELIAL AND OTHER TUMORS OF THE BREAST

471

belong to normal involution, but they are so frequently observed in breasts,
many of which have suffered from the effects of repeated lactations or
previous disturbances of structure, that their presence in moderate degree
must be included in the usual picture of involution. A pronounced degree
of these changes should be classed with chronic productive mastitis.

The advanced atrophy of simple involution distinctly favors forms of
atypical proliferation of the lining cells of persistent ducts.

Chronic Interstitial Mastitis. — The characteristic type of this condition
is a diffuse interstitial productive inflammation, with a new growth of con-
nective tissue about ducts, lobules, and acini.

FIG. 183. — Chronic mastitis. Atypical proliferation of acinar cells.

Usually one breast only is involved, and the lesion may be more pro-
nounced about the larger ducts. When affecting a circumscribed portion
of the breast, the condition resembles a true adenofibroma but without en-
capsulation. It begins with diffuse and somewhat painful enlargement of
the breast, which progresses slowly until the organ is moderately increased
in size. Exacerbations occur chiefly at menstruation when the breast may
become painful and the axillary nodes enlarge, after which the process remits
leaving new nodules or indurated areas. After months or years contraction
and sclerosis begin, the skin becomes roughened (Labbe and Coyne, peau
d'orange) adherent and contracted, and the breast may be reduced to a de-

472 N EOF LA STIC DISEASES

formed area of hard cicatricial tissue (Billroth). Usually the whole organ
remains permanently enlarged, diffusely fibfosed, and with or without small
cysts. The whole original area of gland distribution may become converted
into a bulky solid mass of elastic connective tissue. Cysts, isolated fibromas,
and foci of carcinoma frequently interrupt the smooth texture. The gross
appearance of these organs is quite specific.

In the acute stage the lesion consists in a diffuse growth of cellular con-
nective tissue which surrounds ducts and lobules and penetrates between
the acini. This tissue may be richly infiltrated with lymphocytes. The
acini are compressed and show only moderate hyperplasia but the ducts
may be filled with desquamated epithelium. Cyst formation is not promi-
nent. In the later stages the new tissue may contract with atrophy of the
parenchyma. In some cases, especially in circumscribed areas, the process
resembles adenofibroma, but on careful analysis the structure is found to
consist of a limited growth of fibroblasts chiefly about ducts and acini, pro-
liferation of capillaries, and infiltration by lymphocytes and plasma-cells.
The very abundant overgrowth of fibroblasts and the encapsulation observed
in true adenofibroma are missing. That true adenofibromas may develop
on such lesions has been maintained by many authors (Cornil, Theile,
Lecene and Lenormand, Delbet, Borst). My own observations lead to the
same conclusion. Yet the natural tendency of the process is progressive
fibrosis. Epithelial tumors develop in the course of diffuse interstitial
mastitis but rather less frequently than in the glandular cystic mastitis of
Reclus and Schimmelbusch.

Chronic Glandular Mastitis. — Cystic Mastitis. — The common form of
productive mastitis is marked by the production of many small cysts; by
considerable epithelial proliferation and by diffuse growth of firm fibrous
tissue. On account of the prominence of epithelial changes the process may
be designated as glandular mastitis, and the presence of many cysts has led
to the use of the term cystic mastitis. It is often called "maladie de Reclus,"
or "Schimmelbusch's disease," and when many small nodules are present
it has been called by Phoca "maladie noueuse." Typical cases differ notably
from the diffuse interstitial mastitis of Werner and Billroth, but there are
transitional cases which connect the two forms, and it is probable that some
cases of diffuse interstitial mastitis later become cystic. Senile atrophic
breasts also develop cysts with epithelial proliferation.

The disease usually develops first in one breast and often later in the
other. The onset is slow and usually painless and the condition may not be
recognized until a cyst of some size attracts attention. There may be a
serous discharge from the nipple. A bloody discharge usually but not always
indicates a cystadenoma or carcinoma (Sasse, Shield). On palpation the
whole organ is firm, of normal or reduced size, and many hard, movable
nodules as large as a pea or bean may be detected. No part of the breast
escapes. There is no adherence to the muscle, nor as a rule to the skin, but
the nipple may be retracted (Renon).

The process continues slowly progressive with exacerbations for years.
It may subside spontaneously but cases lasting 15, 30 and 33 years are
reported by Monod, Trelat, and Reclus. In the late stages the cysts may
open and leave sinuses through the skin. Many cases are complicated with
cystadenoma, nbro-adenoma and carcinoma.

On horizontal section of the breast the organ is found to consist of an
irregular mass of fibrous tissue broken by fat lobules, cysts of various sizes,
and hard opaque nodules. The cysts may be small and extremely numerous,
or larger and infrequent. The contents are serous, fatty or bloody, and thin

EPITHELIAL AND OTHER TUMORS OF THE BREAST

473

or inspissated and yellowish. Larger cysts may show all stages of papillary
ingrowths, and some (butter cysts) contain much caseous fatty material.

The structure presents a great variety of abnormalities. The cellular
or fibrous connective tissue surrounds ducts, lobules and acini. It is usually
acellular and cicatricial in type but at various points it may show local
overgrowth of embryonal type. About small ducts there may be very pro-
nounced nodular thickenings. Between the acini the tissue is more cellular,
and lymphocytes and plasma-cells are often present.

The epithelial changes take many forms but proliferation predominates
over atrophy. Most acini show a compact lining of two rows of well-nour-
ished cells. The lumen is collapsed or contains globules of acidophile
material, or various stages of ectasia are visible. More pronounced over-

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FIG. 184. — Precancerous changes in breast. Filling of small ducts and acini with"atypical

cells. No infiltration.

growth produces more abundant cells of larger size, with hyperchromatic
nuclei. All the acini and ducts of a lobule may show much overgrowth while
adjoining lobules are normal or atrophic. Suspicious or definitely pre-
cancerous changes appear when dilated acini or ducts become filled with
overnourished cells in compact masses or forming secondary alveoli. Such
foci may be scanty and require many sections in different portions of the
breast for their detection. In the fresh tissue they appear in the form of
shot-like solid nodules. Another precancerous change consists in a multi-
plication of small alveoli with increase in the size and nuclear chromatin of
the cells. According to Dreyfuss and Sasse it is the inner row of secreting
cell which multiply in precancerous foci, while McCarthy locates the hyper-
plasia in the sustentacular cells. I have been unable to recognize these
distinctions.

474

NEOPLASTIC DISEASES

Cysts form from dilatation of alveoli or ducts and are lined by clear
polygonal epithelium. Many stages of the proliferation of these cells are
observed, including formation of low papillae, dendritic outgrowths accom-
panied by stroma, up to pronounced papillary adenoma. From the simple
adenomas arise malignant adenoma, and adenocarcinoma. Hemorrhage
and exudation in these cysts may be associated with malignant changes in
the wall of the cyst. Degenerating butter cysts often show such changes
in their walls. Another type of cyst forms in the interlobular ducts which
may be lined by excessive layers of large cells which form papillary projec-
tions or fill the lumen diffusely. Such lesions may pass rapidly into a form
of large alveolar or adenocarcinoma of the breast (tubular or duct cancer,
Labbe and Coyne, R. Williams). Sasse finds that fibrosis about larger ducts
gives rise to one or more large and several smaller cysts in which there is/a
notable tendency to develop adenoma and carcinoma.

A third form of cyst develops from the sweat glands incorporated in the
breast (Moullin, Dreyfuss, Krompecher). These are easily recognized by
the lining of columnar, strongly acidophile cells which are often thrown into
papillary projections. Beneath the epithelium there may be overgrowth of

FIG. 185. — Precancerous changes in the breast. Atypical proliferation in a segment of

a duct.

muscle spindles. All stages of the development of papillary projections,
papillary adenoma, adenocarcinoma, and carcinoma have been traced by
Creighton, Borst, Kuru, Krompecher, and others.

The frequency of the development of benign or malignant tumor processes
in cystic mastitis is a question of prime importance. Delbet represents a
large body of surgical opinion in stating that the affection is too benign to
justify extirpation and while he admits that there is no other satisfactory
treatment, he recommends pressure, iodide of potash and injections of
carbolized glycerin into the cysts. This conclusion is based on the rather
frequent observation that characteristic cases pursue a very chronic course
without any neoplastic complication, benign or malignant. In support of
this view may also be cited the fact that the epithelial overgrowth is at first
inflammatory and that the suspicious carcinomatous areas cannot in any
one case be traced into fully developed carcinoma and may never pass be-
yond the stages actually seen in the simple cystic breast. It is also assumed
that the great majority of carcinomas are not associated with chronic mastitis
or if so, that the carcinoma is a wholly distinct process. Baumgartner con-
cludes that the essential sequence of inflammation, adenoma, carcinoma, is

EPITHELIAL AND OTHER TUMORS OF THE BREAST

475

not based on irrefutable proof nor disproved by established facts. This
conclusion is not helpful.

Against this view stand the interpretations of Brodie, Brissaud, Sourice,
Schimmelbusch, and Saar that there are neoplastic qualities in the process
and the step to carcinoma is short. The very chronic cases which remain
free from complications are clinically impressive, but when cancer develops
little attention is commonly paid to the condition of the remaining portions
of the organ. I find that a very large proportion of mammary cancers occur
in breasts which are the seat of chronic mastitis. Billroth long ago stated
that small cysts are very often seen about carcinoma of the breast. Tietze
in 43 cases of cystic disease found cancerous areas in three, and computes

FIG. 1 86. — Diffuse proliferation of atypical cells in ducts in chronic mastitis.

cerous lesion.

A precan-

that about 10 per cent, of cases of cystic mastitis develop cancer. He de-
scribes 5 cases of cancer with cystic disease in the outlying breast tissue.
In 5 of 1 8 breasts classed as senile involution he found suspicious areas
suggesting cancer, especially in the peripheral portions. Of 295 cases of
various types of chronic mastitis collected by Speese, 15 per cent, were reported
as showing carcinomatous changes. In 28 cases of cancer of breast
Verga found that in five the organ was the seat of cystic mastitis with pro-
nounced carcinomatous metaplasia. In my own material about 50 per cent,
of the breasts excised for cystic disease show pronounced precancerous changes
or miniature carcinomas. Very few cancerous breasts fail to show phases
of chronic mastitis in the outlying portions of the parenchyma.

476

NEOPLASTIC DISEASES

It is therefore clear that chronic mastitis is a very important predisposing
condition to mammary cancer. It appears also from the histological evidence
that many cancers arising in chronic mastitis do not represent wholly new
processes but on the contrary are the natural result of steadily increasing
epithelial overgrowth which is originally inflammatory and affects not embry-
onal or misplaced tissues, but the normal and adult glandular epithelium.

When carcinoma develops in chronic mastitis it usually arises early
or progresses actively so that the malignant tumor overshadows the in-
flammatory changes. When the cystic disease passes a critical period
without the development of a tumor it tends to maintain a benign course
over many years. Hence the clinical impression of the benign character

FIG. 187. — Adenoma of axillary sweat-glands. An occasional source of mammary car-
cinoma.

of the process is strongly emphasized by a limited group of cases. Yet
I find precancerous changes in the outlying atrophic and cystic breast tissue
in cases of cancer developing after 70 years of age.

The treatment of chronic mastitis must be determined after consideration
of all the factors in the case. To remove all such breasts would certainly
entail must useless surgery. It seems to be a safe rule to remove the whole
breast or the whole affected segment when an incision is required for diagno-
sis. The presence of carcinoma can nearly always be made by the gross
examination of the amputated breast, and the correct surgical procedure
can then be determined with certainty. The decision to leave untouched a
definite grade of cystic mastitis should be made only with the knowledge
that carcinoma frequently develops in such organs. On the other hand,

EPITHELIAL AND OTHER TUMORS OF THE BREAST 477

simple cysts often disappear spontaneously and do not constitute a definite
indication for surgical interference. Yet the course of the established disease
is generally progressive and most cases eventually terminate in carcinoma or
surgical removal. Physical agents are worthy of trial.

MIXED TUMORS OF BREAST

Of mixed tumors of the breast in which a tumor process affects more
than one element there are two main groups and several varieties.

In one group the structure is comparatively simple and presents adult
connective tissue and glandular epithelium, as in adenofibroma and its
malignant derivative adenosarcoma. In a secpnd group the structure is
more complex and often embryonal, as illustrated in growths which contain
connective-tissue, cartilage, bone, or mucous tissue, and epithelium of both
glandular and squamous types. Such tumors are usually malignant.

There is a tendency for one element of the tumor to predominate. Thus
some pure fibromas, of which R. Williams has collected several cases, prob-
ably belong with the adenofibromas in origin, and the pure osteomas,
chondromas, and sarcomas are probably often one-sided developments of the
complex tumors. Yet the majority maintain a uniform growth of more than
one tissue and must be classed with mixed tumors. Many writers have
interpreted these growths as simple tumors chiefly epithelial. Beneke
has shown that the development of the early gland acini exerts a strong
stimulus on the supporting connective tissue. At puberty and in pregnancy
there is an active new growth of acini which may incite proliferation of the
supporting stroma. Hence a tumor process originating in the epithelium
may be assumed to affect secondarily the connective tissue. Many French
authors hold that the majority of benign mammary tumors are primarily
adenomas (Delbet). On the other hand many German authorities locate
the primary influence in the connective tissue (Virchow). The attempt to
interpret the growths as simple thus meets with difficulties. Since the
tumors are usually well encapsulated and both epithelium and connective
tissue are well represented it seems most probable that they arise from super-
fluous or misplaced portions of breast tissue containing both elements.
In the more complex and embryonal tumors the mixed composition is
unequivocal.

An inflammatory origin for many of the simpler fibro-adenomas and
especially of the cystadenomas has been maintained by many authors.
Theile studying 19 tumors concludes that it is impossible to establish a
sharp limitation between the cystic changes of chronic mastitis and fibro-
adenomas. Cystadenoma is often multiple and associated with chronic
mastitis. Occasionally one finds several stages of the growth of diffuse
or intracystic fibro-adenoma in the same case of chronic mastitis. I find
as a rule that the tumor-like areas in chronic mastitis are not well circum-
scribed and show many inflammatory changes, such as the growth of fine
capillaries and infiltration with round-cells, while the pronounced tumors
are free from inflammatory signs. It seems probable that an inflammatory
process is a frequent inciting factor especially with the cystadenomas, but
that a true tumor arises only when there is a tissue predisposition in the
form of superfluous or misplaced material. A constitutional element may
also be assumed.

The earliest stages of fibro-adenoma have been observed by Borst in
the form of small groups of acini which are not sharply circumscribed but
exhibit neoplastic characters in the epithelium. Ribbert pictures a very

478

NEOPLASTIC DISEASES

small, sharply circumscribed, typical fibro-adenoma. Very early and
circumscribed cystadenomas are frequently observed. The isolation of the
blood-supply, which is usually from one set of vessels without free lateral
anastomoses, points to the origin from misplaced tissue, as do also the con-
genital and aberrant adenomas.

Adenofibroma ; Fibro-adenoma. — Two gross forms of fibro-epithelial
tumors occur in the breast, (i) Massive and (2) Papillary or intracystic
fibro-adenoma.

(i) Diffuse massive fibro-adenoma is best illustrated in some cases of
diffuse hypertrophy of the whole breast which exhibit neoplastic characters.
More frequently the tumor forms a circumscribed mass of considerable

FIG. 1 88. — Intracanalicular fibre-adenoma of breast.

dimensions which is firm and fibrous or more often soft and vascular. A very
common tumor occurring especially in young persons is the solid encapsulated
fibroma which forms a firm, translucent, tabulated and freely movable growth.
In cystic fibro-adenoma the acini are often dilated, forming cysts which are
single or multiple, large or small, while the contents are serous, mucous,
bloody, or semifluid fatty material containing cholesterin crystals.

The structure of these tumors presents varying proportions of stroma,
and epithelium. In diffuse adenomatous hypertrophy both glands and
stroma are well represented and active but the adenomatous element usually
predominates. In the large soft circumscribed adenomas the alveoli are
abundant, large and lined with several rows of overnourished cells, while
the stroma is abundant, very cellular, and sometimes quite vascular. The

EPITHELIAL AND OTHER TUMORS OF THE BREAST 479*

firm solid encapsulated tumors are chiefly fibromatous. The connective
tissue is cellular and either surrounds the acini in broad bands (pericanal-
icular), or grows diffusely, or forms complex papillary projections into the
acini (intracanalicular fibroma). In these growths the epithelium is quite
subordinate and merely covers the enlarging connective-tissue papillae. In
the typical -cystic fibromas the cysts are lined by one or several rows of cubical
epithelium which may be thrown into low papillary projections. In one
case Buday found ciliated epithelium.

(2) Papillary Infracystic Fibro-adenoma, Cystadenoma. — Cystadenoma is*
a comparatively common tumor. It appears usually after the menopause
(average 50 years), but occasionally in young or very old subjects. The usual
features are of a single or multiple rounded tumor, movable beneath the
nipple which may be retracted, of slow growth, and often accompanied by a
serous or bloody discharge from the nipple. The typical Cystadenoma is.

FIG. 189. — Multiple cysts of breast, in some of which are papillary adenomas.

inclosed in a cyst wall. The tumor may appear as a papillary growth attached!
to one segment of the wall and incompletely filling the cyst, or it may
occupy the entire cavity distending the wall, or numerous points of fusion--
unite the tumor with the wall. These tumors develop by papillary growths-
into the larger ducts. They are usually encountered when they have-
reached the size of a hen's egg but may grow considerably larger. They
are usually single but occasionally multiple and rarely bilateral. The*
position in the central portion of the breast is characteristic but not invariable^
Cornil describes cases exhibiting rapid growth which is usually due to accu^
mulation of fluid or myxomatous degeneration. Rarely they distend or
adhere to the skin or open externally. Johada found an adenoma floating:
free in the pus of an infected cyst. Delbet and Mintz consider a bloody
discharge as a sign of probable malignant degeneration. During pregnancy

480

NEOPLASTIC DISEASES

and lactation these tumors may rapidly enlarge and secrete milk, so
that they suggest a malignant process or galactocele (Deaver, McFarland).

The structure shows a papillary or complex dendritic growth of connective
tissue covered by epithelium. In some tumors the connective tissue pre-
dominates and forms coarse branching masses which are fibrous, mucoid,
vascular or cellular, or infiltrated with lymphocytes. In " cystosarcoma
phyllodes" the papillae are largely of connective tissue which is very cellular,

FIG. 190. — Segment of benign fibre-adenoma growing into a large cyst in chronic mastitis.

and when this tumor perforates the skin a false appearance of malignancy is
presented. This term was first employed by J. Muller to designate the
cauliflower-like polypoid masses of connective tissue which fill a cystic
cavity in the breast. The same tumor Virchow called intracanalicular
myxoma. It is evident that these observers encountered much later stages
of these growths than are now commonly seen.

EPITHELIAL AND OTHER TUMORS OF THE BREAST

481

In most cystadenomas the epithelium predominates and the growth may
resemble the ovarian cystadenomas. The lining cells are cubical or cylin-
drical epithelium in one or several rows. Malignant forms of intracystic
fibre-adenoma are relatively common but whether they represent malignant
transformations of a benign tumor or are malignant from the first is difficult
to determine. The malignant forms are described by many writers as duct
or villous cancer. Delbet holds that the transformation is so common as
to demand radical treatment of all intracystic fibro-adenomas. Malignant
changes have been recorded by Guinard, Speese and others. Hansen extir-
pated a carcinoma which appeared at the base of a fibro-adenoma excised
1 6 years previously. In 20 cases of cystadenoma Greenough and Simmons
found adenocarcinomatous areas in three. The structure of the malignant
tumors is characteristic and follows the type of adenoma destruens,hnalig-

FIG. 191. — Fetal fibro-adenoma of breast in a girl of 10 years. Marked overgrowth of

epithelium.

nant adenoma (Tietze), or adenocarcinoma. This structure is often pre-
served in the metastases which appear late. Fully developed carcinomas are
not infrequently seen which give every appearance of having developed in a
segment of a duct. These tumors are solid, and sharply encapsulated. An
outlying cyst or cystadenoma may accompany the solid tumor. The struc-
ture usually preserves traces of a papillary or adenocarcinomatous type.
Long immunity of the lymph-nodes may also characterize this group of
mammary carcinomas. When mucous degeneration attacks the stroma
very bulky tumors may result. I have examined such a tumor as large as a
child's head of 10 years' duration, without involvement of lymph-nodes.

The prognosis of cystadenoma varies widely, corresponding to the struc-
tural type. The simple adenomas are benign and an extirpation of the

482 N EOF LA STIC DISEASES

whole breast or even of the tumor alone is all that is called for (Warren).
Adenoma destruens is long confined by the cyst-wall and when well encap-
sulated may safely be removed with the breast. When the capsule is
traversed these tumors are fully malignant and the radical operation is
indicated, especially the dissection of the axilla. A definite tendency to
invade the muscles is not common.

(3) Fetal Fibro-adenoma. — A peculiar form of nbro-adenoma presents
several structural features of the fetal breast, including very cellular con-
nective tissue, alveoli without membrana propria, and imperfect differentia-
tion between ducts and acini. In a characteristic case the tumor was soft,
circumscribed, and as large as a goose egg. The structure showed a moderate
number of alveoli lined by several layers of cubical cells without membrana
propria or the peculiar sustentacular " basket" cells of the adult organ.
The cellular overgrowth was pronounced and suggested malignant tendencies.

Pure adenoma of the breast is a very rare tumor, but has been described
by several authors (Kuru, Lit.). Ziegler describes tubular and acinous
varieties. In most of these tumors the growth of connective tissue is con-
siderable and approaches that seen in fibre-adenoma with which they are
connected by transitional forms. The gross appearance and course are
very similar to those of fibre-adenoma.

Pure fibroma also is rarely observed and bears a close relation to fibro-
adenoma. Williams has collected several cases from the older literature.

Teratoid Mixed Tumors. — Mixed tumors in which mesodermal or ecto-
dermal tissues differentiate toward the adult type are not infrequent in the
human breast. In the dog this type of complex mixed tumor is very fre-
quently observed and the tissue changes are presented far more extensively
and clearly than in man (Virchow, Cornil and Petit, Gushing).

Two main groups of teratoid tumors of the breast may be recognized,
which are chiefly (i) mesodermal, or (2) ectodermal (Baumgartner).

(i) Mesodermal tumors appear to be closely related to adenosarcoma,
both in origin and structure. Thus Bowlby described a cystic adenosarcoma
throughout which were many nodules of hyaline cartilage. Pilliet found
myeloid giant cells about the bony trabeculas in an adenosarcoma. In the
dog breast I find that most adenosarcomas yield islands of bone or cartilage.
Diffuse calcification of a large sarcoma of three years' duration was observed
by B. Clark, and in an axillary tumor Dubar found much diffuse osteoid
tissue.

Frequently true bone tissue is found replacing islands of cartilage in
normal development, as occurred in cases reported by Stilling, Battle, Cornil
and Souligoux.

Nearly pure chondroma of the breast is not extremely rare (Lange,
Cambria, Leser, Davidsohn). Happel's tumor was large and cystic. Sou-
lier observed extension to the superior maxilla. Not a few are cellular and
embryonal in type and malignant (Desoil). Myxomatous degeneration is
often present and tends to increase the size of the growth. Chevrier and
Debral found a large tumor occupying the whole breast and containing
fibroma, myxoma, chondroma, osteoma and gland alveoli. Combinations
of chondroma with carcinoma are recorded by Wagner, Coen, and others.
Kaufmann has described a large cystic chondrocarcinosarcoma. Warren
saw three cases combined with scirrhus cancer. S. W. Gross described a
bony stroma inclosing islands of lymphoid bone-marrow with giant-cells
and surrounded by carcinoma simplex. Coen analyzed a slowly growing
tumor with vascular well-formed bone, which he attributed to metaplasia.
Hacker's case contained bone, cartilage, carcinoma, and fibrocystadenoma,

EPITHELIAL AND OTHER TUMORS OF THE BREAST 483

and he regarded it as a terminal product of an original cystadenoma. I
have examined a very large solid and cystic tumor containing chiefly masses
of poorly developed cartilage, myxomatous tissue, and areas of diffuse em-
bryonal carcinoma. Metaplasia could not have accounted for the extensive
development of cartilage.

Chondroma and osteoma of the breast are usually associated with
sarcoma or carcinoma, but in the series of reported cases there is a gradual
reduction in the malignant elements leaving eventually pure chondroma or
osteoma. Some of these growths are therefore probably one-sided develop-
ments of mixed tumors.

(2) Ectodermal mixed tumors take the form of multiple cholesteatoma
or squamous-cell carcinoma, often combined with sarcoma. The multiple
sebaceous cysts of the breast were early noted by Astley Cooper and by
Virchow and have later been studied by Grohe, Wilms, and others. The
true tumors resemble cystic fibro-adenomas with characteristic sebaceous
material and epithelial detritus in the cysts, which are lined by squamous
epithelium. This lining may show differentiation into strata, both horny
and Malpighian, with eleidin granules. Stoerk and Erdheim point out that
13 of 14 reported cases showed the general architecture of sarcoma phyllodes.
The gland alveoli may show adenomatous growth and the stroma is often
sarcomatous. In Konjetzney's case the squamous epithelium had suffered
malignant transformation.

In another group of cases squamous epithelium appears in isolated foci
associated with fibro-adenoma or glandular carcinoma without cholesteato-
matous features. Beginning with the case of Stoerk and Erdheim in which
scanty islands of squamous-cells appeared in a fibro-adenoma, one finds a
series of cases in which squamous epithelium becomes more and more
abundant. I have studied one case in which glandular and squamous
epithelium were about equally divided, while the transformation of one type
into the other seemed obvious. In Duval's tumor the cells were squamous,
cuboidal, or giant. Walther described a large tumor the periphery of which
was pericanalicular fibroma, in the center cystic adenoma, while a single
cyst was lined by well-developed skin. Nadal found many squamous-cell
groups scattered in a sarcomatous matrix.

The course and prognosis of the teratoid mixed tumors vary with their
structure, but as a rule they are slowly growing and comparatively benign.
Yet carcinomatous and sarcomatous metastases are observed reproducing
the original structure. Nadal found in the spleen a nodule of chondro-ade-
noma resembling the original tumor.

The origin of the teratoid tumors of the breast has been attributed to
complex embryonal inclusions containing mesodermal skeletogenous material
and fetal ectoderm. This view has been maintained by Wilms, Lecene,
Nadal, Menetrier, and others. The encapsulation of the early growths and
the wide diversity and fully adult character of the tissues produced favor this
view. Some rapidly growing complex chondrosarcomas strongly suggest an
origin from cells of undiminished and embryonal growth capacity. On the
other hand it has been clearly shown that this series of tumors includes
many transition stages from fibro-adenoma up to the most complex forms.
Close histological study appears to show every stage of metaplasia from the
ordinary gland- and stroma-cells of the breast into cartilage, bone and squa-
mous epithelium. In the dog tumors this histological evidence is unequivocal.
Hence it appears necessary to accept the theory of autochthonous or local
development of mammary mixed tumors as maintained by Grohe, Cornil,
and Herrenschmidt.

484 X EOF LA STIC DISEASES

In the breast one sees the most remarkable forms of metaplastic tumor
growth, and while this view does not exclude the origin of the tumors from
embryonal and misplaced cell groups it renders this assumption no more
urgent for the teratoid growths than for the simpler fibro-adenomas.

Adenosarcoma. — Adenosarcomas represent the malignant form of adeno-
fibroma but their many striking clinical and anatomical features render them
a rather specific form of mixed tumor of the breast. It is quite probable,
as Delbet suggests, that most pure sarcomas are identical in origin with
adenosarcoma. This view must be accepted at least for the true spindle-cell
sarcomas. Not only is their structure identical with that of adenosarcoma,
but recurrence of adenosarcoma may take the form of spindle-cell sarcoma
(Finsterer). These tumors form from 7 to 10 per cent, of mammary neo-
plasms (Gross, Schmidt, Schouler). While the chief age of incidence is
between 30 and 50 years (average 40) the condition has been observed by
Gross at Q years and at 75 years. Labbe and Coyne early pointed out that
nearly half the cases represent a malignant transformation of a long-standing
fibro-adenoma, and that gestation, lactation, and trauma appear to be excit-
ing causes of the change. Ropke and Gebele emphasize the relation to
trauma, but identical histories are observed without trauma. Tumors of
very long duration eventually becoming malignant are satisfactorily recorded
also by Gross (40 years), Schouler (39 years), Mornard, Masson (24 years),
Borchmeyer (6 years).

The form of the tumor isusually rounded and lobulated. Cornil describes
solid and papillary cystic types, the former developing from solid adeno-
fibromas, the latter from cystadenofibromas. The same breast may contain
adenosarcoma and benign fibromas. The cystic forms produce the largest
tumors seen in the breast, Velpeau's tumor weighing 20 kg. Labbe and Coyne
evacuated a liter of fluid. In the early stages the tumors are circumscribed
or encapsulated, but active growth leads to dissemination through the organ,
and f ungating masses perforate nipple and skin with ulceration. Edema, hemor-
rhage, necrosis, and suppuration complicate the advanced stages. In some cases
myxomatous changes and overgrowth of blood-vessels are prominent.

The structure presents considerable variations. Most tumors are com-
posed chiefly of spindle-cells, large or small, surrounding gland acini or ducts,
or growing within distended channels or spreading diffusely. The glands
may participate for a time in the overgrowth but in advanced cases they
usually disappear, or are found in isolated islands. Round-cell growths are
less numerous and rather more malignant. Such cells usually show traces of
a spindle or polygonal form, and sometimes an alveolar arrangement. Myxo-
matous changes may appear in large areas of bulky tumors. Giant-cells of
myeloid type occur in spindle- and round-cell growths.

It is evident that some European authors have included among adeno-
sarcomas certain rather cellular adenofibromas which have no distinct ma-
lignant qualities but have reached a large size by virtue chiefly of long
duration. It also seems highly probable that some cases reported as adeno-
sarcoma are rapidly growing carcinomas in which the anaplastic tumor-cells
assume a spindle or rounded form and grow about hypertrophied ducts.
The true adenosarcoma of the breast is very rare and usually follows a long
standing adenofibroma.

Definite association of sarcoma with carcinoma is reported by Lecene,
Cornil, and Kettle. In several such cases I have not been satisfied that
the spindle-cell areas were not modified epithelium.

The course of the true adenosarcoma when once established is usually
rapid and fatal. Yet in early stages remissions in the growth are recorded,

EPITHELIAL AND OTHER TUMORS OF THE BREAST

485

without satisfactory explanation. Gross emphasized the capricious character
of the growth of both cystic and solid sarcoma but a rapid growth once
established was usually maintained. In the late stages the progress is
continuous or fulminating, the skin becomes adherent and ulcerated, dilated
veins appear over the surface, and cachexia develops from absorption of
degenerating and necrotic material, and from metastases. The relative
immunity of the lymph-nodes has frequently been noted. Gross in 156
cases of various types of sarcoma found the nodes invaded in only three,
one of which was a melanoma. A much higher proportion of invasion of
lymph-nodes is recorded by Finsterer, Gebele, and Rosenstein. Generaliz-
ation by the blood-vessels with internal metastases is recorded by Schouler
in 12.4 per cent, of the cases. Secondary tumors have been found in lungs,

FIG. 192. — Mammary cancer. Alveolar and diffuse carcinoma, simulating carcino-

sarcoma.

liver, pancreas, bones and brain and elsewhere. Persistent local recur-
rence is observed in a high proportion of cases. In Hoffmann's remarkable
case proliferating gland acini persisted in the twelfth recurrence but were
missing in metastases in the abdominal wall. Recurrence as round-cell sar-
coma and as carcinoma are recorded by Poulsen. Pean reported local return
after 25 years. Gross observed recurrence in 51 per cent, and metastases in
1 2 per cent, of cystic sarcomas, with 1 2 per cent, of cures by operation. Many
cases requiring multiple operations are recorded, in one of which by S. D.
Gross 21 excisions during four years eventually eradicated the disease.

PURE SARCOMAS OF THE BREAST

When one excludes from the group of mammary sarcomas, the adeno-
sarcomas, the malignant forms of mixed tumors containing cartilage, bone,
mucoid, or fat tissue, and certain malignant round-, spindle- and giant-cell

486 NEOPLASTIC DISEASES

alveolar pseudosarcomas which are really atypical carcinomas, there is
little remaining of a once formidable group of mammary neoplasms. There
are reasons for believing that such a disintegration of the group is justifi-
able. In fact the situation to-day is much as it was in 1894, when Williams
found it impossible to write the history of pure mammary sarcoma because
of the absence of requisite data.

Of Gross' collection of 156 cases, 33 per cent, were adenoid, 50 per cent,
cystic, and 50 per cent, solid. On clinical grounds Billroth and Konig
concluded that the cystic sarcomas were closely related to adenofibroma,
and Schimmelbusch from thorough anatomical study reached the same
conclusion. Gross mentions that adenoid structures persist chiefly in the
spindle-cell sarcomas, and that myxomatous changes are almost peculiar to
spindle-cell and cystic tumors. The great predominance of the forms
thus entangled in the group of malignant nbro-epithelial growths is indicated
• in Finsterer's recent series — cystosarcoma, 18 cases; spindle-cell 10; myxo-
sarcoma 5; round-cell 6; lymphosarcoma i.

The pseudosarcomas of epithelial origin probably cover a considerable
subgroup of mammary sarcomas. A definitely alveolar structure points
at once to an atypical epithelial tumor process. Not a few such tumors are
included in the lists of sarcoma. They are difficult to distinguish in the
gross from medullary carcinoma. Billroth fully recognized the difficulties
of diagnosis and seems to have reached the conclusion that they belong in
a group of carcinosarcoma. I have studied several rapidly growing cellular
tumors of alveolar or diffuse structure and failed to find any definite evidence
of a mesoblastic origin. On the contrary, as Billroth observed, areas can
usually be found which are duplicated by portions of undoubted medullary
carcinoma. Finsterer saw a supposed alveolar sarcoma recur as frank
carcinoma. G. B. Schmidt's angiosarcomas consisted of cells of " distinct
epithelial form" in alveolar arrangement. The uncertain significance of
perithelial structures in breast tumors is well elucidated in the discussion of
Nadal's case of mixed osteosarcoma and perithelioma.

Melanoma also figures among the alveolar and giant-cell sarcomas.
Fioriana describes a melanotic lymphangiosarcoma, a form not infrequently
assumed by melanoma. The lobular and encapsulated form of some reputed
cases of giant-cell sarcoma suggest an origin from cystic adenocarcinoma
in which diffuse areas of round- and giant-cells are not uncommon.

The round-cell sarcomas of various authors form an ill-defined group.
They probably include very atypical tumors of the same nature as the
spindle-cell sarcomas, malignant and atypical carcinomas, and some pig-
ment-free melanomas. Gross found their chief occurrence at 48 years,
the period of beginning physiological decline of the breast, while the spindle-
cell tumors appear earlier, 36 to 38 years. Six of Finsterer's 40 cases, 5
of Gebele's 34 cases, and 27 per cent, of the series collected by Gross were
round-cell tumors. That the nature of these tumors is often highly un-
certain is indicated by the simultaneous occurrence of small round-cell
sarcoma in one breast and glandular carcinoma in the other, as in Finsterer's
case 21 ; or by his case 23, of lymphosarcoma of alleged traumatic origin.
That the structure of round-cell sarcoma may be duplicated by carcinoma
is demonstrable in certain atypical acinar carcinomas in which considerable
areas may fail to show any alveolar arrangement. Billroth's case of acute
lymphosarcoma of both breasts arising in gestation and fatal in five months
is very suggestive of the atypical carcinomas of pregnancy. Battle in
reporting a large fungating round-cell sarcoma states his belief that the
growth was some form of fungating tumor arising within a cyst.

EPITHELIAL AND OTHER TUMORS OF THE BREAST

487

True sarcomas composed of rounded or short spindle-cells probably
represent an atypical form of spindle-cell sarcoma. They are highly ma-
lignant, 60 per cent, recurring and 25 per cent, becoming generalized (Gross).
In one of Finsterer's cases the malignant tumor followed excision of a cysto-
sarcoma, and in most cases a slowly growing tumor has existed for some
months.

Pure spindle-cell sarcomas of the breast form a rather well-defined group
which closely resemble both clinically and anatomically their more complex
homologues, the adenosarcomas. They vary greatly in consistence, ^ cell
content and form, vascularity, and in the degree of secondary especially
myxomatous degeneration. Combinations with osteoma, chondroma and
lipoma are occasionally observed (Gross). They formed 68 per cent, of
Gross's cases and the great majority of Finsterer's. The prominence of
cysts emphasizes their relation to adenosarcoma. In clinical course and

FIG. 193. — Mammary cancer. Diffuse growth of large polyhedral and spindle cells.

gross appearance they are not to be distinguished from the adenosarcomas,
but there is a tendency toward occurrence at earlier ages and persistent local
recurrence.

Even the presence of an apparently pure spindle-cell structure does not
positively assure a mesoblastic origin. Diffuse or atypical carcinomas, espe-
cially the malignant forms, may yield broad areas of small spindle-cells, and
only a thorough study of many areas as well as of the history of the tumor can
establish a positive diagnosis.

Osteochondromyxosarcoma is a relatively common variety of complex
mammary sarcoma. Its relation to the teratoid growths is clearly brought
out in the combinations with dermoid cysts, adenoma, and carcinoma. More
often the tumors are purely mesoblastic (St. Arnold, Lit.). The tumors are
large, solid, or cystic, actively growing and tend to ulcerate and suppurate.
The sarcomatous areas are composed of spindle-, round-, or giant-cells
(Gross, Manx, Durham). Two tumors of this type in the same breast with
areas of spindle- and round-cell sarcoma were observed by Borst.

488 N EOF LA STIC DISEASES

MISCELLANEOUS TUMORS OF THE BREAST

The usual benign tumors of the skin occasionally develop in the mammary
region.

Angioma, beginning near the nipple, after trauma, and gradually extend-
ing as a pulsating tumor throughout the breast is described by Image and
Hake and by Langenbeck. Subcutaneous angiomas, cavernous or cystic, and
erectile, are reported by Williams, and Quenu and Kiiss. A peculiar diffuse
erectile angioma involving the stroma of the gland and the peri- and inter-
acinar connective tissue with atrophy of gland tissue has been studied by
Malapert. Lymphangiomas of large dimensions are described by Wegner.
Miiller, and Pinner, and some large serous cysts in this region probably arise
from lymphangiomas.

Sebaceous cysts and papillomas occur chiefly about the nipple and may
be the source of carcinomas.

Leiomyoma of the nipple or skin has been recorded by Virchow, Sokolow,
and Niklas.

Melanoma has been reported by many authors, and presents its usual
malignant features. It occurs in both sexes, chiefly about the nipple. Vier-
egge records a case in an infant. Billroth and Cornil and Ranvier described
melanotic carcinoma involving the breast tissue, but there is no evidence that
the tumor arose from the gland tissue. In these and other cases an origin
from moles of the skin or included epidermal rests, or a secondary pigmenta-
tion from hemorrhage must be assumed.

Dermoid cysts of the breast are rare, but several cases have been collected
by Williams and Baumgartner. They are of interest in connection with the
mixed tumors and cholesteatomas. A large dermoid described by Reverdin
and Mayor was associated with fibro-adenomas. In the middle line, between
manubrium and gladiolus, there is sometimes a congenital fossa, and here
simple dermoids have been observed (Williams, Lit.).

Lipoma of Breast. — Diffuse lipomatosis is often associated with diffuse
hypertrophy. Intraglandular lipomas are very rare, but are described by
A. Cooper, Koehler, and Begouin. They show lobulated overgrowth of fat
tissue with scattered gland alveoli. Hof er found a small mass of bone in the
center of a mammary lipoma.

Retromammary lipomas may reach very large dimensions. Billroth's
case measured 43 cm. in its long diameter. Queirel's tumor arose from the
tissues of the pectoralis and weighed 800 gm. Paget describes a case in a
male subject. The subcutaneous lipomas may be single, multiple, or bilateral
(Reclus, Baker and Bowlby). They are subject to central softening and in a
group of cases some of which are congenital myomatous areas appear (Moore,
Ashby and Wright).

Epithelioma of the skin of the breast occurs along thoracic and mam-
mary fold, where it is favored by intertrigo (Richet, Winiwarter), along the
axillary border, and in the nipple whence it may invade the breast and simu-
late carcinoma. In this last situation it requires differential diagnosis from
Paget's disease which is more superficial and widespread (Hauser), and from
metaplastic squamous changes in duct carcinoma. Cornil traced a squamous
epithelioma of the nipple extending some distance into the large ducts. Mor-
estin observed epithelioma of the nipple associated with true carcinoma of the
gland. Robinson described a rodent ulcer at the nipple. The tumors may
be preceded by a papilloma or a sebaceous cyst (Bryant). They do not
differ essentially from epitheliomas in other regions, but in the nipple the
course may be unusually active.

EPITHELIAL AND OTHER TUMORS OF THE BREAST 489

CARCINOMA OF BREAST

General Etiology. — Incidence. — The U. S. Census for 1914 reports 5423
deaths from cancer of the breast among 52,420 total cancer deaths. The
mortality rate rose enormously between 1900 and 1912, the average annual
death rate from 1901 to 1905 being 18.45 per cent., from 1906 to 1910, 30
per cent. There has certainly been no such increase in the incidence of the
disease and the recorded increase must be due largely to improved diagnosis
and registration. Since a certain proportion of breast cancers are cured by
operation the morbidity record must be somewhat higher. R. Williams from
4628 cases of cancer in women in London Hospitals, 1868 to 1888, calculates
that 40.3 per cent, were mammary, 34 per cent, uterine. English mortality
statistics, however, placed uterine and ovarian cancer, 34.7 percent.; mam-
mary cancer, 21.2 percent. In Ireland the ratio was: stomach, 22 4 per cent.;
breast, 21.5 per cent.; uterus, 14.1 per cent. In Frankfort-am-Main: 1860
to 1889, uterus, 27.5 per cent.; stomach, 18.3 per cent.; breast, 11.3 per cent.

In 1912 the mortality from mammary cancer in England and Wales was
19.8 per 100,000 of population. Hoffmann points out that there is great
variation in the mortality in different countries. Thus from 1906 to 1910
the rates per 100,000 of population were, England and Wales, 17.9; United
States, 13.3; Bavaria, 9.1; Italy, 5.8; Japan, 1.8.

Of all mammary tumors carcinoma forms 82 to 84 per cent. (Delbet).

Age Incidence.—

U. S. Census, 1914. Age Incidence of Mammary Cancer

Years

15-19 20-4^25-9 30-4 35-9 40-4 45-9 50-4 55-9 60-4 65-9 70-4 75-9 80-4 85-9 90-4 95-100

Cases

4 6 44 '• roi 301 46oi 646 671 658 551 529' 435 311 207 93 23 6

British mortality statistics, 1901 to 1903, place the highest mortality
between 55 and 65 years. Mortality statistics of Williams, Paget, Nunn and
of most surgeons place the mean age of incidence at 45 to 50, or about the
48th year (Schmidt).

The earliest authentic cases recorded appear to be those of Kaufmann, 17
years, Henry, 21 years and Williams 24 years. Brewer reports a fibro-
adenoma with carcinomatous areas in a negress of 16 years.

Lactation. Of 628 cases of Velpeau, Gross, and Winiwarter, 441 had
nursed children, 187 had not. Lehmann offers statistical evidence that nurs-
ing is a prophylactic against mammary cancer. Pregnancy is without
definite influence.

Hereditary influence has appeared to exist in 5-10 per cent, of various
series of cases studied specifically for this purpose (Delbet). With more
rigid criteria Guleke reduces the possible hereditary cases to 2.36 per cent.
Williams found cancer in the family in 24.2 per cent, and quotes Sibley's
observation of a mother and five daughters who died of cancer of left breast.

There is a slight predominance of the disease in the left breast. It appears
to originate in both breasts in about 1.5 per cent. The frequency of bilateral
cancer at the time of observation is, however, much greater. Handley finds
5 per cent, of advanced cases bilateral and Hubbart 9 per cent. Benassey
rightly distinguishes between (i) cancer of the second breast developing after
amputation of the first, which is not uncommon, and (2) cancer developing
in the second breast from an original focus in the first, and (3) primary bilateral

490 N EOF LA STIC DISEASES

cancer, which is rare. The upper axillary segment is the chief site of origin
(Delbet). Trauma tism has been asserted or suspected in 5 per cent, by
Schmidt, 12.5 per cent., by Schultheis, and 12.7 per cent, by Fink. Its
essential relation to mammary cancer is still unproven, but injury not infre-
quently accelerates growth. In an organ. constantly exposed to trauma as is
the breast an apparent relation to cancer must be subjected to the most rigid
criteria. Thus Williams who obtained a history of antecedent trauma in 25
per cent, of his cases found not a single instance in which the disease had
developed out of induration or other obvious lesion thus induced.

Previous exudative inflammation often leaves tissue changes predisposing
to cancer. Winckel found such lesions in 17.5 per cent, of a series of cases,
including abscesses in 15; lesions of the nipple, 8; and inflammation without
suppuration in one of 24 cases.

Developmental anomalies are traceable chiefly in the origin of cancer
from sequestrated portions of the breast. Of 132 cancers observed by Wil-
liams 13 arose from aberrant tissue, in axillary, sternal or infraclavicular
regions. In not a few of these aberrant tumors the structure is nearly pure
adenoma with evidences of functional capacity but the true carcinomas in
these regions are often highly malignant and may be atypical. The milk
secreting adenomas of Birkett and Power and the tumor-like swellings of
aberrant breast tissue described by others, are regarded by Williams as hyper-
trophic rests rather than true neoplasms. Williams calculates that 14 per
cent, of fibre-adenomas arise from such rests. Many of the complex mixed
tumors are probably of identical origin, but it seems unnecessary always to
include skeletogenous material to account for the bone and cartilage found
in them. Epidermal inclusions may be held responsible for certain dermoids
and melanomas of the breast, but metaplasia is a sufficient explanation for
the majority of cholesteatomas and the squamous-cell islands of mixed
tumors.

The alveoli of sweat-glands, which are nearly constantly found scattered
through the breast, especially in the neighborhood of the larger ducts,, give
rise to a specific form of mammary carcinoma which corresponds to the duct
cancer of many writers.

According to Creighton the duct system of the breast is a derivative of
the cutaneous sweat-glands. Superfluous or aberrant portions of this system
retain the characters of sweat-glands, persist in the adult organ and give
rise to most of its tumors. The secreting gland-cells he derives from the meso-
blastic fat-cells about the ducts, which readily become transformed into the
acinar epithelium when the demands for functional activity arise. This
interesting conception once had considerable authoritative support but is
now almost entirely ignored. There are not a few facts in the physiology
and pathology of the organ which are consistent with this hypothesis.

The effective causation of mammary cancer is to be traced in the combi-
nation of several predisposing, contributing and exciting factors. There is
ground for assuming that many subjects are predisposed to mammary neo-
plasms. Some of these subjects appear to develop simple glandular hyper-
trophy in early life, and this same instability of the organ may under favorable
conditions be an important factor in precipitating malignant tumor growth in
later life. Developmental anomalies leading to fibro-adenoma and seques-
tration of breast tissue form a tissue predisposition in a certain group of cases.
By far the most important element in the tissue predisposition is chronic
productive mastitis. The great majority of cancers develop in organs altered
by reactive inflammatory processes. Minute histological analysis of the con-
ditions surrounding the beginnings of cancer in chronic mastitis point to

EPITHELIAL AXD OTHER TUMORS OF THE BREAST 491

mechanical isolation of cell groups in fibrocarcinoma, and irritation by chem-
ically altered secretion and exudate in adenocarcinoma, as the immediate pre-
cursors of atypical overgrowth. This irritation may very well come from va-
rious microorganisms and animal parasites, such as the Demodex folliculorum
described by Borrel, none of which can be regarded as specific exciting factors.
In fact there appears to be no need of introducing the conception of a specific
exciting factor in mammary cancer, since the disease is satisfactorily ac-
counted for as the liberation of growth tendencies of overnourished and
proliferating cells, under peculiar anatomical relations and often but not
necessarily in predisposed subjects.

Pathological Anatomy. — While there are several well-defined anatomical
forms of mammary cancer the specific features characterize chiefly the early
stages of the disease. Arising under markedly different conditions of a wide
variety the anatomical distinctions are often obliterated when the disease is
fully established and the local lymphatics are invaded.

On chiefly anatomical features the disease may be considered under the
following forms:

1. Adenocarcinoma arising chiefly in cysts of ducts or sweat-glands.

2. Duct carcinoma arising from the lining cells of ducts.

3. Acinar carcinoma arising from the epithelium of the acini.

Of these main groups there are several subdivisions, such as gelat-
inous or mucous carcinoma, fibrocarcinoma, and carcinosarcoma, while
striking clinical features stamp certain cases of the disease as highly
specific.

Although no other form of carcinoma absorbs more attention from sur-
geons and pathologists, the morphology of mammary tumors still requires
more searching analysis than it has yet received. So variable and complex
are the forms and structure of mammary cancer that the attempt to employ
a histogenetic classification may be premature. The present effort must be
acknowledged as only tentative. Yet the rough grouping of these tumors
In the current fashion, according to cell content, as carcinoma solidum,
medullare, and scirrhus, while involving no risk, is wholly lacking in any il-
lumination of the subject. Not until the anatomical structure and histogene-
sis of these tumors is more fully understood can any significant knowledge
be obtained of their etiology, prognosis, and the value of treatment. The
separation of the sweat-gland tumors of the breast may be accomplished
with considerable certainty on morphological grounds, but specific clinical
features of this group remain to be defined.

Ribbert has stated that no one has ever seen a beginning carcinoma of
the breast. While few have accepted this dictum it is not necessary to
observe the initial stages in order to deduce the origin of many cystadeno-
carcinomas, duct cancers, or even of certain acinar tumors.

Clinical features seem to be a less satisfactory basis of nomenclature
and classification of cancer of the breast than with many other organs.
When the lymph-nodes or blood-vessels are once invaded the further course,
while extremely varied, may be much the same with tumors of very divergent
antecedent history. On the other hand the early stages of most tumors
are closely correlated with their histogenesis, structure, and the conditions
under which they arise.

The condition of the breast at the time of the development of the tumor
has a prominent influence on the anatomical characters and clinical course of
the disease. In elderly subjects various forms of carcinoma develop, but
the disease is usually of slow course, and fibrosis and cicatrization are promi-
nent. In small atrophic breasts at any age, glandular tissue being de-

492 N EOF LAST 1C DISEASES

ficient, carcinoma usually takes the form of duct cancer, of the comedo type,
and often affects the sweat-glands.

In atrophic but very fat breasts there is often a very small fibrous car-
cinoma, difficult to detect in the organ, with bulky, extensive and cellular
growths in lymph-nodes.

Very active, anaplastic, and atypical forms of carcinoma develop usually
in comparatively young women in the child-bearing period. During preg-
nancy the disease is usually particularly active, anatomically atypical,
and rapidly fatal.

Acute carcinosis with fulminant febrile course, occurs usually in women
under 35 years of age, with well-developed breasts. The anatomical type
varies, but often presents an adenocarcinomatous structure in primary areas,
or a diffuse and highly anaplastic structure.

FIG. 194. — Single small nodule of carcinoma in the center of an atrophic and fatty breast.

An origin in cysts, in adenofibromas, in the congenitally hypertrophic
breast, or after diffuse fibromatosis, or other pathological conditions, stamps
the early stages of the disease with rather definite clinical features.

The more chronic forms of mammary carcinoma, especially those recur-
ring after operation, take a great variety of anatomical types, which compose
an extensive chapter in the history of the disease.

Adenocarcinoma. — Adenocarcinoma is characterized by its origin chiefly
in cysts, by the markedly circumscribed character of the growth, the bulky
local tumor often produced, the long immunity of the lymph-nodes, the rela-
tively favorable prognosis, and the specific structure. Various terms have
been employed to designate types of adenocarcinoma, as carcinome mlleux
(Cornil), epitheliome intracanaliculaire (Labbe, Coyne), villous duct cancer
(Williams). A sharp distinction between the benign adenomas and adeno-

EPITHELIAL AND OTHER TUMORS OF THE BREAST 493

carcinomas has not always been attempted, and the more malignant forms
have not been separated from other mammary cancers as clearly as they
should be.

The majority of these tumors arise in the cysts of chronic mastitis.
They are frequently multiple, and simple cysts, or cysts with papillary ade-
nomas may accompany the main tumor. In the early stages and often to
a late period, they form sharply circumscribed masses near the nipple or
in outlying regions. They are large, solid, opaque, usually soft, and free
from fibrosis. Later they may break through the skin, producing fungating
superficial masses which bleed and ulcerate, and they perforate the capsule,
invading the breast and the lymphatics. There is much variation in the
rapidity of growth and malignancy. Some take the form of papillary or
villous adenoma with carcinoma tous areas; others are uniformly solid and

FIG. 195. — An adenocarcinoma of breast. The upper half is slightly pedunculated and the
vascular system telangiectatic.

carcinomatous from the first, but encapsulated. A few are highly atypical
and malignant and early perforate the capsule and invade the breast and
lymph-nodes. In this form they yield some of the tumors commonly called
"encephaloid."

Secondary changes are relatively frequent in the advanced tumors.
Fatty degeneration is often observed and considerable areas of necrosis may
appear in gross section. Overdevelopment of blood-vessels produces a
vascular tumor prone to hemorrhage, infarction and necrosis. I have found
the entire tumor infarcted and black, or necrotic without infarction. Re-
peated hemorrhages may leave much pigment and give the appearance of
secondary melanoma.

494

NEOPLASTIC DISEASES

The structure shows marked variations from a typical benign papillary
adenoma to nearly diffuse growth in which only traces of papillary or ade-
nomatous structure are retained. Portions of the growth may be quite
diffuse. Typical adenoma malignum or destruens is occasionally observed.

i. The simplest structure is a papillary adenoma with carcinoma tous foci.
This type covers the majority of the cases described by Cornil, Williams, and
many of the older authors, who have clearly presented its relatively benign
clinical features. The papillae are low, and freely anastomosing bands of
stroma tend to yield an alveolar structure with many secondary sacculations;
or the outgrowths are long and villous. The cells are cuboidal or low and
cylindrical, granular, opaque, but usually overnourished and atypicaL

FIG. 196. — Mammary cancer. Adenocarcinoma of ducts.

This tumor is of slow growth, long remains encapsulated, is slow to involve
lymph-nodes and in this stage a radical operation is not required.

2 . A more malignant form shows little evidence of papillary structure in the
gross but is solid and opaque. The structure presents the complex features of
papillary carcinoma or adenoma malignum. The few strands of connective
tissue or the large alveoli are covered or lined by large cuboidal or cylindrical
cells with hyperchromatic nuclei. Everywhere epithelium predominates
over stroma. These tumors frequently perforate the cyst capsule and grow
diffusely in the form of small alveolar carcinoma. In the lymph-nodes,
lungs, and especially in the blood-vessels their growth tends to revert to the
type of adenoma malignum or papillary carcinoma.

3. The most malignant forms of adenocarcinoma developing in cystade-
noma produce bulky tumors invading most of the breast, perforating the skin
as fungating masses, and early involving the lymphatics in various directions.

EPITHELIAL AND OTHER TUMORS OF THE BREAST

495

The adenomatous structure is visible only in the central portions or in metas-
tases, while the infiltrating portions resemble other forms of mammary
cancer. These tumors occur at all ages and are among the most malignant
in clinical course. A characteristic form presents one or more circumscribed
nodules of moderate size with more bulky tumors in the axilla. Or the main
tumor is found of large size having long remained localized until a rather
sudden access of growth leads to rapid infiltration of vessels and wide
dissemination.

Histogenesis. — The gross appearance, transitional types, and minute
structure point clearly to the origin of these tumors from the papillary
ingrowths of mammary cysts. The remaining portions of the breast when
available often show the changes of cystic mastitis, but adenocarcinoma

•'•w-*%"-: •••>•-•/

•v-^ , ;.V£K

FIG. 197. — Mammary cancer. Adenocarcinoma of ducts, beginning to infiltrate.

develops in breasts in which any preceding inflammatory changes are local-
ized and soon obliterated. Two types of cysts are included in the sites-
of origin: (i) dilated interlobular ducts, and (2) the sweat-glands of Moullin,
Creighton, Dreyfuss and Krompecher. From the study of this group of
tumors I have been led to conclude that the lacteal ducts produce most of
the low papillary and glandular adenocarcinomas with cuboidal clear cells,
while the sweat-glands give rise chiefly to papillary and villous adenocar-
cinomas with cylindrical cells of acidophile character. This latter group
constitutes a well-defined structural group of mammary carcinomas charac-
terized by large, strongly acidophile cells. Many of them take the form of
comedo carcinoma in shrunken breasts.

Mucoid carcinoma is usually an adenocarcinoma with mucous degenera-
tion of stroma or cells and owes its slow course both to its comparatively

496 NEOPLASTIC DISEASES

adenomatous structure and to the mucoid changes in its stroma which greatly
interfere with nutrition. Gelatinous changes may also occur in the stroma
of ordinary duct cancers. The mucoid tumors reach the largest dimensions
of any mammary carcinomas and their encapsulation or local confinement
may be maintained for several years. They are easily recognized by their gela-
tinous texture and large bulk. Doutrelepont's case was bilateral. These
tumors are comparatively rare. Gaabe collected 49 (1.66 per cent.) among
2944 mammary cancers and analyzed in detail their clinical peculiarities.
The average duration before operation was 31.43 months as compared
with 13.28 months with ordinary carcinoma. Involvement of the lymph-
nodes occurred at 20 to 36 months, of skin, 36 to 54 months, and of muscle
28 to 60 months, all about three times as long as the periods fixed by Guleke
for ordinary carcinoma. Late metastases constitute a striking feature, the
average period being 40 months (ordinary cancer 13 months). A limitation
of metastases to the thoracic organs is often observed. In three cases the

FIG. 198. — Mammary cancer. Bulky fungating adenoma malignum.

undisturbed course of the disease was n, 12 and 14 years (ordinary cancer
20 to 27 months). The duration of life after operation was 5 years, and the
recoveries after 3 years 53.85 per cent., as compared with 30.68 months
and 28.79 per cent, respectively with ordinary breast cancer.

The structure shows a small alveolar carcinoma or adenocarcinoma with
extensive mucinous degeneration. The mucinous material is usually found
in the stroma, while the epithelium is compressed into small islands of inactive
cells. Much discussion has occurred regarding the source of the mucus.
Its usual position outside of and surrounding compact groups of well-pre-
served cells is not in accordance with an epithelial origin and has not been
satisfactorily explained by those who maintain this origin. Lange found the
source of the material exclusively in the stroma. Most authors trace its
origin to the epithelium with subsequent discharge into the stroma and solu-
tion of epithelial cells. (Cornil, Ziegler, Ribbert, Zimmerman.) Kaufmann
finds that both elements in different tumors give origin to the mucus. In
four cases I have not seen mucous degeneration of epithelium, but the compact

EPITHELIAL AND OTHER TUMORS OF THE BREAST

497

alveoli lay in broad areas of mucinous stroma. There was strong evidence
that the mucinous change had involved and partly originated in the fat
tissue in the stroma. In another case of adenomatous structure the alveoli
were filled with mucus as described by Cornil. There are thus evidently two
forms of gelatinous carcinoma of the breast.

The causes of mucous degeneration are obscure and the origin of some of
the tumors is uncertain. The long initial quiescent period observed in some
cases by Lange, suggested that the tumor arose through transformation of
an adenoma. Elsasser describes a mucoid stroma in a carcinomatous fibro-
adenoma. One of my cases showed the usual structure of duct carcinoma
with large groups of clear polyhedral cells quite isolated in gelatinous stroma.
The metastases are not always gelatinous. In Walther's case they appeared
in the cicatrix in a form like sago grains.

PIG. 199. — Mucoid carcinoma of breast. Mucoid degeneration of stroma and fat tissue.

Duct Carcinoma. — Carcinoma arising in the interlobular and large ducts
produces tumors of characteristic gross and microscopical structure and
somewhat peculiar clinical course. One of these has been fully described by
Cornil as epitheliome canaliculaire, and its peculiar features are recognized by
many authors, by Kaufmann as flat-cell carcinoma, by R. Williams as
tubular carcinoma. All of these terms seem distinctive and appropriate, but
the phrase, "tubular carcinoma," introduced by Billroth has been loosely ap-
plied to various structures.

Gross Anatomy. — The tumor process usually begins near the nipple and
affects the central portions of the gland, or it may first appear in any por-
tion of the breast. Eventually it tends to invade the entire organ, with marked
fibrosis and reduction in size. The entire breast may be drawn up into a
small cancerous mass beneath the nipple. In the more malignant forms the

498

NEOPLASTIC DISEASES

organ may be considerably enlarged by diffuse growth in which case the typ-
ical gross features may be lost. The whole organ may be completely trans-
formed while rather reduced in size. Retraction of the nipple is an early

FIG. 200. — Mammary cancer. Advanced carcinoma simplex. Retraction of nipple;

dimpling of skin.

sign in central tumors, less constant with peripheral growths. On section
a striking appearance is presented by a few or very numerous yellowish

FIG. 201. — Mammary carcinoma.

Diffuse fibrocarcinoma with contraction and fixation
of breast.

points or small cysts filled with caseous and fatty matter (comedo carcinoma).
In pronounced cases the breast is firm, opaque, and honey-combed. In
advanced or rapidly progressing cases the small cysts may be obscured by

EPITHELIAL AND OTHER TUMORS OF THE BREAST 499

diffuse infiltration of all tissues, and the organ may be enlarged. In very
cellular tumors the gross appearance falls in the group often called encepha-
loid, but close inspection reveals some of the characteristic cysts with case-
ous contents. In a rapid case of four months' duration, in pregnancy, the
enlarged organ resembled diffuse sarcoma, but several cysts were detected
and microscopical study revealed characteristic duct carcinoma largely over-
grown by diffuse carcinoma. Very extensive involvement of the skin and
subcutaneous tissue extending even beyond the breast is a striking feature of
some cases.

This form of carcinoma develops frequently in breasts which are the seat
of chronic diffuse mastitis. In such cases the uniformly smooth section of
the fibrosed organ shows at one or more foci a more dense and cicatricial ap-
pearance which is the result of the desmoplastic quality of the carcinomatous
process. At the same time grayish yellow points appear from fatty changes in
groups of tumor-cells or from accumulation of fatty material in ducts. The
tumor often takes the form of nbrocarcinoma with varying cell content, but
in many cases the typical small cystic types are observed.

The structure presents marked proliferation of the lining cells, first of the
larger then of smaller ducts, or vice versa. The walls of the ducts are thick-
ened, fibrous, or hyaline and the lumen moderately dilated. Cysts wider
than 2 mm. are uncommon.

The form and arrangement of the cells vary with the degree of malignancy
of which three grades may be considered with advantage:

1. Small Cystic Adenocarcinoma. — The cells are cylindrical, only slightly
atypical, and they line the dilated ducts in the form of fusing papillae or in a
solid multiple layer in which secondary alveoli appear at regular intervals.
Wide areas of such cells with secondary alveoli appearing at regular intervals
may form in dilated ducts. The process may be traced from the nipple
to the peripheral lobules. This structure constitutes a form of tubular
adenocarcinoma.

Tumors of this type are of slow growth, the tumor-cells long remain
confined to the ducts and do not break through the basement membrane, the
lymph-nodes are usually free from involvement, and extirpation of the
breast is frequently successful. Unfortunately, most duct carcinomas are
more atypical in the whole or in portions of the growth and the tumor falls
in the next subgroup.

2. Small Cystic Duct Carcinoma. — The alveoli are lined by stratified
layers of atypical overnourished, large, clear, polyhedral cells resembling
squamous epithelium, without secondary alveoli. The ducts are partly or
completely filled with these cells and with homogeneous detritus. Many of
them are distended and ruptured and the cells, under evident signs of com-
pression, are found in all stages of infiltration of the stroma. Many lateral
sacculi form, the process invades the intralobular ducts and even the im-
mature or atrophic acini and the whole breast may become transformed
into a tubular or large alveolar carcinoma in which the prevailing cell is
large, clear and polyhedral or squamous-like. Very varied pictures are
produced in the different phases of these tumors. Some are very cellular,
plexiform, or show broad sheets or very numerous small groups of clear cells.
Many are strongly desmoplastic. Some present areas of very large giant-
cells. Nearly all the structures commonly designated as alveolar, tubular,
encephaloid, simplex, solid, scirrhus, and small cystic carcinoma may be
produced in the established forms of duct carcinoma. All are locally aggres-
sive, highly invasive of lymph- and blood-vessels, and fully malignant.

3. Fibrocarcinoma arising in chronic mastitis presents a varying structure

500 N EOF LA STIC DISEASES

chiefly of the type of duct carcinoma. The earliest stages include the lesions
described under chronic mastitis as precancerous changes or miniature
carcinomas and consist in single ducts or groups of ducts in and between
the lobules, which are filled with atypical overnourished cubical or flat cells.
The altered acinar epithelium also frequently participates in these early
changes. Soon the distended ducts rupture and groups of large clear cells
infiltrate the lymphatic spaces. Marked increase of connective tissue often
richly infiltrated with round-cells accompanies the process and it is this excess
of fibrous tissue which alters the gross and microscopical features of ordinary
duct carcinoma and stamps the disease with peculiar characters.

Distinctly fibrous carcinomas are as a rule less malignant than the
cellular forms, but their clinical course varies greatly. Some take the
course of scirrhus cancer and in elderly subjects may long remain localized,
[n the absence of a notable tumor surgical interference is often long delayed
so that little advantage is gained from the slower course. In a well-known

Carcinoma simplex. Tubular carcinoma.

group of cases there is a relatively small mammary tumor while the lymph-
nodes are found involved by a very cellular growth.

Duct carcinoma, originally typical, may develop anomalous forms which
are very active, diffuse, sometimes pseudosarcomatous, and highly malig-
nant. In the case previously mentioned in pregnancy, the main tumor was
composed of a diffuse growth of polyhedral round- and spindle-cells which
soon disseminated through blood- and lymph-vessels. In other cases of
diffuse carcinoma with indifferent rounded or spindle-cells, I have found areas
of more typical plexiform or large alveolar carcinoma with large clear cells,
indicating an origin from duct epithelium.

Histogenesis. — The origin of this form of mammary carcinoma has been
satisfactorily traced to the lining cells of the interlobular ducts. In central
tumors lying beneath the nipple the larger ducts are especially involved
and the lesion may extend to the nipple or even to the skin, as in some cases
of Paget's disease. The lesion also extends to the intralobular ducts.

EPITHELIAL AXD OTHER TUMORS OF THE BREAST

501

That the acini themselves may become involved and contribute to the
sources of these tumors is indicated by minute examination of early cases.
The present group of duct carcinoma, especially the fibrocarcinomas, does
not therefore arise exclusively from duct epithelium. Yet specific acinar
epithelium is very scanty in the lobules of many cases of chronic mastitis
and may be practically absent in involuting breasts in which duct carcinoma
usually develops. The intralobular ducts, on the other hand, persist and
widen and the scanty acinar epithelium assumes the morphology of duct
tumor-cells.

It cannot, I think, be denied that the minute analysis of these lesions
indicates a gradual diffusion of the cancer process over adjoining lobules
until at least the focus of origin reaches considerable dimensions, after

> f ** r ' <*>** *T-*m *•* *rffc ^* * " ^ J -V *^X *% *

^^s^l^^^S^

Primary fibrocarcinoma in a young woman.

which the tumor progresses from its own resources. Every portion of the
organ may be completely invaded without demonstrable increase in size.
Nadal traces the origin of such diffuse forms of the disease and concludes
that the neoplastic process may originate from all portions of the breast.

The aberrant sweat-glands of the breast give rise to tumors which may
be difficult to distinguish from true duct carcinoma. The separation is
especially difficult between different cases of comedo cancer, many of which
arise from the sweat-glands. As a rule the cells of the duct carcinoma
are clear and as they become more atypical the cytoplasm becomes less
prominent. The cells of the sweat-gland tumors are large and the cytoplasm
is opaque and strongly acidophile, while these features tend to persist in ex-
tensions and metastases.

502

NEOPLASTIC DISEASES

The present classification of duct carcinomas somewhat enlarges the
scope of this group as recognized by some authors. It includes especially
the tubular and some acinar carcinomas of Cornil and others. It is im-
possible to claim that every tubular carcinoma originates from ducts, yet
many such growths are certainly of this origin, while their development from
true acinar epithelium is less certain. The cell characters are of much
importance in the diagnosis and wherever the cells are large and clear, of
polyhedral form and mosaic arrangement, an origin from ducts is indicated.
An exclusive origin from ducts or acini is not always to be assumed. In

FIG. 204. — Mammary cancer. Sclerosing fibrocarcinoma. Typical hard scirrhus.

cellular duct cancers the acinar epithelium may be involved and in many
acinar tumors the duct epithelium, as Cornil points out, shows various phases
of malignant proliferation. Under these conditions the tumor must be classi-
fied according to its predominant features.

Acinar Carcinoma. — Although the earlier observers as Waldeyer and
Langhans traced certain mammary carcinomas to the acinar epithelium,
minute distinctions were not at first attempted between intralobular ducts
and acini. In 1865 Cornil described in detail the cancerous transformation
of acinar epithelium and his views were elaborated by Cornil and Ranvier

EPITHELIAL AND OTHER TUMORS OF THE BREAST

503

and lately by Cornil in his work on tumors of the breast. Many of the
structures interpreted by Cornil as demonstrating the acinar origin are of
somewhat uncertain significance and, asLecene andLenormant conclude, may
equally well be regarded as the invasion of acini by tumor-cells from other
sources. In the previous discussion of the histogenesis of duct carcinoma
it has been pointed out that the acini often contribute to the origin of
tumors which are chiefly derived from the ducts. Such tumors are here
classified with duct carcinoma.

FIG. 205. — Mammary cancer. Large and small alveolar carcinoma. Sweat gland type.

There are, however, mammary carcinomas which are derived chiefly or
exclusively from the acinar epithelium and such growths may be separated
from the duct carcinomas and included in the present group. They occur
under several different conditions but their total number is distinctly less
than that of the duct carcinomas. Acinar carcinoma in this restricted sense
develops in the malignant transformation of fibro-adenoma, it occurs in
rare cases of small alveolar carcinoma, and it produces a type of fibre-

504 N EOF LA STIC DISEASES

carcinoma. These tumors are characterized in general by a diffuse growth
and lack of encapsulation, by absence of the specific gross features of many
duct cancers, by a structure in which small alveoli predominate, while the
cells are usually small, and lack the pavement form and clear cytoplasm
of the duct epithelium. Rarely they suffer mucoid degeneration of the
stroma.

(a) Acinar Carcinoma Following Fibro-adenoma. — While the malignant
transformation of intracystic adenoma is frequently observed and forms a
well-defined group of mammary adenocarcinomas, the development of a
malignant epithelial tumor from fibro-adenoma is rare. Diffuse adeno-
matous hypertrophy of the breast is said to have terminated in adenocarci-
aoma in cases described by Billroth and by Aitken.

The common fibro-adenoma appears to have developed carcinoma in a
few authentic instances. Birch-Hirschfeld regarded the transformation as
not infrequent, but specific and detailed reports are rare. Langhans de-
scribed a bilobed tumor, one portion of which was fibro-adenoma, and the
other scirrhus cancer. Elsasser studied two large fibro-adenomas with small
cysts and single well-defined masses of carcinoma. One of the tumors had
the structure of small alveolar acinar carcinoma, the other was very vascular,
pigmented, the stroma mucinous and both ducts and acini contributed to
the growth. J. Miiller describes multiple areas of carcinoma in a fibro-
adenoma. Many new acini filled with atypical cells and diffuse invasion
of the connective tissue appeared in these foci. Kuru described a large
elastic tumor, 14 X 9 cm., in one portion of which was a hard area. Here
the alveoli were much increased in number and filled with atypical cells
giving the appearance of carcinoma medullare solidum. This observation
does not support Borst's view that the carcinoma develops not from the
fibro-adenoma but from another misplaced embryonal tissue mass. I have
encountered several moderately malignant mammary carcinomas which
appeared to have been derived from fibro-adenomas. They contained
considerable cellular connective tissue and many small alveoli, with or
without lumen, lined by atypical cuboidal epithelium. In a recent case the
tumor had the gross appearance of an encapsulated fibroma but with fatty
points of carcinomatous epithelium. In most of these tumors the structure
suggests an acinar origin and this origin is accepted by the authors, but in
some both ducts and acini appear to have been involved. The usual history
indicates that a slowly growing fibro-adenoma existed for some years and
eventually grew much more rapidly with the onset of malignant changes.
The malignancy has been moderate.

(b) Primary Acinar Carcinoma. — -Although Cornil and others have traced
the development of many common mammary cancers to the acinar epithe-
lium, reasons have been advanced to show that the majority of the tubular
and small alveolar tumors are forms of duct cancer or are derived chiefly
from the ducts, while the acini are subsequently invaded by the tumor-cells or
contribute only secondarily or to a slight degree to the neoplasm. The
present group includes tumors of a peculiar and specific histology which
is rarely observed.

In one form this tumor is partly circumscribed, rather soft, vascular,
and solid. The structure presents a very large number of extremely small
cell groups or acini lined by small atypical epithelium.

In another form which Cornil has described there is an extensive mul-
tiplication of the acini in rather well-defined lobules. The lumen is long
retained but the cells are small cuboidal and atypical and a disordered growth
may extend beyond the lobules. The structure somewhat resembles the

EPITHELIAL AXD OTHER TUMORS OF THE BREAST 505

lactating breast. No signs of proliferation of duct epithelium are observed.
Rarely the cells are extremely small, the acini imperfectly formed, and the
structure resembles an embryonal alveolar sarcoma.

All these tumors show limited malignancy especially in the early stages,
but when fully established they invade the lymph-nodes and pursue the
usual course of advanced carcinoma.

C. Fibrous Acinar Carcinoma. — -In some cases of productive mastitis
and possibly in otherwise unaltered breasts the acinar epithelium may
give rise to a malignant form of scirrhus or fibrocarcinoma. The structure
is highly characteristic. About the unaltered larger and the intralobular
ducts the acini become increased in number and break up into many small
groups of atypical cells with hyperchromatic nuclei. The connective tissue
is much increased and soon becomes fibrous while the tumor cells are com-
pressed into narrow rows or small groups. Many cases of primary scirrhus
cancer develop in this manner. The process is fully malignant.

Modes of Extension. — i. In the Breast. — Extension in the mammary
parenchyma must be interpreted in some cases as a local evolution of the
tumor; in other cases as a local dissemination. Some acinar and many duct
cancers arising at one focus gradually exend over adjoining areas by a gradual
transformation of normal duct and acinar epithelium into neoplastic cells.
The whole organ may thus be found to be cancerous while only slightly
increased in size. Long segments of ducts may show many grades of epithe-
lial proliferation without filling of the lumen by growth from a distance.
Extension through the ducts also occurs in several forms of the disease but
not to the extent observed in the first-named process (Nadal). Perforation
of ducts by cells traveling in lymphatics has been demonstrated by Gold-
mann. The chief mode of extension is undoubtedly through the lymp atics
of the breast, by cells which have broken into lymph-spaces and artificial
clefts, and this method is almost exclusively followed by highly malignant
tumors, fibrocarcinoma, acinar carcinoma, and adenocarcinoma. The
stage of growth at which extension begins as well as the early paths pursued
vary widely with the character of the growth, which is therefore the chief
index of malignancy. At one extreme stands the encapsulated adenocarci-
noma, at the other the locally invasive forms of duct carcinoma.

Rapid local extension may be accompanied by signs of inflammation
as in the mastitis carcinomatosa of pregnancy. On the other hand the
whole organ may be invaded without attracting the patient's attention.

The effects of local extension are usually cicatricial changes in the affected
tissue, which is the most reliable sign of the presence of carcinoma, or increase
in the size of the part, which may be local or diffuse. Handley attributes the
effects largely to a sclerosing perilymphangitis which follows the permeation
through lymphatics, and to this condition he attributes the retraction of the
nipple and fixation of the skin. There is also the desmoplastic property of
the cancer process which is not connected with lymphangitis and which pro-
duces cicatrizing effects beyond the zone of invasion.

The condition of the unaffected portions of the breast varies widely
but is almost never normal. The most distant portions usually show diffuse
or cystic mastitis with periacinar infiltration, and overnutrition or prolifera-
tion of epithelium (Waldeyer, Leopold). Very small tumors beneath
the nipple or in any segment may involve all the breast tissue that can
be found, suggesting either a congenital hypoplasia or an extreme grade
of involution. On the other hand, outlying lobes not previously noticeable
may become indurated, as the sternal prolongation of Rieffel, the axillary
lobe of Kermisson, and the xiphoid appendix of Zocher and Hennig. Each of

506

NEOPLASTIC DISEASES

these lobes may be the seat of carcinoma. In some cases I have lound tumors
originating in these lobes atypical in structure and relatively malignant.
2. Invasion of Skin. — The chief mode of extension to the skin is by way
of the subpapillary lymphatic plexus from the periductal lymphatics. Hence
extensive cutaneous cancer of the breast is observed in central duct cancers
which early reach the nipple. In such cases the derma is infiltrated by
nodules and masses, discrete or diffuse, encroaching more and more upon the
subcutaneous fat tissue. The area of skin thus involved may be much
wider than the underlying tumor. Many of the widespread cancers 'en
cuirasse' involving the skin of the entire thorax originate in this way. Very
extensive pustular and ulcerating lesions of the skin involving much of the
trunk are described by Handley as illustrating an extreme grade of lymphatic
permeation, not through the dermal, but by way of the deep aponeurotic
plexus.

FIG. 206. — Mammary cancer. Pibrocarcinoma. Reduction in size of breast; retraction
and elevation of nipple; retraction of skin about nipple; invasion of axillary and supracla-
vicular nodes.

A second mode of skin invasion is through the lymphatics of Cooper's
ligaments which join the subcutaneous lymphatics from the outer surface of
the breast. These ligaments connect outlying tooth-like projections of gland
tissue with the derma and are markedly developed in many subjects (Stiles).
Invasion of this type causes dimpling, retraction, corrugation and fixation
of the skin, without marked thickening.

A third mode of invasion of the skin consists in the destruction of the
epidermis by carcinoma. This process may begin at the nipple by a con-
tinuation of the lesion in the ducts as in Paget's disease. Or extensions
from below may traverse the derma and lead to erosion and ulceration of
the epidermis. Early perforation and extensive ulceration of a fungating
type belong to the adenocarcinomas.

Active superficial extension through dermal lymphatics may be accom-

EPITHELIAL AND OTHER TUMORS OF THE BREAST 507

panied by hyperemia and reddening of the skin. Rarely a vesicular erup-
tion accompanies the erythema. It has been attributed to dilatation of the
subpapillary lymphatics.

Cancer en cmrasse is a term applied by Velpeau to a remarkably extensive
cancerous invasion and thickening of the skin and subcutaneous tissues.
He described the condition as involving the thorax, neck, arms, and trunk
down to the umbilicus, the skin being greatly thickened, very hard, and over
the chest thickly sown with scirrhus ulcers and nodules. The rigidity of the
tissue greatly interfered with movement of the limbs and with respiration.
Erichsen describes also a brownish discoloration, formation of desquamating

FIG. 207. — General plan of cervical and axillary lymphatic system. {After Bonamy and

Beau.)

crusts resembling the bark of a tree, but without ulceration. Handley ap-
plies the term to a condition of elephantiasis best seen in cases of extensive
edema of the arm in which there is no definite carcinomatous invasion and he
interprets the process as the result of perilymphatic fibrosis in the deep f ascial
plexus. In many cases, however, there is diffuse cancerous infiltration from
the epidermis to and even through the chest wall. Simple edema or elephan-
tiasis may precede or accompany the cancerous process.

Dissemination. — Lymphatics of the Breast. — The knowledge of the impor-
tant lymphatics of the breast in relation to cancer is based on anatomical
studies of Sappey, Gerota, Grossman, Bartels, and others, and the clinical

508 NEOPLASTIC DISEASES

and pathological observations of Heidenham, Oelsner, Stiles, Handley and
others.

The subpapillary plexus is a rich network encircling the dermal papillae and is par-
ticularly well developed at the areola. It is limited at the level of junction of the superficial
and middle thirds of the derma. P'rom this plexus vessels run vertically communicating
with those of the breast, over the organ, and with the deep fascial plexus elsewhere.

The fascial plexus lies just below the subcutaneous fat and is the main channel of dis-
semination of cancer. This entire plexus is divisible into three thoracic regions, by the
median line, the clavicles, and a line running through the umbilicus, along which the main
trunks are interrupted by five branches capable of arresting cell emboli (Handley).

Yet Oelsner found in two of nine cases large trunks in the fascial plexus connecting the
mammary region with the opposite axillary nodes. Tumors of the internal segment of the
breast are in the most favorable location for extension to the opposite axillary nodes, as in
Volkmann's case (Billroth). Riefel found that mercury injected into the skin of this
quadrant passed into the opposite axillary nodes. Such crossed metastases are rare in
early cases (i per cent.) but more frequent in advanced cases (7 per cent.) (Handley),
while at autopsy Williams observed them in 10 of 44 cases.

The lymphatics draining the breast belong in this system. Fine lymph-spaces are
found in the intralobular connective tissue but the first definite vessels or sinuses demon-
strable by injection encircle the lobules (Waldeyer). They unite to form the main efferent
trunks which pass in several directions.

(a) Axillary trunks, usually two, pass from the outer upper and under segments, along
the border of the pectoralis major to the axillary nodes. One or two nodes, Sorgius'
group, may be interposed at the third digitation of the serratus muscle. A paramammary
trunk and node may also exist at the edge of the pectoral in the anterior axillary line, at
the fourth intercostal space.

The axillary trunks are the chief channel of dissemination. They are especially in-
volved from tumors in the upper outer quadrant of the breast, which is the most frequent
location of carcinoma, and they are commonly invaded by all tumors which have extended
through the breast tissue.

They are reached not only by the main axillary trunks but through anastomoses with
the subpectoral and infraclavicular groups which drain the intermuscular trunks passing
from the under surface of the breast through the pectoral muscle (Hyrtl, Grossmann.)
By the latter route the nodes at the extreme apex of the axilla may be involved while the
lower superficial axillary nodes escape (Stiles). Deep axillary nodes lie along the external
mammary artery and the nerve of the serratus magnus, and these connect freely with the
humeral chain accompanying the axillary vein and with the subscapular nodes. These
three groups are frequently the seat of recurrences.

The number and position of the axillary nodes are subject to variations. All stages of
the development of new nodes in cases of mammary cancer are described by Fage. The
number varies also with the physiological state of the breast. On the other hand fat in-
vasion and atrophy of the nodes is frequently observed and influences the spread of the
disease. Those usually present may be grouped as follows: (i) Pectoral group, on inner
wall of thorax, in angle between pectoral muscles and serratus magnus, draining breast and
front of chest; (2) humeral group, lying on axillary vessels and draining the arm. The
highest of these (subclavian) lie in Mohrenheim's space behind the costocoracoid mem-
brane; (3) subscapular group along subscapular vessels on the posterior wall of the
axilla.

The close apposition of many of these nodes to veins and nerves favors early invasion of
the lumen of veins and the sheaths of nerves. It is chiefly from such secondary foci that
the lumen of veins is reached in mammary carcinoma. The significance of this event in
the generalization of the disease is not clear, but it does not always lead to immediate
widespread metastases. The sheaths of nerve-trunks are readily invaded, with pain and
degeneration of fibers, and within the lamellar sheaths tumor-cells may permeate long
distances (Mousseau).

(b) Intermuscular trunks pass from the under-surface of the breast in the pectoral fascia
and over and through the pectoral muscle leading to nodes lying between the pectoralis
major and minor or to infraclavicular nodes. Between the axillary and infraclavicular
nodes there are limited communications, but between the infra- and supraclavicular
nodes the connections are free so that both groups are usually involved together. Ex-
ceptions in which the nodes above the clavicle are involved, while those below are free,
Grossmann refers to extension from the axillary nodes by way of the brachial lymph-
plexus. Since the brachial plexus often communicates with the cervical vessels, the cervical
and supraclavicular nodes are often involved together. In these cases a cancerous node^of
the supraclavicular group is often found at the inner end of the clavicle in close contact
with the thoracic duct which is easily ruptured on removal of the node.

EPITHELIAL AND OTHER TUMORS OF THE BREAST 509

(c) Intercostal lymphatics pass from the inner and under segments of the breast through
the pectoralis and intercostal muscles to the sternal nodes lying behind the sternum in the
parasternal line. Stiles found these vessels invaded by carcinoma, and Oelsner was able
to inject them in the first and fourth intercostal spaces. Extensions also pass into the
thorax along the intercostal nerves.

The importance of the intermuscular trunks in the dissemination of carcinoma was
pointed out by Heidenhain and confirmed by Rotter, Grossmann and others and forms the
ground for excision of the pectoral muscle. Rotter in 15 of 33 operable cases, several of
which were early, and only five adherent to the muscle, found invaded lymph-nodes beneath
the pectoralis major. The remarkably close apposition of the breast to the pectoral muscle,
especially in cases of chronic mastitis, facilitates early invasion of these deep trunks.
Moreover Heidenhain found islands of gland tissue within the muscle. Yet actual in-
vasion of the muscle is not frequent. Heidenhain who found the pectoral fascia involved in
1 2 of 1 8 cases, observed growth i mm. within the muscle only once. Hence many operators
deem it sufficient to remove the pectoral fascia without sacrificing the muscle (Van verts).
Invasion of the pectoral fascia occurs without fixation of the breast, but when the organ is
adherent to the muscle the latter is usually invaded by fine nodules or diffuse cicatrizing
carcinoma. In advanced cases such invasion of the muscle is often observed. Yet
Hardouin found recurrence within the pectoral after operation on an early case, and Cabot
reports recurrence in the pectoral alone after removal of a small central carcinoma. Such
experience must be rare. Xadal describes miliary carcinosis of the pectoral.

It is obvious that no uniform rule can apply to the treatment of the muscle and that
an effort should be made to determine its condition from all the data in the case. Since
the subpectoral nodes are involved in some comparatively early cases and the muscle tissue
usually escapes even in advanced conditions, the attack should be on the nodes and fascia
rather than on the muscle. The question of continuous permeation through the muscle
must also be considered, but is rarely demonstrated.

In a recent study of the breasts of 100 infants up to two and one-half years Mornard
finds several types of lymphatic distribution:

1. In 25 per cent, of cases the lymphatics carrying off methylene-blue injected into the
breast pass along the lower border of pectoralis major, under that muscle to central axillary
trunks, meeting nodes on axillary vein which communicate readily with subclavicular
nodes.

2. In 12 per cent, of cases a trunk passes from the above to humeral nodes at the in-
sertion of the tendon of the pectoralis.

3. In 54 per cent, of cases there is a double set of axillary trunks, (a) Same as above.
(b) Superior external trunk passes beneath pectoralis minor near its costal insertion, to
subclavicular nodes. They do not penetrate the muscle.

4. The above main trunks may pass between the pectoralis major and minor.

5. Three cases showed a deep trunk passing beneath muscles directly to supraclavicular
nodes.

6. In 10 per cent, of cases the injection passed from the inner quadrant along the
internal mammary artery reaching nodes in second or third interspace.

In no case were any lymphatics found perforating muscle.

Generalization. — After reaching the axillary nodes and the muscular
aponeuroses, mammary cancer usually becomes generalized and nearly any
tissue in the body may become involved. The location and course of the
metastases present some of the most remarkable features of the disease, which
have called for very searching analysis.

Gross, from 423 autopsies, placed the organs in the frequency of involve-
ment in the order: pleura, 50.9, per cent; lungs, 49.9; liver, 48.6 ;bones, 20.5,
brain, 9.4; ovary, 8; opposite breast. 7.8; dura mater, 5.9; kidneys, retro-
peritoneal nodes and uterus, 5.7 to 5.2, other organs, less than 5 per cent.
Pearce Gould in 128 autopsies found the nodes involved in 115, the liver in
55, the lungs excluding pleura in 28. Williams, also excluding pleural ex-
tensions, finds the liver more frequently invaded than the lungs, but the
grounds for such exclusion may be questioned. In 2534 mammary cases
collected from Gross, Colwell, Paget, Handley, Gould, and Torok, the liver
was invaded in 928, or 36.6 per cent. Torok and Wittelshofer, finding in
366 autopsies 191 free from enlarged nodes, among which 62 per cent, had
metastases, concluded that failure of axillary invasion is no guarantee against
internal metastases. Yet they did not examine all the nodes microscopically.

510 NEOPLASTIC DISEASES

Handley reports two cases of abdominal metastases without axillary
invasion.

The pleura is invaded by (i) fine lymphatics which pass from the
pectoral fascia straight through to the subpleural lymphatics and (2) from
the sternal and anterior or deep mediastinal nodes. The latter route is
uncommon, as Torok and Wittelshofer in 366 autopsies found these nodes
invaded in only 6.5 per cent. Occasionally cancerous, subclavian, supra-
clavicular, or bronchial nodes invade the pleura at adjacent points. The
first effect is a permeation through the parietal and later the visceral lym-
phatics which may be outlined with remarkable delicacy. A serous or bloody
pleurisy usually follows. Breaking into the pleural cavity the cells gravitate
below, cause thick adhesions, and rarely perforate the thickened diaphragm.
Handley observed polypoid pleural tumors. He estimates the frequency
of pleural invasion at 38 per cent., and reports three cases in which an ad-
herent pleura of the side of the growth escaped while the other pleura was
non-adherent but cancerous.

The lungs are reached superficially from the pleural lymphatics, while
from the bronchial nodes extensions pass along the lymphatics of the blood-
vessels. Extension to lungs through the blood-vessels is rare.

The importance of extensions along the muscular aponeuroses has been
strongly emphasized by Handley.

By means of vertical gross sections of the skin and muscles hardened in Orth's fluid,
dehydrated and cleared in cedar oil, he was able to trace lymphatic invasion with unusual
success. He finds that mammary cancer travels by continuous permeation chiefly in
the vessels of the muscular aponeuroses, and extends not only over the pectorals but over
the serratus magnus, obliques, rectus, below the xiphoid, and across the median line,
covering. an oval area 25 cm. in diameter. Approaching the center of this area and the
main tumor the underlying muscles and overlying skin become more and more involved.
By the same methods he has concluded that invasion of the peritoneum from the epigastric
aponeuroses by way of the parietes or the falciform ligament of the liver is of frequent
occurrence (44 per cent.). Thus in 422 autopsies the abdominal organs were involved and
the lungs were free in 53, indicating that the abdominal extensions did not pass through the
thorax. In three cases by microscopical sections he traced peritoneal invasion through the
rectus muscle and into the falciform ligament and liver.

Metastases in humerus and femur he also brings in relation to the growth in the aponeu-
roses since both humerus and femur appear to be invaded at the insertions of tendons and
aponeuroses. All the very wide extensions in the subcutaneous tissue of the trunk, which
rarely pass beyond elbow and knee, are most readily traced to the same route.

The conclusions of Handley favor wide excision of the aponeuroses rather
than of the skin, and have greatly influenced surgical procedure. Gerota,
1897, in a subject of recurrent mammary carcinoma with invasion of epigas-
tric and inguinal nodes was able to inject the lymphatics from the breast
along the superior and inferior epigastric arteries to the inguinal nodes. He
assumed that the recurrent tumor had widened these vessels by disturbing
the normal lymph flow. Stiles (1899) points out that the xiphoid is only 2^
cm. from the inferior border of the breast, less than the distance to the medias-
tinal nodes, and that here only a thin fibrous layer rich in lymphatics sepa-
rates the mammary fat tissue from the subperitoneal fat tissue and the sus-
pensory ligament of the liver.

Retroperitoneal, adrenal, renal, lumbar, and spinal extensions Handley
traces from a preexisting pleural invasion with growth downward along the
diaphragmatic crura. Yet in six cases there was retroperitoneal invasion
with the thorax free.

The bones most frequently involved are the sternum and ribs, femur,
vertebral column, cranium, humerus and clavicle. The humerus is invaded
usually at the junction of the upper and middle thirds, the femur in its su-

EPITHELIAL AXD OTHER TUMORS OF THE BREAST 511

perior third, where spontaneous fractures occur. Williams collected 533
cases of which the cranium was invaded in 36, the vertebrae in 12, the femur
and humerus each 8. J^-ray examinations are considerably increasing these
proportions. Kaufmann in 63 autopsies found 33 (53.3 per cent.) with bone
metastases. The osseous invasion is sometimes very widespread and about
14 per cent. (Kaufmann) show osteoplastic changes.

Peritoneal invasion occurs chiefly through the epigastric region, through
the crura of the diaphragm and rarely by the blood-stream. Epigastric
infection alone was demonstrated in at least 12 per cent, of Handley's cases,
combined with thoracic infection in 37 per cent, of early and 46 per cent, of
late cases. If it does not occur early it seldom develops at all. The event is
often indicated by epigastric pain and tenderness. The first effect is usually
extension to the liver, which yields superficial implantations beginning
at the falciform ligament, or involvement of the portal nodes, with subsequent
central invasion of the liver by retrograde growth. Handley describes
efferent lymphatics leading from portal nodes through falciform ligament and
diaphragm, thence between pericardium and chest wall, connecting with
internal mammary lymphatics.

The hepatic lesions vary greatly, from a single nodule to complete trans-
formation of the organ into cellular or fibrous carcinoma. During the prog-
ress of this lesion primary or superficial tumors often regress. The liver may
be the only abdominal organ involved, as in 36 cases of Handley's series, but
frequently the peritoneum itself, the omentum, intestines, and pelvic organs
are invaded. The subserous lymphatics may be injected over a large area
but soon there is rupture into the cavity and transportation of cells to the
surfaces of viscera. A low grade of peritonitis may be established, with
opacity, thickening, and adhesions and serous or cnylous exudates. The
omentum may be contracted to a small epigastric mass. Gravitation of
cells to the pelvis leads to adhesions of all pelvic organs and invasion of
ovary, tubes, uterus, and vaginal vault. The ovaries are a favorable nidus,
especially before the menopause, and the lesion here presents the structure
of Krunkenberg's tumor, or of fibrocarcinoma.

Diaphrenic invasion of the abdomen occurs only in the late stages of
thoracic disease. It passes through the substance of the diaphragm with
invasion of the liver, or through the crura, when the further course more
often leads to the retroperitoneal nodes and kidneys.

Cerebral metastases occur in about 4 per cent, of autopsies. Any portion
of the brain may be chosen, most frequently the cerebellum. Their late
appearance indicates an origin through blood-vessels. The dura and skull may
be affected when the brain is free, suggesting an access by cranial lymphatics.

In a notable group of cases paraplegia develops early in the course of
mammary carcinoma from dural or spinal metastasis. Very remarkable
are the cases of diffuse carcinoma of spinal and cerebral meninges of which
Peabody's report from this laboratory is illustrative. The tumor-cells in
flat strands and groups extend from the cauda to the vertex. Humbert
and Alexieff have collected several cases of this type.

The part played by the blood-vessels in the dissemination of mammary
carcinoma is distinctly less than that of the lymphatics. Invasion of veins
is commonly observed about cancerous lymph-nodes, in the deep fascia and
less often in the breast itself. It becomes a prominent feature in very
cellular and rapid growths with which also the metastases are more wide-
spread. The occurrence of metastases sometimes early, in the brain, spinal
cord, spleen, bone-marrow, and heart-muscle, indicate that intravenous foci
often escape the encapsulation by fibrin and organization described by M. B.

512

N EOF LA STIC DISEASES

Schmidt. Cases of general miliary carcinoma also indicate dissemination
at least in part by the blood-vessels (Petit).

Regressive Phenomena. — Regression in mammary carcinoma is often
observed in the older lesions. Partial or complete atrophy of tumor-cells,
with cicatrization, occurs especially in cutaneous nodules and ulcers when
internal metastases are growing actively. It is commonly assumed that
the lymph-nodes are capable of destroying not only embolic cells, which
may be granted, but even established secondary tumors, an event which
must be held excessively rare or even as yet unproven. Handley accounts
for the discontinuous character of lymphatic permeation by assuming that
perilymphatic nbrosis causes pressure atrophy of tumor-cells in advancing
segments of invaded lymphatics, so that the zone of active growth is ring-

FIG. 208. — Mammary cancer. Alveolar carcinoma invading vein.

shaped rather than disc-shaped. Union of cancerous fractures occurred in
several cases in the Middlesex Hospital series.

A constitutional immunity is the only satisfactory explanation for
the resistance which some subjects exhibit to the progress of a disease,
whose course varies from a few weeks to twenty years. The slow atrophic
scirrhus is the best illustration of a repressed and yet progressive carcinoma.
In Hodenpyl's case in which large superficial tumors disappeared, I found
the liver almost completely replaced by hyaline connective tissue with com-
paratively few active foci in the extremely emaciated body. Gould and
Mackay have reported cases of apparently complete disappearance of
advanced mammary cancer with restoration of health, but histological
studies of the tissues of such subjects are still wanting. Osier records
shrinkage of a spinal metastasis with relief of paraplegia.

EPITHELIAL AND OTHER TUMORS OF THE BREAST 513

Clinical Varieties.- — The clinical course of mammary carcinoma is
influenced by the conditions of origin and the structure of the tumor; by
the age, susceptibility and physiological condition of the patient; and
by many intercurrent factors. Most prominent is the influence of structure
and conditions of origin and most current clinical classifications show a
definite relation to these features. Age has a pronounced influence on
most anatomical varieties. The relatively malignant course of most struc-
tural types of the disease in young subjects is uniformly recognized.
The cellular varieties belong to the early decades, the scirrhus forms to the
late periods. Yet there are many exceptions to this general rule. Cystic
adenocarcinoma and colloid tumors are of relatively late occurrence. In
some old and resistant persons the disease seems to reach a certain limit of
growth. I have observed an apparently stationary large adenocarcinoma
of 10 years' duration in a woman of 80 years who suffered little apparent
inconvenience. The very marked aggravations in the disease produced
by gestation and lactation are commonly observed. Cancer may apparently
arise during gestation and prove fatal before its termination. While there
are doubtless marked variations in the susceptibility of patients to the
progress of the disease the nature of this constitutional element is as obscure
here as elsewhere.

A possible reflex influence of the ovaries led Beatson to perform ovari-
otomy in two young subjects. The results were disappointing. Lett in 99
inoperable cases saw notable amelioration in 23 per cent., slight change in
13 per cent. Rarely, as in the cases of Quinard and of Reynes, distinct
inhibition appears to follow castration.

More or less striking clinical peculiarities have led to the recognition
of several clinical varieties of mammary cancer.

(1) Cystadenocarcinoma corresponds in part to a specific anatomical
type arising in mammary cysts or large ducts. It occurs after the chief
age of incidence and in many elderly women who have nursed children
(Bowlby, Delbet). A circumscribed tumor appears in the center, less
often in the periphery, of the gland. It is preceded by an intermittent, serous
or bloody discharge from the nipple, which may temporarily reduce the size
of the tumor. A definite tumor may be difficult to demonstrate, especially
in fat subjects, or the growths may be multiple. The progress is slow and
growth may be inhibited for long periods. Invasion of lymphatics and
nodes is delayed until the tumor capsule is perforated, or the breast invaded
or the skin eroded. As previously pointed out there are many grades of
malignancy observed in the late stages and atypical forms of this tumor,
but many of them are comparatively benign, and they furnish the highest
proportion of successful extirpations, as well as the most difficult field for
properly adjusted surgical treatment.

(2) Medullary or encephaloid is the term commonly applied to the
average bulky, soft, cellular tumor which pursues the course of very malignant
mammary cancer. The majority of these tumors are duct carcinomas, but
the clinical group includes also cellular acinar carcinomas, malignant adeno-
carcinomas, and pseudosarcomas. They are characterized by the occurrence
at relatively early age, by their considerable or large bulk, fungating form,
rapid progress, early invasion of skin, muscle and lymph-nodes, extensive
dissemination, and early cachexia. Ulceration, necrosis, hemorrhage and
gangrene may be prominent. Yet some of them by attracting attention
early may be cured by radical operation, so that the formidable appearance
is no bar to active measures.

(3) Acute Carcinosis. — Very rapid progress with local inflammatory

514

NEOPLA S Tl C DISK A SES

signs, fever, and early intoxication are observed in a remarkable group
of cases occurring at early ages and notably in gestation. The process
begins actively and one or both breasts rapidly increase in size without
localized tumor formation. There is well-marked hyperemia, local heat,
and slight tenderness. The consistence is uniformly firm, but the tissues
about the breast or over the chest and back may be edematous. The
lymph-nodes are swollen from the first and invaded probably very early.
After reaching a certain stage the subsequent course may vary. Some
cases are rapidly fatal with generalization or pneumonia, as in Billroth's,
six weeks; Aitken's, 38 days(?); and Schmidt's, three months. The

FIG. 209. — Disseminating carcinoma of breast. Extensive invasion of skin reaching beyond
line of incision on both sides. Miliary carcinoma of pectoral muscle.

shortest duration I have observed was four months. Others are subacute
but succumb within a year with very widespread lymphatic and visceral
metastases. A patient of Delbet's survived amputation first of one breast
then of the other for three years. In two cases I found this clinical course
with large-cell duct carcinoma, in one with a tumor composed of diffuse
hyperchromatic round and polyhedral cells.

(4) Scirrhus carcinoma is an ill-defined anatomical variety but clinically
quite characteristic. The majority of mammary cancers are distinctly
fibrous in much of their growth, but the typical scirrhus is a small and very

EPITHELIAL AND OTHER TUMORS OF THE BREAST 515

hard acellular process which usually fails to enlarge the organ and often
results in atrophy and shrinkage. It is a form frequently assumed by local
recurrences. Atrophic scirrhus occurred in 7.9 per cent, of Gross' series,
and chiefly but not always in elderly subjects. The breast is usually flat,
hard, and nodular. The skin is commonly adherent, the nipple retracted,
and the breast becomes fixed to the chest. Superficial erosion of the epider-
mis or ulceration may occur. The progress is very slow and may be pro-
longed 10 or even 20 years. Yet the typical small scirrhus carcinoma
is also notable for the extensive dissemination in lymph-nodes and distant
organs which occurs in some cases. Hence the breast always requires careful
examination in cases of visceral carcinoma of uncertain origin.

The skin may become the seat of very numerous secondary nodules or
small ulcerating tumors derived from a scirrhus tumor in the breast. In a
notable case of Handley's, scores of nodular tumors and excavated ulcers
covered the skin from chin to navel, illustrating the effects of wide dissemina-
tion in the deep fascia with multiple excursions to the derma through the
vertical lymphatics. These cases were described by Velpeau as "scirrhus
pustuleux." Moderate grades of the cutaneous eruption are relatively
common in recurrent cases. The nodules may disappear at one point while
developing at another.

Cancer en cuirasse develops in the late stages of cases in which the early
history is variable, but some cases follow primary scirrhus carcinoma and
maintain this character throughout. The pronounced cases show deep
thickening and wooden induration, eroded spots, ulcerated areas, reddish
and brownish discoloration of the skin over a wide area, including arm,
neck, chest, and even encircling the trunk, with pain, elephantiasis, and
embarrassment of respiration. The typical condition is rare, and many
authors have described imperfect copies of the startling pictures this condi-
tion may present.

5. Fibrocarcinoma following chronic mastitis constitutes one of the
most definite of the clinical entities in mammary cancer. After a variable
period of chronic induration of one or both breasts, which often escapes the
attention of the patient, one or more areas of the organ become very hard,
the skin becomes dimpled and adherent, the nipple often retracted. A
definite tumor being difficult to define, the suspicion of carcinoma is delayed,
the growth slowly increases, often pain is added, the breast becomes adherent
to the muscle and the axillary nodes enlarge. The progress may be very
slow and usually extends over several months before its serious nature is
realized, or it may develop actively while remaining hard and fibrous. The
familiar picture of fibrocarcinoma without marked tumor formation is thus
unfolded.

It is especially in this group of cases that errors of diagnosis, expectant
treatment, and indecision of patient and physician prove costly. Many
of these cases recur after early operation and when they have infiltrated the
breast or reached the lymph-nodes they form one of the least favorable for
successful treatment. Very small fibrocarcinomas occur which cannot be
definitely located by palpation, but which early give rise to well-marked tu-
mors in the axillary nodes. Occasionally the dissection of the amputated
breast has been pronounced negative, but subsequent recurrence in the
lymph-nodes proves that a carcinoma has been overlooked.

(6) Mucoid carcinoma is a relatively benign form which has been discussed
in the anatomical section.

When the different subvarieties of mammary cancer have been sufficiently
distinguished little remains of the so-called banal form of the disease. Such

516

N EOF LAST 1C DISEASES

FIG. 210. — Mammary carcinoma arising on chronic mastitis and involving nipple and

ducts.

FIG. 211. — Chronic diffuse productive mastitis, with many small cysts, and a single nodule

of carcinoma.

EPITHELIAL AXD OTHER TUMORS OF THE BREAST

517

a result is desirable owing to the individual character of the various clinical
forms of this protean malady.

The simple diagnosis, "mammary cancer," must be regarded as inade-
quate.

Mammary Carcinoma in Males.— Since the thesis of Hourteloup, 1872,
carcinoma in the male breast has attracted much attention. The estimates
of its frequency have varied from 0.86 per cent, of all mammary cancers (Wil-
liams) to 6 per cent, by La Fogue. Of 269 tumors of the male breast 244
were carcinoma and three sarcoma (Schuchardt) . Contributing factors
observed include repeated trauma, zona, chronic eczema, and attempts at
nursing (Baumgartner, Lit.). It occurs at slightly later age than in women
but has been observed at 20 years. Poirier saw affection of both breasts.
Unusual development and activity of the breast are predisposing conditions.

FIG. 212. — Cicatrizing carcinoma in an atrophic breast. Bulky metastasis in axillary

lymph-node.

Owing to the prominence of the large canals, duct cancer is relatively fre^-
quent, and the scirrhus type is often followed, but cellular tumors are not
uncommon. Williams classified 89 of 100 cases as of acinar or alveolar
structure. Chronic inflammatory processes may long precede the develop-
ment of the tumor which is slow and insidious. When fully established the
process is less malignant than in women, the growth is persistent, many of
the features of ordinary mammary cancer are observed, and local or general
metastases may develop. Of 16 fatal cases Williams found the average
duration 61 months, in 13 unoperated cases, 38 months. Recurrences were
notably early, average period 9.7 months.

Development of Surgical Treatment.— Moore introduced the modern
operation for mammary cancer in 1867 when he contended that recurrences
were due not to blood infection but to incomplete extirpation of the tumor.
He recommended a general removal of the breast, skin, fat, axillary nodes,

518 NEOPLASTIC DISEASES

and pectoral muscle. He even undermined the skin flaps. His views were
supported by Lister and Banks. Gross adduced convincing statistics show-
ing the necessity of removing the axillary nodes in every case and he excised
the skin widely, looking for aberrant lobules of the gland, and portions of
the pectoral muscle if suspicious. The free excision of underlying muscle
followed Heidenhain's demonstration of the invasion of deep intermuscular
lymphatics. Stiles limited the excision of skin, enlarged the ablation of
mammary fat tissue, and excised all underlying muscle.

Halsted excised the sternal half of the pectoral and divided the clavicular
portion and pectoralis minor in order to expose the upper axilla. He had
three successful results after removal of supraclavicular nodes. Handley
limits the excision of skin, greatly extends that of the muscles and aponeu-
roses to a circle 10 inches in diameter, and clears the epigastric space.

Many other surgeons in England, France, Germany and America have
contributed observations influencing the present accepted form of the opera-
tion. Statistical reports of the improving results obtained have shown that
the wider the operative field the better the result. The proportion of cases
presenting themselves at the Middlesex Hospital with recurrence fell from
54.5 per cent, in 1858-75 to 13.8 per cent, (plus operative mortality of 1.5
per cent.) after 1894. Survival of recurrent cases after operation decreased
from 34 to 26 months, partly because of the increased scope of cases judged
operable. The same improvement appears in De Page's report of cases well
after three years in different periods: From 1865 to 1875, 9.4 per cent.;
1875 to l885> I0 Per cent.; 1885 to 1895, 33.8 per cent.; 1895 to 1905, 46.5
per cent. Walther's statistics from Paris hospitals gave 52 per cent, of cures
after three years.

The effects of late recurrences are illustrated in Le Dentu's table showing
47.45 per cent, well after 4 years, but only 6.77 per cent, known to survive after
19 years. Many others could not be traced.

Surgical statistics may be made more significant by more detailed atten-
tion to the gross anatomy and microscopical structure of the tumor. Statis-
tical studies include encapsulated adenocarcinoma, miniature cancers or
even precancerous lesions, and early circumscribed duct cancers, all of which
may be eradicated by ablation of the breast, along with the highly malig-
nant forms of the disease. It is possible to select cases which will give 100
per cent, of recoveries and others which will invariably prove fatal. Too
often the radical operation is performed on comparatively innocent growths
and the good result attributed to the sacrifice of tissue. No uniform rule
can guide in the excision of skin when some cases show cutaneous invasion
over a very wide area, others none at all. It would be interesting to know
but is impossible to state how much a constitutional resistance influences
a favorable result after some very wide excisions. Experimental and, clin-
ical data strongly urge great caution against producing mechanical emboli
in blood- and lymph- vessels by vigorous preparation of the skin and blunt
dissection, especially in those advanced cases subjected to wide excision.

General Prognosis.- — The prognosis in mammary cancer can be estimated
only after consideration of the many factors involved, including the age of the
patient, the duration and extent of the disease, the structural type and posi-
tion of the tumor, and the condition of the patient. According to Handley
the condition is inoperable when there is extensive ulceration of the skin;
with tumors adherent to chest; when axillary nodes are fixed; with edema of
arm; when supraclavicular nodes are involved; when there are signs of dis-
tant metastases; and in acute carcinosis.

The proportion of cases presenting themselves as inoperable was estimated

EPITHELIAL AXD OTHER TUMORS OF THE BREAST

519

by Primrose at 32 per cent., after an average duration of the disease of four-
teen months, and by Deaver at 25 per cent. Before 30 years of age mammary
cancer is extremely fatal, so that some surgeons prefer not to operate during
this period. Schwartzoff reports 15 such cases all rapidly fatal in spite of
early operation, yet Deaver reports three cures in patients under 30 years.
In aged women on the other hand, the disease usually runs a prolonged course,
and according to Deaver many of the patients with well-established cancer
live longer \vith palliative instead of operative treatment. In obese subjects
with much fat invasion of the breast and atrophy of parenchyma, small
tumors very often metastasize early and give disappointing operative results.
The position of the tumor is often of importance. The most favorable
position is at the nipple. Aberrant tumors in axillary, sternal, or xiphoid
prolongations are frequently atypical and anaplastic, and the initial exten-
sions are relatively inaccessible. Small deep-seated tumor-masses may de-
velop on the under surface of the breast, immediately invade the pectoral
fascia or muscle, and soon reach the deep nodes or chest wall.

FIG. 213. — Mammary cancer. Postoperative recurrence.

The duration, extent and structural type of the tumor, are the common
factors influencing the results of operation. They may be taken together in
considering the sources of recurrence.

Recurrences. — Recurrent tumors develop in the skin, in the outlying
lymph-nodes, and in distant organs. In each instance they develop from
undisturbed tumor foci or loose tumor-cells which have escaped removal.
In or under the skin recurrent tumors may arise from aberrant portions of
the breast in axillary, sternal, or epigastric region, of which Williams col-
lected 29 cases. Many incisions supposed to surround the breast really
pass through outlying portions of the organ which are not distinctly aberrant.
L. Heidenhain long ago, and later Stiles, pointed out that all portions of the
breast in carcinoma must be removed and that many recurrences are due to
failure to accomplish this object and to the late development of carcinoma
in such remnants of the organ. Cancer may develop anew in the opposite
breast.

In young subjects recurrences develop earlier (average 2^ months)
than in patients over 65 years (8}-£ months) (Durand). In the malignant

520

N EOF LAST 1C DISEASES

histological forms recurrences are earlier and more frequent than in relatively
benign cases, but the more important influence is the extent of the disease.
Both these rules are amply apparent in operative statistics. Mucoid carci-
noma is notable for the long delay in recurrences. Of 47 recurrences Williams
recorded before 3 months, 4; i year 1752 years 10; 3 years 6; 4 years 2; after
4 years 8. RansohofT collected a series of very late recurrences. Thirty-
seven cases of which 26 were local occurred after 7 years, others at late periods
up to 25 years. Recurrence in brain, spine or liver, alone, after 10 to 13 years
was observed by Bull.

The striking influence on prognosis exerted by the type of carcinoma
is illustrated in Halsted's table.

Cases

Cures

Per cent.

Cancer cysts . .

33 2

Adenocarcinoma
Medullary carcinoma
Circumscribed scirrhus

32
25
28

24
12
I T.

75-o
48.0
46 .4

Small infiltrating scirrhus

1°

35 • 5

Lar(re infiltratin^ scirrhus

•?o ^

Total. . ,

210

42 .4

In this series the neck operation was performed 119 times. Of 44 cases
in which both axillary and supraclavicular nodes were found microscopically
to be involved three were definitely cured. Pilcher reports three cured
cases of this type.

The influence of the extent of the disease was even more notable.

No.

Cured, per cent.

Well 3 years

Axilla and neck negative
Axilla positive, neck negative. . . .
Axilla and neck positive

60
no
40

75-0
24-5

7-5

85
31
10

At the Massachusetts General Hospital, Greenough reports that of 236
cases with palpable axillary nodes only 12 per cent, were cured by operation,
while of 275 similar cases Finsterer reports only (12) 4.3 per cent, cured. I
believe that the last figures represent the average success obtained by surgical
treatment, which means that when a woman presents an established mam-
mary cancer with axillary nodes palpably infected she has about one chance
in 25 of being cured by operation.

In mucoid carcinoma Gaabe found 53.8 per cent, of three year
recoveries.

The influence of improving operative technic is strikingly shown in
De Page's report (1907):

RECURRENCES AFTER OPERATION (DE PAGE)

Local

Lymph-nod

186 15-75

76 o

6 o

1875-85

72 . o

6 2

1885-95
180^-0^.. .

45-5
20 . o

8.4
o. o

Distant

7-5
10. o
19.0
23-0

EPITHELIAL AND OTHER TUMORS OF THE BREAST 521

Many authors have stated their belief that the extent of the disease
rather than the extent of the operation determines the prognosis. It is
regarded as proven that loose tumor-cells may become implanted in the
wound and give rise to recurrent nodules. The implantation experiments
of Bergmann and Hahn, and the occurrence of tumors at the site of injection
of tumor vaccine, favor this view, while the location of nodules exclusively
in the line of incision is highly suggestive. An equally or even more im-
portant source of cutaneous recurrence is the incomplete removal of infected,
cutaneous and deep lymphatics, while the mechanical displacement of tumor-
cells from invaded- in to normal lymphatics is probably rather common. The
persistence of cutaneous recurrences in spite of the best modern technic
seems to justify the use of various adjuvants to surgery, which may destroy
superficial cell groups, and not a few operators claim to secure better results
by re-ray, radium, fulguration, or escharotics, at or soon after operation
(Ochsner, Cabot, Deaver).

Recurrence in the lymph-nodes and muscles is largely under the control
of the operator, and the conditions governing their appearance have been
fully indicated in discussion of the paths of dissemination. It is notable
that this form of dissemination has been reduced to a minimum.

The increased proportion of visceral recurrences has been referred chiefly
to the increased scope of operability, but it seems quite possible that mechan-
ical dissemination of tumor-cells may account for some of the distant recur-
rences. It may be suggested also that the removal of a tumor withdraws
the natural local barriers against it and may leave the system in a less
favorable position to inhibit the growth of vagrant cells. Gay lord (1916)
offers experimental evidence to show that prolonged anesthesia and hemor-
rhage reduce the resistance to cancer. Against such a possibility stands
an apparent increased tenure of life of operative cases even after recurrence.
The average duration of life in untreated cases was placed by Paget at 4
years, by Odekop at 29 months, by Sprengel at 27 months. After operation
Handley s recurrent cases lived an average of 29.6 months and many others
were cured. Reports of Sibley, Baker, Gross and Williams give an average
life in unoperated cases of 34 months, of operated cases 52 months.

The operative mortality was estimated by Delbet, 1898, to average about
5 per cent., but in many clinics it is now much less. De Page reports 2.8
per cent. (1906). M. Richardson lost four patients in 1500 breast operations.

Regarding the significance of these statistics the following comments seem
to the writer permissible.

(1) The figures (four years-27 months) are too divergent to permit accu-
rate conclusions regarding the natural duration of mammary cancer. The
attempt to establish an average duration of this disease should be replaced
by the systematic classification of cases according to the factors known to
influence prognosis. The total duration of life in all forms of this disease is of
no clinical significance.

(2) The comparison of operated and unoperated cases is sophistical.
The choice of operable cases tends to throw into the untreated class the
majority of rapid and unfavorable cases.

(3) Statistics favor the conclusion that operation on the whole shortens
life in recurrent cases, although sometimes rendering it more tolerable.
Handley's recurrent cases lived 29.6 months while in the above series the
duration of life of unoperated cases was 27, 29, 34, and 48 months respectively.
This conclusion is strengthened by theoretical considerations, as well as by
observations on the rapid course of many recurrent cases. It is clearly proven

522 NEOPLASTIC DISEASES

in many instances by the increasing anaplasia exhibited in the structure of
recurrent tumors.

(4) The high proportion of clinical cures from the modern operation has
resulted largely from the earlier recognition of cancer and the inclusion of a
larger number of minute carcinomas or precancerous lesions in the operated
class.

(5) The choice of therapeutic measures should not be made under the
impression that the duration of the untreated disease is 27 months and
that 40 per cent, of operated cases are cured. Since the duration of the dis-
ease may vary from six weeks to 25 years and the favorable results of opera-
tion from o-ioo per cent., the first essential in treatment is accurate diagno-
sis and prognosis of each individual case.

(6) In estimating the economic importance of the surgical treatment
of mammary cancer there must be charged up the cost of acquiring surgical
skill, and the deplorable conditions following local recurrence. There
can be no doubt that operation shortens life and aggravates the terminal
suffering in the great majority of recurrent cases. Most of those who deal
with the great number of these unfortunate patients would welcome a judi-
cious limitation of the scope of operability in this disease.

From clinical and pathological studies I have drawn the impression that
in dealing with mammary cancer surgery meets with more peculiar difficul-
ties and uncertainties than with almost any other form of the disease. The
anatomical types of the disease are so numerous, the variations in clinical
course so wide, the paths of dissemination so free and diverse, the difficulties
of determining the actual conditions so complex, and the sacrifice of tissue so
great, as to render impossible in a majority of cases a reasonably accurate
adjustment of means to ends.

The scope of the operative field having apparently reached a limit, the
chief hope for a reduction in the mortality from mammary carcinoma lies
in its prevention and earlier diagnosis.

Both these objects point to the excision of many breasts before carcinoma
has become established in the clinical sense. The growing tendency to
remove the breast for recognized chronic mastitis or suspected carcinoma,
while probably sacrificing some organs unnecessarily, has justified itself
in the writer's material by securing the early removal of some miniature car-
cinomas, and more precancerous lesions. In this field too much reliance
should not be placed on the examination of resected areas and nodules.
When the condition of the organ becomes sufficiently suspicious to demand
a partial excision for diagnosis it is usually safer to excise the whole breast,
make the diagnosis complete, and remove a source of anxiety or actual danger.

CHAPTER XXVII
CANCER OF UTERUS, VULVA, VAGINA

CANCER OF UTERUS

General Etiology and Classification. — Statistics may be cited to show that
the uterus is first in the list of organs affected by primary cancer. Welch
collected (from the literature) over 31,000 cases of cancer of which 29.5
per cent, were of the uterus and 21.4 per cent, of the stomach. Orth states
that uterine cancer forms 30 per cent, of all those occurring in women, and
Birch-Hirschfeld places it first in order of frequency. The British statis-
tics of Williams gave 38 per cent., 31.4 per cent., and 22.5 per cent, in 1868,
1888, 1900. The U. S. Census, 1911, shows a very marked predominance
of cancer of the stomach and liver over cancer of the female generative organs,
viz.: 17,365 to 6707. The uterus is still probably the most frequent seat of
the disease in women. Kaufmann, dealing with the material of the Basel and
Gottingen institutes, found cancer of the uterus in a smaller proportion,
14.74 per cent, and 15.59 per cent, of the total in both sexes, and Borst places
the uterus fourth in the list of organs. Owing chiefly to better separation of
sarcoma, myoma and cancer of the vagina and ovaries from cancer of the
uterus, the cases of the latter disease have tended to diminish in statistical
observations (Weinberg).

About 10 per cent, of uterine cancers affect the corpus (Koblanck).
R. Williams, however, finds the proportion of corpus carcinoma in clinical
material much lower, while Backer and Blumenfeld found it at autopsy
below 3 per cent.

The frequency of uterine cancer must be referred in general, partly to its
anatomical and physiological characteristics, more especially to its exposure
to various forms of trauma and irritation. Cervical carcinoma is strongly
influenced by childbirths, which average over five in such patients (Gusserow,
Koblanck, Williams). While carcinoma seldom develops in scars, yet re-
peated cervical lacerations disturb the normal structure and functions of
this tissue, interfere with its nutrition and expose its weakened structure
to chronic irritation and inflammation. A chronic endocervicitis precedes
cancer in the great majority of cases (34 out of 48, Polese), and the routine
examination of this tissue reveals abnormalities in the morphology and posi-
tion of the epithelium which constitute precancerous conditions. The most
prominent of these conditions is the cervical erosion, many of which show
suspicious hypertrophy and heterotopia of the lining epithelium. Beckmann
saw the development of carcinoma in an erosion which he had treated for
five years.

For corpus carcinoma the chief definite etiological factor is the associa-
tion with myoma, 10 per cent, of which are combined with carcinoma (Ols-
hausen) . Taussig, in a personal communication from the Mayo clinic, learned
that of 40 cases of corpus carcinoma there were 10 associated with
myomas. Local hyperemia, chronic endometritis and ulceration of the mu-
cosa are frequent concomitants of myoma which favor the development of
carcinoma (Winter, Sutton) . The carcinomas which arise from adenomyoma,

523

524 NEOPLASTIC DISEASES

localized or diffuse, present peculiar anatomical and clinical features which
usually permit of their identification. Genital tuberculosis has been ob-
served with carcinoma in several instances (Koblanck), but as, in Cullen's
cases, the association may be accidental.

Age. — Uterine cancer chiefly affects child-bearing women in the fifth
decade, but occurs from the second to the eighth decades. Cervical cancer
appears rather earlier than disease of the corpus. A peculiar case of carcino-
sarcoma of the cervix in a child of two years is reported by Rosenstern,
and several cases in very young subjects are collected by Engelhorn. Cer-
vical carcinoma in a child of 7 years is described by Glockner.

Two main histological and clinical varieties of uterine carcinoma are
recognized: (i) Squamous-cell carcinoma of the cervix, and (2) glandular
carcinoma of the body. The vaginal portion of the cervix is almost exclu-
sively the seat of epidermoid carcinoma; in the cervical canal the two types
meet and intermingle, while glandular carcinoma, or malignant adenoma,
predominate in the corpus. These relations naturally accord with the struc-
ture of the organ, squamous epithelium lining the portio and extending a
variable distance up the canal; high cylindrical cells of pavement type line
the corrugated surface and gland ducts of the cervical canal; and specific
glandular epithelium covers the endometrium and forms its glands.

Anatomy of Cervical Carcinoma.— The earliest stages of the disease are
seldom recognized grossly. Very small tumors appear in the form of (i)
a hard nodule in the substance of the cervical lip, or (2) a circumscribed
indurated ulcer of portio or cervical canal, or (3) more diffuse low papillary
outgrowths, covering a portion of the lip or canal.

As usually observed the lesion is more advanced and exhibits (i) an
extensive induration and swelling of the cervix; (2) an excavated ulcer, or
(3) extensive papillary or cauliflower outgrowths covering much of the canal
and portio.

Three stages of the progress of the lesion are emphasized by Cullen:
(i) Induration without loss of tissue; (2) disintegration, and (3) excavation.

The established and advanced process varies greatly according to the
predominance of certain of these tendencies. In one group of cases there is
wide superficial extension of the process, and the whole canal and even
portions of the endometrium, the posterior fornix and much of the vagina
are covered by polypoid or cauliflower outgrowths. These may become
bulky and obstruct the canal, causing retention of secretions or filling the
vagina. Ulcerating carcinoma produces wide excavations of tissue in the
cervix and vagina, or completely destroys the cervix, and may perforate
into the bladder or rectum, or both.

Infiltrating carcinoma thickens the cervix, extends along the vagina,
and up the canal into the endometrium, causing obstruction to the canal
with pyometra, firmly fixing the uterus to the parametria, and invading
the bladder and rectum. In some cases the entire uterine mucosa and part
of the wall is replaced by tumor-tissue extending from the cervix, and eventu-
ally becoming excavated.

Ruge and Veit distinguish sharply between cancers of the portio vaginalis
and those of the cervical canal. Their distinctions are anatomical and
clinical. Squamous-cell tumors and adenocarcinoma frequently arise from
both regions. Portio cancer produces marked thickening with indura-
tion of one lip or the whole lower portion of the cervix, while the canal
long remains intact. Cervical tumors involve the canal from the first and
may long spare the portio while extensively thickening the whole length of
the cervix and ultimately excavating it. The portio carcinoma arises super-

CANCER OF THE UTERUS, VULVA, VAGINA

525

ncially and tends to involve the vaginal mucosa and wall, often by a pro-
gressive hypertrophy and cancerous transformation of normal epithelial
papillae. Contact metastases are also claimed to occur. On the other hand
portio carcinoma seldom invades the canal and never beyond the os internum,
while metastases in the endometrium have not been demonstrated.

Cervical carcinoma may be regarded as a true uterine tumor which does
not tend to invade the portio or vagina, although the whole cervix may be
excavated. It readily invades the peritoneum. In a series of cases metas-
tases in the endometrium have been observed (Winter, Lit.), for which several

FIG. 214. — Island of beginning carcinoma in a cervical erosion.

modes of origin are under discussion, including multiple primary growths?
contact implantation, and extension through the lymphatics.

Structure and Histogenesis. — In cervical carcinoma two histological
types of structure appear, epidermoid carcinoma and adenocarcinoma, but
the two types are often combined. The most frequent form presents cords
of pavement epithelium in which neither alveoli, pearls, spine-cells nor
hornincation are demonstrable. Rarely adult acanthoma is observed with
abundance of pearls and much hornincation. These structures usuallv
affect the portio and early ulcerate.

526

N EOF LAST 1C DISEASES

The earliest cervical carcinoma that I have seen consisted of localized
downward growth of hypertrophied papillae in portions of chronic erosions.
Since heterotopia of the epithelium was missing these cases might be desig-
nated as precancerous. In one case a localized indurated patch, i J-^ X i cm.
in the lower cervical canal, was composed of atypical hypertrophied squamous
epithelium with elongated papillae extending to a depth of 25 mm. In
another case a chronic erosion showed early squamous epithelioma of its
edges and beginning neoplastic overgrowth and metaplasia of cylindrical
cells in the gland ducts. Early stages in the development of carcinoma of
the cervix are described by Waldeyer, Ruge and Veit, Cullen, Kermauner,
Stone, and others.

The established tumor is usually composed of columns of transitional
epithelium with cells of large dimensions, polyhedral or rounded, without
a trace of pearl formation or keratosis. Giant-cells are commonly present.
The stroma is usually scanty, vascular, and infiltrated by mononuclear

.".- f •<• ':'\\ <*?t r * iv,vV"J S»Jr /. " '." • » * «

Mm <# $. '•'"" v®

M**>& ,;&*.'', *#z*2'O& fa&%mi

FIG. 215. — Atypical epithelial overgrowth in cervix uteri.

or eosinophile leukocytes. It may be completely wanting in certain areas
so that neighboring columns of cells cohere. Evidently this structure is
produced by the growth of the epithelial layer as a whole, which, in order
to accommodate its enlarged dimensions, becomes variously folded, incurved,
or everted, thus producing a bulky tumor of essentially papillary type.
Lateral outgrowths from the original layer progressively complicate the
picture, but the cells do not early split off in small groups as in acanthoma,
so that lymphatic involvement is relatively late. The presence of free
lying foci of pus surrounded by tumor-cells, and the abundant growth of
blood-vessels in elongated papillae, are structural features resulting from this
mode of growth. From the same point of view Ruge has described these
tumors as carcinoma evertens and carcinoma invertens, the former growing
outward in papillary form, the latter inward, pushing and invading the tissues
before it. This structure produces the majority of the papillary or cauli-
flower, superficial or deep, and widely distributed tumors of the cervix.

CANCER OF THE UTERUS, VULVA, VAGINA

527

Their histogenesis has been traced to the stratified epithelium lining the
cervical canal and the ducts of the glands. The distribution of this type
of epithelium is subject to considerable variations, and it is probable that
before and during the development of carcinoma the cylindrical epithelium
is transformed into stratified cells, or replaced by these cells from a lower
level. This metaplasia may extend even to the endometrium and its phases
may often be traced in chronic erosions.

Changes in the endometrium occur in many cases of cervical carcinoma.
Abel and Landau describe a form of glandular and interstitial hypertrophy,
with warty projections of enlarged and dilated glands, overgrowths of spindle
and epithelial cells, and exudation of round-cells in the stroma. These
changes constitute chronic endometritis. A transformation of cylindrical
epithelium into stratified flat or polyhedral cells is a form of epithelial
metaplasia seen with cervical carcinoma (Kraus) and in chronic endometritis.

Adenocarcinoma, reproducing the alveoli of the cervical glands, occurs
in a small proportion of cervical carcinomas. They first appear as submucous

FIG. 216. — Fungating epidermoid carcinoma of the cervix.

nodules in cervix or portio, but in their later stages they reach the surface as
papillary, cauliflower, or ulcerating growths which cannot be distinguished
from other types of cervical tumors. At the same time, their structure
tends to approach that of epidermoid carcinoma. The tumor process begins
in the ducts or f undi of one or more cervical glands, where the cells multiply,
become stratified, and often assume squamous characters. Cullen pictures
a very early but probably secondary focus of origin of carcinoma affecting the
superficial ceils of the cervical lining. The alveoli have become elongated,
dilated and filled with tumor-cells which have usually lost their cylindrical
form. Yet the alveolar arrangement is long retained and reasserts itself in
lymphatic metastases. Large alveoli filled with tumor-cells, forming second-
ary alveoli, is a common structural type of cervical adenocarcinoma. In
advanced and in some early cases there is the usual variety of structures of
established carcinoma, including alveolar, diffuse and scirrhus types.

Adeno-acanthoma.- — Tumors composed of glandular and squamous ele-
ments are often designated as adenocancroids, or adeno-acanthoma. They

528

NEOPLASTIC DISEASES

arise in the portio, cervical canal, or in the endometrium, and their histo-
genesis has formed the topic of much discussion (Frankel, Wiener, Hitsch-
mann, Offergeld, Hauser, Buttner). It is now rather apparent that such
structures do not as a rule signify a multicentric origin from cylindrical and
squamous-cells, and do not require an original heterotopia of squamous-
cells, but that metaplasia of cylindrical tumor-cells into squamous is a fre-
quent characteristic of uterine growths as of some other processes in the
endometrium. Hitschmann has shown that the metaplasia is complete,
producing spine-cells and keratohyalin. On the other hand Hauser reports a
case of adenocarcinoma of the cervix with separate acanthoma of the portio,
showing that with multicentric origin the tumors may remain separate.
Finally, in several cases the histological study strongly suggested that the
adenocancroid developed from a double origin, and not through metaplasia

FIG. 217 — Adenocarcinoma of fundus uteri developing over point of greatest pressure

from a myoma.

(Hofmeier, Buttner, Sitzenf rey) . In a chronic erosion I have observed rarely
acanthoma arising from the squamous lining and precancerous changes in a
neighboring group of cervical glands. It thus appears that a variable histo-
genesis must be assumed for the cervical adeno-acanthomas.

The Cervical Erosion. — The facility with which cylindrical mucous cells and squamous-
cells replace each other in the cervix appears in the study of erosions and pseudo-erosions.
Ruge and Veit concluded that the mucous cells lining pseudo-erosions were the trans-
formed basal cells of the squamous layer. Meyer and Adair fail to find evidences of this
transformation, and Meyer states that true mucous lining cells always develop from the
glands of the pseudo-erosion. He finds that erosions always result from inflammation and
are attended by extrusion of the glands into cervical tissue and a replacement of squamous
by cylindrical gland epithelium. Schottlander holds that the proliferating glands may
pierce the squamous lining of the cervix. In healing, the squamous epithelium from edges

CANCER OF THE UTERUS, VULVA, VAGINA

529

or persistent islands grows beneath the mucous cells, even into the glands, causing exfolia-
tion of gland-cells and eventually complete replacement by squamous-cells, if the lesion
heals completely. The attendant overgrowth readily gives rise to papillomas and ade-
nomas, and these and other secondary changes determine the different features of chronic
erosions, as simple, papillary, cystic, and glandular. Fischel holds that the pseudo-erosion
of the adult is usually in part a congenital condition. The indifferent epithelium of
the fetal cervix differentiates in the third month into glandular and squamous types, the
latter covering much of the cervical canal. Later the glands and mucous cells encroach
upon the squamous lining and often extend over segments of the portio, producing the con-
genital pseudo-erosion of infants. At birth the squamous-cells begin to regain their
position in the canal, undermining the mucous layer, so that both types of epithelium are
often seen in contiguity. Meyer recognizes persistent congenital erosions. Most authors
accept the direct transformation of mucous into squamous lining cells, and, in this respect
Meyer's view, which sharply separates the two cells types, is probably too rigid. The
influence of simple ectropion is also emphasized by many, especially for multiparae. All
these observations bear directly on the histogenesis and variable structure of cervical

carcinoma.

Mucous adenocarcinoma of the cervix is rare. Miller collected five cases
in which the alveoli were filled or distended with mucus, while the stroma was

FIG. 218. — Adeno-acanthoma of endometrium.

unaffected. In Albrecht's case there was extensive diffuse infiltration of
the cervix, corpus, parametrium and lymph-nodes. In Cullen's case the
tumor involved both cervix and corpus. For these cases an origin from
an aberrant group of intestinal or ovarian glands is suggested by Williams.

Atypical Forms of Cervical Carcinoma. — (a) Scirrhus carcinoma of the
cervix has been described by several observers who had to deal with over-
growths of cellular or fibrous stroma and corresponding suppression of epithe-
lial cells, which here may assume a small spindle form (Wagner, Gebhard,
Cullen). This structure usually occurs in late cases, and signifies a local
inhibition of tumor growth. As in other localities, the outlying areas of the
tumor may exhibit undiminished vitality.

(b) Simple Adenoma or Cystadenoma of the Cervix. — The cervix is occa-
sionally the seat of a characteristic adenoma composed of regular alveoli lined
by a single layer of cylindrical cells, reproducing the structure of the normal
cervical glands (Ruge, Veit). While many of these tumors are benign, some
recur locally, and have produced metastases in the vagina. The microscopic

530 NEOPLASTIC DISEASES

structure has also revealed adenocarcinomatous and carcinomatous changes
(Ruge, Krukenberg). Winter interprets these tumors as a slowly developing
adenoma of cervical glands with carcinomatous tendencies. Stone describes
precancerous changes in these glands.

(c) Endothelioma. — Unusually small tumor-cells growing in long narrow
columns or in small groups, or diffusely, may give the appearance of endothe-
lioma, and hence have led several authors to assume an endothelial origin for
certain cervical tumors (Kroemer, Graefe, R. Meyer, Poworecke). Since
the gross appearance of these tumors is identical with that of certain epithe-
liomas, and since they are usually quite malignant, it seems most probable
that they represent atypical forms of epithelioma (see Endothelioma of
Uterus).

(d) Perithelioma.- — In certain rapidly growing and atypical epitheliomas of
the cervix the cells become arranged about blood-vessels, giving a peri-
theliomatous structure. Hansen describes an intravascular hemangio-
endothelioma. The existence in the uterus of a tumor of vasoformative cells
is uncertain.

(e) Sarcomatoid structures are sometimes seen in portions of early or
advanced cervical carcinoma, but they are more frequently observed in the
corpus (Forssner).

The cells have no definite squamous or glandular character, they grow
diffusely with little stroma, and giant-cells may be numerous. The gross
appearance of such tumors is nevertheless rather characteristic of carcinoma,
and thorough microscopical study may reveal epithelial and alveolar struc-
tures. In all such cases the gross appearance of the lesion should weigh
strongly in the diagnosis. Tumors of this type are described by Cullen and
many others, and they are sometimes wrongly called carcinosarcoma (see Sar-
coma of Uterus).

Precancerous Changes in the Cervix.' — The alterations in structure which
precede the development of definite carcinoma of the cervix have been
variously interpreted. Schauenstein, Sitzenfrey, and Schottlander describe
as characteristic of beginning carcinoma the following changes:

(1) The appearance of groups of irregular, hypertrophied epithelial cells
with hyperchromatic nuclei, with irregularity and indistinctness of cell
borders.

(2) Loss of regular stratification of cell layers, especially of the proliferating
basal cells. Schottlander also emphasizes the importance of marked nuclear
granulation.

The significance of these changes is contested. Heurlin and Pick inter-,
pret them as atypical hypertrophy and regeneration. Yet when to them is
added the features of (3) downward growth of epithelial papillae and definite
heterotopia, there is little doubt that one has to deal with the early stages of
carcinoma. In a uterus partly lined by squamous-cells, Sitzenfrey describes
early downward growth of squamous-cell groups and cylindrical cell alveoli
into a tissue infiltrated with round-cells, a condition which must be accepted
as beginning carcinoma. Rubin pictures extremely early but quite definite
proliferation of atypical, cylindrical and squamous-cells on the surface
and in the glands of old erosions, and the routine study of such erosions reveals
many phases of such precancerous lesions. Schauenstein's cases illustrate
extensive epidermization of the canal and corpus, and downward growth of
atypical papillae at a few points. In my own material the changes consist
chiefly of epidermization of ducts and fundi of glands, with atypical pro-
liferation of both squamous- and cylindrical cells. Pronai would not insist
on heterotopia and downward growth of epithelium, but describes as early

CANCER OF THE UTERUS, VULVA, VAGINA

531

carcinoma a flat extension over cervix of foci of atypical epithelium. Yet
there is a condition of epidermization of the canal which seems to have no
definite tendency to develop into carcinoma. It need not be assumed that
every case presenting the above changes will necessarily develop cancer,
focal epidermization often remaining stationary, but it is highly important
to recognize that the majority of cervical cancers develop from such altered
cells. When atypical hypertrophic and hyperchromatic cells are growing
downward from the epidermis or fill enlarged gland alveoli the diagnosis of
beginning carcinoma is justified.

Stone has shown that several different anatomical forms of cervical
carcinoma develop from equally specific precancerous lesions, such as
leukoplakic patches, areas of epidermization in erosions, atypical cervical
polyps, and adenoma toid overgrowth of cervical glands.

Anatomy of Corpus Carcinoma. — The rather numerous anatomical forms
of this group of tumors may be divided into (i) circumscribed, and (2)

FIG. 219. — Beginning epidermoid carcinoma of uterus.

diffuse growths (Ruge and Veit). The latter usually represent the advanced
stages of the former, but it is probable that certain diffuse tumors originate
over a very wide area, and present specific features from their inception.

The earliest stages of the circumscribed growths appear as low thickenings
of a segment of the mucosa, usually in the fundus, or at one horn, or near the os
internum. Very soon there is a definite outgrowth reaching into the cavum,
with papillary or polypoid projections. Some tumors long remain distinctly
papillary and are designated as papillary adenoma, or adenocarcinoma
(Lindquist, Kaufmann). The circumscribed tumors are usually well demar-
cated from the adjoining mucosa, sometimes very sharply, but others, espe-
cially early forms, grade off insensibly. In advanced stages they produce
bulky growths which destroy the cavum, and invade the wall.

The diffuse tumors either originate from a wide area or early extend
laterally in all directions. They are more frequent than the circumscribed
forms, Huerlin finding in his series 29 diffuse tumors, 15 circumscribed and
2 papillary, and of these 9 covered the entire mucosa, 18 others at least

532

N EOF LA STIC DISEASES

one-half. Other authors classify as diffuse only those tumors which involve
the entire endometrium. The character of the advancing edge should here
be considered. The cervical canal is very rarely involved in corpus carcinoma,
although a short cervix in an atrophic uterus may suggest a cervical lesion, the
cervical mucosa may be partly undermined, and rarely it may show implan-
tation metastasis.

A marked general enlargement of the uterus results from the diffuse
thickening of the mucosa, for these tumors produce considerable bulk of
tissue before invading the wall. Or the enlargement may be due to myomas
which are often associated with malignant adenoma, less frequently with
carcinoma. Rarely there is hypertrophy of the muscular wall (Theilhaber,
Hollinger). When fully established both localized and diffuse growths may

PIG. 220. — Adenocarcinoma involving the entire endometrium.

be sharply denned from the muscular wall which gradually becomes thin
while still free from invasion.

The integrity of the myometrium is the chief factor in the favorable
prognosis of many uterine cancers. In early stages the growth may be
strictly limited to the mucosa, and Vassmer has reported the successful
eradication of the disease by the curet. Eventually the thin wall is
perforated, subperitoneal nodules appear, and the peritoneal cavity, or
bladder, or rectum may be invaded. In more malignant cases there is an
early tendency toward invasion of the myometrium by groups of tumor
alveoli, and the whole wall may thus be infiltrated and thickened. Rarely a
deep invasion of adenocarcinoma occurs early at one point; and in such areas I
have seen the subserous tissue reached by infiltration along vessels from a
flat tumor 2 cm. in diameter. Gravity figures in the early extension of
corpus carcinoma so that the vagina from the introitus to the fornix may be
the seat of secondary ulcerating growths through blood- and lymph-vessels.

CANCER OF THE UTERUS, VULVA, VAGINA

533

Secondary changes in the tumor mark the advanced stages, and include
excessive polypoid formation, ulceration, necrosis, and calcine deposits.
These degenerative changes may greatly alter the gross and microscopical
appearance. Pyometra occurs rarely. Loose calcined myomas were found
by Cullen and Thorn, in cases of carcinoma.

In the late stages the growth may extend into the parametrium, ovaries,
tubes, and lymph-nodes, beyond which its progress is very similar to that of
cervical adenocarcinoma.

FIG. 221. — Adenocarcinoma involving cervix and lower half of fundus uteri.

Structure of Corpus Carcinoma. — Corpus carcinoma appears in several
distinct histological varieties.

(i) Malignant adenoma, the most frequent type, presents greatly enlarged
and elongated alveoli, giant reproductions of the uterine glands, lined by
several compact layers of cuboidal and cylindrical cells. The cell bodies
are usually paler than the normal lining cells, but the large hyperchromatic
nuclei give a dark staining character to the gland linings. There is much
-variation in the number and depth of the cells in the tumor alveoli. Some
tumors rigidly maintain the pattern of the enlarged uterine glands and in the
lymph-nodes, liver, and spleen the same orderly but malignant structure
persists. Secondary alveoli form by convolutions of the lining within the

534

NEOPLASTIC DISEASES

distended alveolus and yield a structure characteristic of a large group. In
all these cases the stroma is greatly reduced and adjacent alveoli become
contiguous, and may fuse.

(2) Papillary adenocarcinoma is a form assumed by certain tumors which
probably arise from superficial cells or adenoid forms. They may closely
resemble in structure and gross appearance the coarser papillomas of the
bladder, but are usually more diffuse and compact (Cullen). Many adeno-
carcinomas exhibit a certain papillary tendency in their superficial portions.
Various stages of malignant transformation of benign polyps are observed.
Special interest attaches to one group of polypoid carcinomas because, while
the curettings show carcinoma, the extirpated uterus retains no trace of the
disease. This situation may arise when a polypoid tumor attached by a
narrow pedicle is completely removed by the curet (Gessner, Ladinski,
Lit.). Of Ladinski's cases I found one to be an atypical embryonal adeno-
carcinoma, another was malignant adenomyoma.

'*s

•-i»

FIG. 222. — Acanthoma of endometrium with extensive hornification.

(3) Alveolar carcinoma is rare in the uterus, but some tumors early show
solid masses of cells forming alveoli and smaller cell groups infiltrating spaces
and vessels. Extremely small, numerous and indistinct alveoli may form,
giving a structure that is almost or quite diffuse. These structures are more
aggressive- than the malignant adenoma, and they are subject to degenerative
changes which may lead to the diagnosis of giant-cell or round-cell sarcoma.

(4) Squamous-cells may form a prominent element in adenocarcinoma of
the corpus, and in rare cases they predominate over the glandular structure
and produce a true adeno-acanthoma. While in many cases neither spine-
cells nor keratohyalin granules are demonstrable, in others both these criteria
of true squamous epithelium are present, and pearl formation is added.
The squamous-cells usually appear in foci in the alveolar lining where the
sharp transformation of cylindrical into flat-cells may be followed. Such
cell foci usually fail to show hornification. Or the tumor may be composed

CANCER OF THE UTERUS, VULVA, VAGINA 535

exclusively of large and small groups of squamous-cells without hornification.
Rarely all the characters of adult acanthoma are observed. At least three
primary acanthomas of the corpus have been described, all in elderly women
(Gebhard, Kaufmann, Flaischlen). As secondary changes one may find
hyaline degeneration of masses of squamous-cells or calcification of pearls.
(C. psammosum, Hitschmann). In elderly subjects in which the uterus is
probably the seat of an old leukoplakia, squamous-cell acanthoma may develop
in many superficial foci or diffusely, giving an opaque, warty appearance in
the gross and leading to infiltration of the mucosa. Some of these cases
probably represent an extension of a cervical acanthoma (Ruge, Benckiser).
A combination of this superficial acanthoma with adenocarcinoma is described

FIG. 223. — Atypical proliferation of uterine glands in a case of myoma uteri.

by E. Kaufmann, who holds that one has to deal with a double origin from
previously altered superficial lining cells and from gland-cells.

The histogenesis of corpus carcinoma presents many difficulties and in
spite of much labor the exact origin of the different histological types remains
uncertain. Although Gebhard claimed that malignant adenomas arise
from hypertrophied glands in chronic endometritis this simple history
has not received verification. Most observers fail to find the transformation
from simple hypertrophied gland-cells to the neoplastic. On the contrary
most early adenomas show a sharp demarcation from the surrounding glands,
and Heurlin, in 44 cases, failed to find any transitions or any signs of glandular
hypertrophy in the endometrium. Such observations indicate that adenoma
uteri arises in a circumscribed group of glands and extends laterally by dis-
placing the normal glands even over the whole endometrium. The frequent
association of adenocarcinoma with myoma suggests that the originating

536 NEOPLASTIC DISEASES

glands may be in some way connected with a myomatous area or other devel-
opmental anomaly. But aside from the rare and peculiar carcinomas derived
from adenomyomas, there are no facts to support this hypothesis. Hence
one is forced to the conclusion that adenoma arises from the normal glands of
the endometrium under conditions which cannot be accurately defined, but
which are probably associated with a peculiar local irritation. Doca de-
scribes early multiple adenocarcinomatous foci in the hypertrophic mucosa
in a case of myoma uteri. Here the hyperemia and local irritation of myoma
appear to have caused the neoplastic overgrowth of normal glands. I have
seen three cases of carcinoma arising in the hypertrophied glands overlying
the most prominent points of submucous myomas. One of these myomas
was calcified.

The papillary adenocarcinomas have been traced with considerable
certainty to proliferating superficial cells (Cullen), but here again no mor-
phological signs of a tissue predisposition are usually observed. An ex-
ception to this rule occurs in the forms of adenocarcinoma arising from
polyps. The transformation of benign polpyi into malignant tumors of
the corpus by proliferation and metaplasia of lining and gland-cells has
repeatedly been observed. Heurlin describes the implantation of carcinoma
from such a malignant polyp upon the opposite side of the uterus, and some-
what similar implantations are reported by Noble and Flaischlen.

The mode of extension of the common adenoma and adenocarcinoma is
still under discussion. While most of these tumors present well demarcated
edges, the gradual inclusion of normal glands in the tumor area may often be
observed in the uterus as in the stomach and colon. It is difficult to account
for certain very diffuse tumors on any other basis. Lancereaux observed
a diffuse tumor covering the entire endometrium and the mucosa of both
tubes (Cit. by Williams). Heurlin's view in this matter is certainly too
extreme. Likewise for the adenocarcinomas which arise after epidermization
of the endometrium, an origin from multiple foci of altered superficial or
gland-cells and a gradual extension of the process must be accepted. In the
vicinity of all these tumors there are often observed signs of collateral hyper-
plasia, low papillary projections of vessels from the stroma capped by epi-
thelium and groups of squamous-cells.

The most definite origin of any corpus carcinoma is that of the rare tumors
derived from circumscribed or diffuse adenomyoma. Arising in circum-
scribed adenomyomas, the carcinoma produces a submucous or intramural
tumor which tends to infiltrate deeply and extend to neighboring tissues,
often with extensive metastases (E. Kaufmann, Roily, Dillmann, Cullen). .

Diffuse adenomyomatosis gives origin to characteristic forms of uterine
cancer. The uterus is uniformly enlarged and most of the myometrium is
the seat of a diffuse myomatous process in which are many gland alveoli
exhibiting more or less neoplastic character. Often they present the struc-
ture of an orderly adenoma, with large alveoli lined by one or more layers of
cylindrical cells. In this form they are capable of producing metastases,
which I have observed in the ovary. Islands of squamous-cells may also be
present. Or the epithelial elements may yield various forms of adenocar-
cinoma or carcinoma (Winter, Schwab, Heurlin). Myomas are frequently
the seat of metastatic carcinoma from ovarian sources.

Precancerous Changes in the Corpus. — From the processes which tend
distinctly to develop into cancer of the endometrium must be excluded a
simple increase in the cell layers lining the surface or glands. In chronic
glandular endometritis multiplication of regular cell layers lining the glands
has repeatedly been observed without any indication of a cancerous tendency

CAXCER OF THE UTERUS, VULVA, VAGINA 537

(Borst, Cullen, Heurlin). Likewise a simple overgrowth of surface epithe-
lium with partial or complete epidermization cannot be regarded as a definite
approach toward a neoplastic process (Heurlin, Lit.). Yet the distinction
between such benign overgrowth and a progressive malignant process is
extremely difficult, and opinions differ as to the essential morphology of this
early form of corpus carcinoma.

Leukoplakia iiteri is a term often applied to this epidermization of the
endometrium (Gebhard). It occurs under a variety of conditions. After
curettage, especially when the uterus has been treated with escharotics and
styptics, the regeneration of surface epithelium may yield groups or a con-
tinuous lining of stratified flat cells (Werth, Sitzenfrey). In certain cases,
especially in atrophic uteri, this epidermization may progress extensively
with atrophy of the mucosa, and scaly material with cholesterin may gather in
quantities in the cavum, producing the condition observed by E. Kaufmann,
as choleastoma uteri.

Rarely diffuse benign epidermization occurs as a form of endometritis
(Zellerr Borst). It has often been observed in connection with chronic
pyometra. In epidermoid carcinoma of the cervix much of the lower endo-
metrium may be found covered with stratified cells, which may be regarded
either as an extension of the tumor process or as an independent process
affecting the endometrium. In many cases of adenocarcinoma of the corpus,
especially when arising from polypi, extensive epidermization of the endo-
metrium has been observed (Hofmann, Hitschmann). Here the process
may affect not only the adenocarcinoma but other portions of the endo-
metrium. Finally, since islands of squamous epithelium may occur in the
normal fetal endometrium, it may be assumed that its occurrence in the
adult is sometimes only a result of such early malformation (Ribbert, R.
Meyer).

The decision regarding the malignancy of uterine epidermization must
in each instance be based on its finer peculiarities. In definitely malignant
processes there are irregularity in cell form and arrangement, atypical mitoses,
hypertrophy and hyperchromatism, and often pearl formation. One may
very well insist, with Heurlin, on heterotopia as an essential sign of malig-
nant qualities, of which Oeri's cases furnish examples. Such conditions are
true early carcinomas. On the other hand, in the absence of such definite
signs of early carcinoma, extensive epidermization must still be regarded with
suspicion and classed among precancerous changes.

Course of Uterine Cancer. — From the nature of the initial symptoms of
carcinoma it is obvious that the disease must exist for some time before it
attracts attention, and since the rate of progress must vary considerably,
observations on the duration of the disease when first recognized must have a
somewhat uncertain value. Under these circumstances the early recognition
of uterine cancer is a very difficult clinical problem. Winter claims to have
observed 13 per cent, of his cases in the first month of symptoms, 30 per cent.
in the second to third months, 27 per cent, in four to six months, 8 per cent,
after one year. Hammer recognized 50 per cent, of cervical cases in the first
three months, but only 19 per cent, of corpus carcinoma. Taylor found that
in 50 per cent, of the cases the symptoms had lasted less than three months,
in 40 per cent, between three and six months, and in only 10 per cent, for
more than six months. The rapid progress of the disease is illustrated by
Mackenrodt's observations, who found the disease beyond the uterus in
half of 1 8 cases examined within four weeks after the earliest definite symp-
toms. After the second month 20 per cent, of his cases were inoperable,
after 6 months 40 per cent. Waldstein points out that cases are very apt

538

NEOPLASTIC DISEASES

to fall into advanced inoperable, and localized operable tumors, if observed
during the first year. Early age, pregnancy, special susceptibility, a malig-
nant structure, and a location in the cervical canal are more important fac-
tors than the duration of the disease. Cervical carcinoma yields symptoms
earlier, but the established forms of corpus carcinoma give more urgent
manifestations.

A serous or mucous discharge is the earliest symptom, long preceding the
tumors arising from erosions, or many of the corpus carcinomas, and being
established early in deep cervical tumors. It results from the preexisting
inflammation, from excessive mucous secretion of affected glands, and from
exudates from eroded surfaces. Only when fetid and mixed with blood,
in the more advanced stages, can it be regarded as highly significant.

FIG. 224. — Uterine adenocarcinoma penetrating the wall of the uterus by way of the peri-
vascular lymphatics.

Bleeding, irregular, at the climacteric, after slight trauma, or sponta-
neous, or as prolonged metrorrhagia, is also an early symptom in the major-
ity of cases.

Aside from the uterine colic of early corpus carcinoma, pain is a late symp-
tom, denoting ulceration, or invasion of sensitive structures, usually beyond
cervix or endometrium.

A definite stage of the established disease is reached by the invasion of the
parametrium, which usually occurs by continuous extension on one or both
sides, through lymph-spaces, lymph-vessels, nerve-trunks, and occasionally
by the veins. Isolated carcinomatous foci also develop in the lymph-nodes,
about the vessels and in the looser tissues of the parametrium, but the para-

CANCER OF THE UTERUS, VULVA, VAGINA 539

metrium may be thickened while still free from carcinoma (Scheib, Samson).
In such tissue one finds thickening and sclerosis of vessels, perivascular
lymphocytic infiltration, development of many new lymph-nodules, and
edema. Bacterial infection of the parametrium by staphylococcus or strepto-
coccus has often been demonstrated (Veit, Bumm, Fromme).

The period of lymphatic invasion varies greatly with the location and
type of the disease, but is relatively early in cervical carcinoma. It has been
present in more than half (43 to 73 per cent.) of patients coming to operation
(Scheib). In later stages the parametrium is perforated and peritoneal
nodules form, chiefly in the sac of Douglas. Diffuse carcinoma of the peri-
toneum, peritonitis, and ascites are occasionally observed.

Lymphatic Invasion. — The course of the lymphatics has been carefully studied by many
observers with reference to the extensions of carcinoma. Two main groups of lymphatics
from (i) the body and (2) the cervix are demonstrable, between which, however, there are
rather free and variable anastomoses.

The main cervical vessels follow the uterine artery through the parametrium, meeting
small nodes in the broad ligament and at the region where the artery crosses the ureter,
and further on the iliac nodes in front of the external iliac artery and about the obturator
foramen. From this plexus other vessels pass along the ureter to the hypogastric vessels
and nodes. A posterior plexus passes forward and backward along the sacrouterine liga-
ment, around the rectum, and to nodes at the promontory of the sacrum (Sappey, Kroemer,
Poirier, Lucas-Championniere).

The lymphatics of the corpus begin in the mucosa, pass upward and outward and leave
the uterus in 4-5 trunks just beneath the tubes, pass through the broad ligament, anas-
tomosing with the ovarian plexus and about the ovarian artery in the pelvic ovarian liga-
ment, to end in lumbar nodes above the bifurcation of the aorta. From the middle of
the corpus other vessels mingle with those from the cervix, reach the iliac nodes and
some pass along the round ligament to the inguinal nodes (Sappey, Bruhns). These six
groups of nodes, parametrial, iliac, hypogastric, sacral, lumbar, and inguinal, form the
regional nodes of the uterus. Beyond them there are rich communications with each other
and with the vessels of the bladder, rectum, kidney and abdomen (Baisch).

Uterine carcinoma as a whole cannot be classed among the tumors which
early invade the lymph-nodes. Post-mortem observations often suggest the
striking tendency of the disease to remain localized, either to the uterus, or to
this organ and its immediate vicinity, including the regional nodes and the
tissues actually destroyed by the tumor. The autopsy records collected
by Kroemer showed the lymph-nodes free in 66 per cent, of the fatal cases.
There is, however, much variation in the course of the disease. As a rule,
tumors of the fundus long remain confined by the muscular wall, while cervi-
cal carcinoma early infiltrates the cervix and invades the parametrium.
Baisch found the regional nodes involved in only four of 24 cases of corpus
carcinoma, and Cullen regularly found the nodes free. The duration and the
type of the disease are doubtless the controlling factors in the rapidity of
extension, but their influence does not appear seriously to alter the above rule,
so that permanent operative cures of corpus carcinoma are often observed
(Doderlein, Fritsch, Landau, Cullen). In cervical carcinoma the early
involvement of the parametrium and its nodes was fully demonstrated by
Kundrat, who in 160 cases found this structure involved in 55 per cent.,
while Lamaris and Kermauner saw such extension in 57.5 per cent., Baisch
in 36 per cent., Schauta in 64 per cent. From a large series of reports of
various types of cases, Baisch concludes that the regional nodes are involved
in 33 per cent, of operable cases of cervical carcinoma; when the parametriun
is macroscopically free the nodes are affected in 5 to 1 6 per cent., and with
invaded parametrium the nodes are affected in 50 per cent, of the cases.
Rarely the regional nodes are said to escape while more distant ones are in-
volved, as in Schauta's postmortem material. V. Herff also reports such a

540 NEOPLASTIC DISEASES

case, but these isolated instances do not alter the rule that uterine carcinoma
extends progressively. The invasion may be by continuous permeation,
or sound tissue may separate the nodes from the cervix (Kundrat). Rarely
extensive lesions may fail to involve the nodes (Cullen), but in many cases
they were already involved with cervical lesions which had the appearance
of simple erosions, or consisted of a small circumscribed nodule (Baisch, Lit.).
It has repeatedly been shown that only microscopical examination is a safe
guide to the conditions of both swollen and small lymph-nodes. Distinct
metastatic nodules in the uterine wall may develop from cervical cancer
(Blau, Winter).

Among Sampson's 27 cases he found only 10 in which the parametrium
was free. The direct extension of the disease through fine lymphatics
is the most frequent manner in which this tissue is invaded by cancer,
occurring in 14 of 17 cases in which parametrial extension was found. Metas-
tases in the lymph-nodes of the parametrium were also present in six of these
cases. Of much clinical importance is the fact that the parametrium may be
cancerous while the pelvic nodes are free, demonstrating that the para-
metrium may be able to check the disease for a time. Hence if one can re-
move the entire local growth it may be possible to cure a certain percentage
of such cases. Induration of the parametrium without cancerous invasion
occurred in one case, while in three cases the parametrium was invaded but
felt normal on palpation. Of 19 lymph-nodes examined 9 were found invaded.
Gellhorn from a full review of the literature and from his own experience
concludes that cervical carcinoma involves the pelvic nodes in less that one-
third of all cases. R. Peterson examined the lymph-nodes removed in 29 of a
series of 51 cases and found invasion in only five. At autopsy on cervical
carcinoma the striking feature is the usual limitation of the disease to the
pelvis or even to the uterus and immediately contiguous tissues. In these
respects cervical carcinoma follows the usual rule of acanthoma, viz., to
destroy the originating tissue, extend with induration and ulceration to the
first barrier of lymph-nodes, and then cease its progress. There are, however,
highly anaplastic epidermoid carcinomas and glandular carcinomas of the
cervix which extend widely.

Many efforts have been made to establish a relation between prognosis
and the structure of the tumor, from which it appears that the transitional
cell cervical carcinomas are distinctly more malignant than the squamous
epitheliomas of the portio. Thus when the parametrium is free Baisch finds
invaded lymph-nodes in 30 per cent, of cervical carcinomas, but in only
10 per cent, of portio acanthomas.

Pregnancy has an unfavorable influence on the course of many uterine
carcinomas, but this influence is not always apparent. The age of the patient
is also of some importance. Between 20 and 30 years the course of the
disease is often unusually rapid. Kroemer finds the everted cauliflower
growths of the cervix and portio are of slight malignancy; the deep unicentric
nodules are more so; while the diffuse forms are highly malignant. Cullen
and Lubarsch attribute special infiltrative powers to the tumors composed of
small cells, a view which accords with the small size of the cells in many highly
anaplastic growths.

The microscopical study of pelvic and other lymph-nodes has revealed
the occasional presence in normal nodes of structures resembling isolated
carcinomatous alveoli. These structures appear as single or multiple well
formed alveoli lined by cylindrical or ciliated cells. They have been inter-
preted as inclusions of the Wolffian duct (Borst), or as groups of altered
lymphatic endothelium (R. Meyer). They are usually located in the tra-

CANCER OF THE UTERUS, VULVA, VAGINA 541

beculae where embolic cancer-cells are not found, but when situated in the
parenchyma they may be difficult to distinguish from carcinomatous cell
groups (Sheib, Lit.). Carcinomatous invasion of nodes is usually pre-
ceded by parenchymatous hypertrophy, and often by catarrhal or exudative
lymphadenitis. Streptococcus infection of such nodes appears to be rather
prominent in cases of uterine carcinoma, and may give rise to suppuration
and peritonitis after operation (Ruhle).

The clinical course of the advanced disease is dominated by the secondary
invasion of neighboring organs. The bladder is invaded by direct extension
from the cervix, and the wall is infiltrated with the formation of metastatic
nodules in the submucosa, or more often with ulceration, necrosis and fistulae.
Invasion of the bladder is relatively common, Williams finding it in 56 of
75 autopsies, wrhile in 29 vesicovaginal fistulae had formed.

The natural termination of most cases of uterine cancer is through uremia
from occlusion of the ureters. This termination very frequently occurs while
the disease remains well localized in the pelvis. These important structures
are commonly invaded from without through the parametrium, and while the
wall long resists destruction, partial or complete occlusion is readily estab-
lished by cancerous infiltration, or by inflammatory processes. The ureter
may also be invaded by extension through the bladder wall, and it may be
occluded by inflammation extending upward from the bladder. Dilatation
of the ureter, hydronephrosis, and chronic nephritis with gradual suppression
of the renal function regularly follow. Suppurative nephritis may arise in
cases complicated by cystitis.

The rectum is often compressed by infiltration of the wall and recto-
vaginal fistulae form in not a few advanced cases (6 per cent., Beckmann).

With invasions of bladder or rectum the pelvic connective tissue is usually
involved, with compression of vessels and edema of vulva and lower limbs.

Visceral metastases, while occurring in many cases, are often conspicuous
by their absence. Yet the disease may become widely generalized, and
secondary tumors have been observed in many organs. Since visceral
deposits occur chiefly in the terminal stages of the disease, they are not
distinctly influenced by the location or type of the original disease, but the
more adult acanthomas rarely extend beyond the pelvis. In rare instances
there is early and very wide extension through the lymphatics, with continuous
permeation through the abdominal and thoracic nodes to the supraclavicular
and cervical regions.

The liver has been invaded through the portal vessels and by retrograde
lymph flow in 5 to 15 per cent, of autopsies.

The lungs have been invaded probably through the blood-vessels in
5 to 7 per cent. Pleural metastases extend- from bronchial nodes in rare
instances. Offergeld collected 56 cases of peritoneal metastases located
in a great variety of positions, and he found records of seven secondary
tumors in the thyroid, n in the adrenals, 31 (2.39 percent.) in the kidney,
5 in the pancreas. The brain is rarely affected (Williamsky 0.2 per cent.).
A few cases of carcinomatous meningitis have occurred from uterine cancer.
The bones are involved in many cases.

Characteristic cachexia in uterine cancer develops in the terminal stages
of the generalized disease, but when the lesion is localized in the pelvis
cachexia is missing, the nutrition may remain surprisingly good, and, if
infection can be avoided, death follows from uremia. Local and general
infection, usually by streptococcus, may be a prominent feature. Fever
is almost always due to infection and local necrosis of tissue.

The mortality from uterine cancer is very high. Jacobson, from an

542 NEOPLASTIC DISEASES

elaborate analysis, shows that of the women who enjoy the services of the
best American operators 35 per cent, are inoperable, the operative mortality
is 15.17 per cent., after five years 8.39 per cent, are well, and i per cent, of the
total are permanently cured. Cullen states that of cervical cases 50 per
cent., and of corpus cases 16 per cent., are inoperable when first seen.

In an effort to extend the field of operability Ries and J. G. Clark
proposed the more radical operation which was developed especially by
Mackenrodt and Wertheim, but the results, at first encouraging, have proven
unsatisfactory. Mackenrodt's original 72 per cent, of successes fell first to
42 per cent., then after eight years to 22 per cent., and after ten years to 12
per cent. Wertheim's statistics have suffered a similar revision. The widest
discrepancies exist between the claims made of permanent cures, as Macken-
rodt, 58 per cent.; Rosthorn, 2.65 per cent. Operable carcinoma of corpus
offers a better prognosis, prominent clinics reporting 53 per cent, of permanent
cures of this form of the disease (Koblanck). In a series of 103 cases,
Cullen reports 16 per cent, of cures of adenocarcinoma of cervix, 21 per cent,
for acanthoma of cervix, and 66 per cent, for corpus carcinoma. Yet in
the latter group fall many comparatively benign tumors.

In America the Wertheim operation has never been distinctly popular
because of the feeling that the additional cases saved by this method do
not justify the higher mortality. Some support of the extraradical operation
in advanced cases has come from a few paradoxical cures. Thus Scheib
collected 14 cases which remained well for several years although the regional
nodes had been involved. From the economic standpoint it must be con-
sidered that a competent Wertheim operation is beyond the reach of the
great majority of the population and that all the phases of the cost of acquir-
ing technical skill should be counted in estimating its utility. Because
of these considerations a marked change has occurred during the last few
years in the aspects of surgical treatment of uterine cancer, most surgeons
preferring to reduce the scope of operability and others abandoning all
operations for uterine cancer, in favor of radium and rv-ray treatment.
Earlier diagnosis has doubtless contributed to improving surgical statistics
and is equally important for radium therapy. In these directions lies the
hope of real advance in the therapeutics of uterine cancer.

EPIDERMOID CARCINOMA AND EPITHELIAL TUMORS OF VULVA

These tumors are peculiar because of the special conditions under which
they originate, their relatively great malignancy, and the late period of
life at which they commonly arise.

Carcinoma of the vulva is not a rare disease, forming 10 per cent., ac-
cording to Gurlt, of all cancers in women. The majority of the tumors are
epidermoid carcinomas arising from the mucous membrane of the vulva,
but the clitoris is also a frequent source of epithelioma, and glandular cancers
develop from the sweat-glands and from the gland of Bartholin. It is most
frequent in the sixth decade (Dittrich) but has been observed in a girl of
20 years (Arnot).

The disease first appears as (i) a thickening of the epidermis which soon
exhibits cracks and fissures, or (2) a localized papule, vesicle or wart, or (3)
deeper tumors of sweat-glands or of Bartholin's gland precede the appearance
of superficial lesions. The initial lesions may be multiple (Fromme). The
chief seat of the disease is in the follicles, in the sulci between the labia, and
about the urethral orifice. Sitzenfrey traced the origin of one case to the duct
of Bartholin's gland. Two notable conditions, pruritus and leukoplakia,
often antedate the malignant process.

CANCER OF THE UTERUS, VULVA, VAGINA 543

Pruritus is a very common precursor of carcinoma of the vulva but its
source is not always clear. Dittrich reports a case of pruritus lasting 12
years due to a benign wart, which terminated in epidermoid carcinoma.
Weir observed a long period of pruritus in a young girl, associated with
kraurosis and ending in epithelioma. Frequently the pruritus exists for
several months before the carcinoma is discovered. The parakeratosis and
round-cell infiltration of the corium in pruritus are distinctly favorable to
the development of epithelioma.

The relation of kraurosis and leukoplakia of the vulva to epithelioma
was first pointed out by Weir and later emphasized by Butlin, Jung, Franque,
and many others. A syphilitic origin is not always demonstrable, but some
form of local infection or irritation is usually present. It produces a pearly
white, warty condition of the mucosa which appears at many discrete points
or affects nearly the whole orifice. The condition begins as a chronic inflam-
mation of the mucous membrane with thickening, edema, and cellular
infiltration of the corium, and hypertrophy and keratosis of epithelium
and it results later in extensive sclerosis and atrophy of the corium with
contractures (Peter). From one or more points or from a broad area of
this lesion epithelioma develops.

Other local conditions related to the disease are psoriasis, syphilitic
scars, elephantiasis, abscess, and various forms of trauma.

When fully developed the carcinoma appears as: (i) a prominent warty
or lobulated tumor; (2) a deep ulcer; or (3) a diffuse infiltration. In the
ulcerating cases a severe infection is often added which greatly complicates
the local condition, causes enlargement of inguinal nodes on one or both
sides, and hastens the progress of the disease. Involvement of lymph-nodes
has been observed as early as three and one-half months from the beginning
of the disease and has been delayed for more than three years. Schwarz
found that the swollen inguinal nodes were invaded by cancer in only about
one-half of his cases. Dittrich finds that involvement of lymph-nodes occurs
in about 50 per cent, of the cases during the second six months of the disease.
Extensions occur along the deep tissues to pubic bones, to the pelvis, and
through inguinal and pelvic lymph-nodes of one or both sides. Fritsch saw
extensive growth about the urethra. The vaginal mucosa usually escapes
involvement but the vaginal wall may be invaded and even the cervix uteri.
Local metastases occur about the anus, in the abdominal wall, and in the
thighs. General metastases have been observed in abdominal nodes, lungs,
heart, liver, spleen and kidneys (Kustner).

Implantation by contact on the opposite labium has been reported by
several observers, but the probability of an extension through the lymphatics
is not eliminated (Dittrich, Lit.).

The course of vulvar carcinoma is usually rapid and terminates, if without
operation, as a rule within two years after the discovery of the lesion.
Deschamps observed a fatal case terminating in four months. The explana-
tion of this rapid course is probably to be found in the abundant vascular
and lymphatic supply of the tissues, in the late discovery of the disease, and
in the complicating infections. Dittrich found no recorded case in which the
patient remained free from recurrence for over six years. Several cases
showed recurrence after five years. H. Schultze in 114 cases found 14 free
from recurrence after five years. Yet it is probable that not a few cases
recognized early have been cured by operation. It may also be noted that in
many cases the early stages of the disease may be slow and that several
years may elapse before the lymph-nodes become involved and the growth
becomes accelerated. Kaufmann, Teller and Rupprecht report cases of

544 NEOPLASTIC DISEASES

long duration. Rupprecht gives a comparatively favorable prognosis
for superficial lesions, and reports cures after invasion of the nodes.

Structure. — Epithelioma of the vulva usually presents a structure of
narrow cords and columns of relatively undifferentiated squamous cells.
Hornification and pearl formation are not prominent. The malignant
clinical character of the process is often apparent in the histological structure.
In the advanced stages the proportions of cells and stroma varies and some
authors speak of scirrhus and encephaloid types. Pick and H. Ruge state
that adenoma of the sweat-glands may become malignant and pursue the
course of epithelioma of vulva. The structure of the benign tumor recalls
that of the sweat-glands (tubular adenoma), and the malignant form occurs
as an adenocarcinoma. Bartholin's gland is the source of rare adenomas and
adenocarcinomas (Veit, Lit.). These tumors usually reach larger dimensions
than epithelioma and present an adenoid structure (Chaboux). Many cases
of melanoma of the vulva are recorded (P. Meyer, Hinselmann, Lit.).

EPIDERMOID CARCINOMA OF VAGINA

Primary epidermoid carcinoma of the vagina is a comparatively rare
condition, forming 0.24 per cent. (Schwarz) or 0.19 per cent. (Gurlt) of all
carcinomas, or about 0.43 per cent, of all carcinomas in women (R. Williams).
Secondary carcinoma, however, is rather common, the vagina being invaded
in most cases of cervical cancer, and from the bladder, rectum, ovaries, and
other more distant organs. The chief age of incidence is between 30 and 40
years, but Winckel saw seven cases between 20 and 30 years and many occur
late in life. Cases reported in infants are of doubtful nature.

Exciting factors include the irritation of pessaries which have been directly
connected with vaginal carcinoma in several reported cases (Wille, Lit.);
the traumatism of repeated childbirth, a factor emphasized by West and
Bernard; and leuokplakia, which has been observed to precede carcinoma
in rare cases discussed by Reclus, Bex, and v. Franque.

In form and location vaginal carcinoma appears as: (i) a papillary or
(2) infiltrating growth arising (a) chiefly on the posterior wall of the upper
segment, (&) on the anterior wall and about the urethra, (c) on lateral wall,
(d) in the fornix whence it invades both cervix and vagina, producing the
''epitheliome luminaire'' of Pozzi, (e] in the lower segment and invading the
vulva, and ( f) as an annular or diffuse infiltration of much of the vaginal
wall (Olshausen).

The initial stages of the lesion are rarely observed but appear as single
or multiple warts; as an elastic nodule in the epithelial tissue; or as a flat
infiltration. In advanced stages cauliflower, villous, highly vascular and
more frequently ulcerated tumors form. Schwartz described a multiple
fungoid epithelioma of upper vaginal segment and cervix.

The extensions of vaginal carcinoma are determined by the location
of the lesion. Ulceration often occurs early, the muscular wall offering
little resistance. With or without ulceration extension through the lymph-
atics is established early in the disease. From the upper segment the lymph-
atics enter the iliopelvic chain and join with those of the cervix uteri; from the
middle segment the vessels enter the lowest nodes of the iliopelvic and hypo-
gastric groups; while from the lower portion drainage is toward the inguinal
nodes (Poirier, Bruhns). Along these channels the nodes become enlarged,
vessels are constricted with edema, and the urethra may become obstructed
with cystitis and hydronephrosis. Ulceration produces fistulous tracts to
rectum or bladder. Extensive suppuration and peritonitis may develop.
The broad ligaments, uterine wall, ureters and ovaries may be infiltrated.

CANCER OF THE UTERUS, VULVA, VAGINA 545

Metastatic deposits have been observed in the tubes, ovaries, kidneys,
liver, lungs, and bones.

The prognosis is very unfavorable. R. Williams calculated the average
duration of life at 16.5 months, longest 26.25 months, shortest 8 months.
Longer immunity from recurrence has followed extensive operations in early
cases, but no definite cure of the established disease seems to have been re-
corded (Lohnberg). The early cases respond well to radium.

Structure and Histogenesis. — Vaginal carcinoma usually arises from the
squamous epithelial lining and takes the form of acanthoma or tubular epi-
thelioma. Pearl formation and hornification are not prominent. The upper
cervical segment contains cysts and follicles lined by cylindrical cells from
which atypical adenoid epithelioma may develop. The variable structure
and origin of these cysts have been discussed by Cullen. Davidsohn regards
the vaginal glands as heterotopic cervical or (below) vulvar structures. R.
Meyer traces the ampulla of Gartner's duct into the lateral vaginal wall
where its structure is often to be seen in infants. He also traces the forma-
tion of follicles by the dipping down of the basal layer of epithelium and re-
ports several forms of congenital abnormalities in the epithelial lining of the
fetal vagina, as well as adenocarcinoma arising from such abnormalities.
In the adult he finds small cysts and aberrant groups of squamous epithelium
in the submucosa. In a remarkable case the entire vagina was the seat of a
cystadenofibromatous degeneration. To what extent these abnormalities
are concerned in the genesis of carcinoma in the adult remains to be shown,
but the occurrence of such conditions must be considered in all atypical
forms of carcinoma of cervix, vagina, and vulva.

Cylindrical cell carcinoma of the vagina is reported by Pintor, and by
Polosson and Violet, and adenocarcinoma by Hoehne, and Hirsch.

CHAPTER XXVIII
CHORIOMA (CHORIONEPITHELIOMA)

Historical.- — The characteristic anatomical and clinical features of
destructive placental polyp were clearly described and depicted as early
as 1867 by R. Volkmann and later by many others (Sanger, Lit.), but the
nature and origin of other highly malignant tumors connected with gesta-
tion proved to be a much more difficult problem, chiefly because the absence
of a core of the villus in these tumors removed the chief basis for connecting
them with fetal structures. The idea gained currency that the chorion pro-
duced only the destructive polyp while the more malignant tumors arose
from decidual cells, and this view was maintained notably by Sanger, 1888-
91, who employed the term deciduoma malignum or sarcoma deciduocellulare.

In this group, I judge from the literature of the period, were included
the more malignant chorionic tumors, certain sarcomas of the endometrium,
and possibly rare tumors of the placenta. The large fusiform and polyhe-
dral cells of the decidua were supposed to give origin to the tumors, but
Pestalozza thought the uterine muscle also contributed to the tumor-cells.
A combination of deciduoma with destructive hydatid or placental moles
was recognized especially by Gottschalk and Schmorl, but such cases were
regarded as of complex origin.

The fetal origin of the tumors was maintained by a number of authors,
especially by Gottschalk, who, however, believed that the connective tissue
of the villi suffered sarcomatous transformation. In this situation, Mar-
chand, by a minute comparison of the tumor-cells with the fetal villi con-
cluded that the tumors arose from the chorionic epithelium, reproducing both
syncytium and Langhans' cells. At the same time J. W. Williams inter-
preted his case as of exclusive syncytial (and maternal) origin, and thus was
led to retain the term deciduoma.

Marchand's view of the exclusive chorionic origin of the tumors has
proven entirely correct and has served to connect the various grades of
proliferation of chorionic epithelium in one general class, while the clinical
relations of the different forms of the disease have been greatly elucidated,
especially the connection with gestation and hydatid mole. Marchand
divided the tumors into two main classes, typical and atypical, the former
covering the actively growing and metastasizing tumors, the latter designat-
ing certain less active or degenerating forms composed chiefly of large giant-
cells. In 1910 it seemed to the writer that the anatomical and clinical
distinctions long recognized to exist between destructive moles, typical
chorionic carcinoma, and atypical degenerating tumors deserved definite
emphasis, and he proposed for them the terms, chorioadenoma, choriocar-
cinoma, and syncytial endometritis. Subsequent experience has confirmed
this conclusion and interpretation.

In recent years many authors have contributed numerous details of our
knowledge of the origin, course, and treatment of the disease, and numerous
monographic studies have appeared (Pestalozza, Veit, Teacher, Risel,
Frank, Schmauch).

546

CHORIOMA (CHORIONEPITHELIOMA) 547

Etiology. — The frequency of malignant proliferation of chorionic epithe-
lium cannot at present be determined. The number of reported cases has
increased notably in recent years, so that Pollasson and Violet (1914) were
able to collect 455. Findley thought that about 16 per cent., of hydatid
moles were malignant. Senarclens found that of 49 hydatid moles
3 (13 per cent.) developed chorioma, while four others died of other
complications. In the cases collected by Pollosson and Violet the disease
occurred in the following relations to pregnancy; after moles, 203 (44
per cent.), abortion 135 (30 per cent.); labor near term, 99 (22 per cent.);
ectopic, 12; doubtful, 6. Multiple gestations seem to increase the liability
to the disease, since Ollivier Bauregard in 178 cases found that 66 had borne
more than five children, while 22 were nulliparae. Curtis and Oui noted
an average of 7 confinements, and a minimum of 3, in women between 40
and 53 years suffering from destructive placental mole. The average peri-
ods of occurrence have been estimated as 8 weeks after hydatid mole, 7
weeks after abortion, and 5 weeks after labor at term.

Destructive mole usually yields symptoms between 4 and 5 months
after the last menstruation. Briquet found that in 14 of 30 abortions fol-
lowed by chorioma and in 17 of 35 hydatid moles, the age of the ovum was
3 to 4 months. The age of the patients has been from 17 to 58 years. At
either extreme of age the probability of a teratomatous origin must be
considered.

Latent chorioma has occurred in some remarkable cases in which the
disease appeared several years after the last gestation. This interval was
three to four years in several cases, five years in Caturani's case and 10 years
in Polano's (Outerbridge, Lit.). . The capacity of fetal villi to maintain their
existence in the uterus for a long period is indicated by Ries' observation of
intact villi in a superficial uterine sinus 18 years after the last pregnancy.
It is of course possible to doubt the accuracy of the history in this case. Yet
the villi had become fused with and were nourished by the walls of the veins.

Gross Anatomy and Structure. — Three main types of the disease may be
distinguished by gross and microscopical structure, while between these there
are transition cases.

(1) Chorio-adenoma destruens. Destructive placental mole.

(2) Choriocarcinoma.

(3) Syncytioma and syncytial endometritis.

(i) Chorio-adenoma Deslruens. — The destructive recurring and perforat-
ing placental mole yields a characteristic gross appearance. The uterus is
usually much enlarged, reaching at times a length of 13 to 17 cm. (Huguenin).
The wall is thick and honeycombed, or a definite cavity appears in the
musculature, or a transverse or longitudinal septum separates tumor cavity
from uterine canal (Volkmann). In advanced cases the serous surface may
present nodular elevations due to subserous veins distended by tumor masses.
and similar extensions may be traced into parametrium, tube, cervix, and
vagina. Perforation of the wall has been recorded in seven cases (Curtis,
Lit.). In Waldo's case hemorrhage appeared to be controlled by a fringe of
omentum, and the patient recovered. All the others died. In Engstrom's
cases separated vesicles were found on the peritoneal surface.

The contents of the uterus vary with many circumstances. When the
mole remains in situ it presents the usual bulky tumor adherent overT the
implantation site and altered by hemorrhage or suppuration. When the mole
has been expelled coarse shreds of necrotic tumor or larger lobulated
masses resembling blood-clot adhere to a portion of the wall, and are con-

548

N EOF LA STIC DISEASES

tinuous with the distended sinuses. Usually after curettage the tumor is
represented by a ragged cavity in the wall.

The endometrium may be normal in early cases or the seat of implanted
vesicles (Mojler) or extensively eroded.

The gross diagnosis of malignant mole may sometimes be approached
from inspection of the discharged material. The occurrence of great varia-
tions in the size of the vesicles, with many small opaque coherent nodules,

in material which comes away in fragments
with difficulty and in rather reduced amount,
are suggestive signs.

The structure of chorio-adenoma is quite
specific. It presents an overgrowth of all
the elements of the chorionic villi, con-
nective-tissue core, Langhans' cells, and
syncytium. The connective tissue is com-
pact cellular but not very vascular. It may
b e greatly increased in thickness and swollen
by edema but mucinous changes are absent
or slight. An unusual overgrowth of fibro-
blasts has occasionally suggested a sarco-
matous tendency. Neumann described rows
of large round or elongated cells in the
stroma, which he derived from the syncytium
and regarded as a sign of malignancy. They
are by no means constant.

The Langhans' cells appear in greatly
increased number, forming multiple layers
at the bases of villi and long broad sheets not
directly connected with the villi. Their size
varies little from the normal but the nuclei
are hyperchromatic. They are sharply sep-
arated from the overlying syncytium. When
denuded of syncytium they are usually covered
by fibrin, which suggests that they yield a
coagulating ferment (Curtis). These cells
present a clear cytoplasm, contain glycogen,
and rarely suffer necrosis.

The syncytium appears in the early stages
in the form of well-nourished actively sprout-
ing buds of strongly acidophile cytoplasm
with abundant compact hyperchromatic
nuclei. The syncytial buds may be very
large and abundant and constitute the chief
element of the neoplasm (Solowij, Gott-
schalk). Some early observers were thus led

to believe that the tumor process resided exclusively in the syncytium. A
pure syncytioma, however, has not been demonstrated.

In more fully developed cases the syncytium grows not only in buds
but in elongated sheets covering the increasing masses of Langhans' cells.
"Syncytial wandering cells" is a term applied to derivatives of the
syncytium, which are large or giant polyhedral cells occurring singly or
in groups, lying in the folds of villi, or loose in the blood-spaces, or infiltrat-
ing the walls of veins or the musculature. They are present in normal
chorions, and in benign hydatid moles, and are distinctly increased when

FIG. 225. — Chorio-adenoma.
vasion of uterine sinuses.

In-

C HO RIO MA (CHORIONEPITHELIOMA )

549

a malignant mole is altered by hemorrhage or inflammation. They are,
therefore, less vigorous than either of the other cell types, if not distinctly
degenerative.

The differential diagnosis between a benign and a malignant hydatid
mole usually presents no difficulty. The distance separating the ordinary
epithelial proliferation of the hydatid mole from a typical chorio-adenoma
is very great and may be recognized at a glance, as may be seen from the
accompanying figures. There is, however, an intermediate group of cases
in which an unusual overgrowth especially of syncytial buds, less markedly
of Langhans' cells, suggests a malignant capacity and leaves the observer
in doubt. After encountering several of these cases and learning of their
wholly favorable course, I have had to extend my ideas of the limits of epi-
thelial hyperplasia in benign moles. There may be very considerable over-
growth of epithelium in moles which pursue a favorable course or in which

9 '*'•';- ^•^U~/<A'-*

; -^ ": ":;l v^^-. \ "\. * pttMSI

FIG. 226. — Chorioadenoma. Preservation of villi, orderly syncytium, and Langhans' cells.

an unfavorable outcome results from hemorrhage or infection. It is possi-
ble, however, that the same structure may not always signify the same degree
of penetration of the uterine sinuses. In Waldo's case a perforating mole
was regarded as of benign structure. It must be admitted that serious
damage to the uterus may result from hydatid moles which are not distinctly
neoplastic, but such cases are extremely rare, and do not belong in the present
category. In Solowij's case, with deported villi in the lung, it was stated
that the epithelium of the villi in the extensively invaded uterus showed
comparatively little proliferation.

Metastases in chorio-adenoma are comparatively rare and their signi-
ficance is peculiar. The intravascular position of the infiltrating villi favors
the separation of portions of the epithelium and even of the core, which
become lodged in various capillary systems, including parametrium, vagina,
and lungs. As a rule the metastases of chorio-adenoma are limited to the
pelvic region, but occasionally they occur in the lung. In the vaginal wall

550

NEOPLASTIC DISEASES

they form small circumscribed bluish projecting tumors. Several of these
have been removed after the expulsion or extirpation of the original tumor
and the patient has recovered (Neumann, Pick, Engstrom, Kaufmann).
The metastases consisted chiefly of syncytium.

Similar vaginal tumors have occurred also with benign hydatid mole.
In such a case Pick found in the vaginal tumor segments of villi with hyaline
stroma and syncytium largely necrotic. In two cases of abortion and three
of hydatid mole Dunger found mild prolif erative changes in embolic syncyt-
ium. It is evident, therefore, that vaginal emboli do not necessarily signify
the presence of a malignant mole in the uterus. The structure of the vaginal
tumor is of first importance in the prognosis. When actively growing Lang-
hans' cells are present, the case may safely be regarded as malignant. I

FIG. 227.— Portion of a benign hydatid mole.

have once found only feebly proliferating syncytium in a vaginal tumor in a
case which progressed unfavorably. When the cores of villi are present the
case is at least relatively benign, but in Lindfors' case which was of this type,
pulmonary metastases followed. It should be remembered that normal villi
may be deported and lodged in small veins. The structure of the original
tumor has important bearing on the prognosis of vaginal metastases. In 15
cases with vaginal metastases which recovered I find that the original tumor
contained villi in nine, the structure was atypical (syncytioma) in three, and
indefinitely described in two. In Schlagenhaufer's case the structure was
possibly that of choriocarcinoma with excess of vacuolated syncytium.

Pulmonary metastases, as indicated by the symptoms of cough and hemop-
tysis, occurred in seven recovering cases of chorioma collected by Fleisch-
mann.

CHORIOMA (CHORIONEPITHELIOMA)

551

(2) Choriocarcinoma. — The majority of cases of chorioma pursue a fatal
course, are marked by a characteristic structure in which villi are absent, and
the epithelial growth is anaplastic and disorderly. They produce widespread
metastases, and are best designated as chorionic carcinoma.

In choriocarcinoma the uterus is only moderately enlarged and may
appear normal in size, but is usually the seat of a relatively small compact
opaque infiltrating tumor, commonly located at the placental site. In a
few cases no tumor has been demonstrable in the uterus, it having been re-

FIG. 228. — Benign hydatid mole. Slight epithelial proliferation.

moved with the placenta or by the curet, or the growth has arisen in
tube or ovary. Schmorl reported a case of malignant chorioma in the organs,
appearing first in the vagina, 18 weeks after normal labor with a normal
uterus.

The chorionic carcinoma is locally aggressive. It invades the "sinuses
without distending them as does the dissecting mole, it splits up the mus-
culature, and it rapidly traverses or perforates the wall, traveling mainly
by the sinuses. While often infiltrated with blood the uterine tumor is

552

EOPL A STIC DISEA SES

FIG. 229. — Benign hydatid mole. Moderate proliferation of syncytiurru

FIG. 230. — Benign hydatid mole. Considerable proliferation of Langhans' cells.

CIIORIOMA (CHORIONEPITHELIOMA)

553

usually cellular and compact but friable. It is not capable of complete re-
moval by the curet, except possibly in very rare cases.

The structure is rather uniform and highly characteristic. The tumor
consists of bands and masses of acidophile syncytium commingled in dis-
orderly relations with islands of actively growing Langhans' cells. The
stroma of villi is absent, showing that the cells, as in other carcinomas, are
capable of growing apart from their ordinary sources of nutrition. The
proportions of the two cell types vary but both are always represented.
The syncytium may appear in abundant isolated, elongated, and coherent
buds resembling the malignant mole, or it may form diffuse sheets with large
vesicular nuclei and resemble giant squamous epithelium. A preponderance

FIG. 231. — Cross section through a uterus the seat of choriocarcinoma.

of orderly syncytium belongs to the less anaplastic growths. Some authors,
as L. Fraenkel, have surmised that variations in the type of syncytium in
chorioma signify a varying origin from villi, or endothelium", or uterine
epithelium. Lebret and others describe pseudochoriomas arising from the
uterine epithelium. Yet there is no satisfactory evidence that the syncytium
of choriocarcinoma has more than one source which is from villi.

The Langhans' cells may appear in compact masses sheathed by
syncytium and differing little from the normal type, or in the more ana-
plastic tumors these cells are hypertrophied, nuclei hyperchromatic, and the
separation from syncytium is imperfect. Mitoses are limited to the
Langhans' cells.

554

NEOPLASTIC DISEASES

S£fcv*M;.7'

3P^lS*£i^:

FIG. 232. — Structure of vaginal nodule in Polano's case of latent choriocarcinoma.

FIG. 233. — Choriocarcinoma. Above, masses of syncytial cells resembling squamous
epithelium. Below, group of Langhans' cells.

CHORIOMA (CHORIONEPITHELIOMA)

555

In the sinuses the tumor masses may lie loosely or they become adherent
to the walls and infiltrate through the endothelium. Fibrin masses are
often mingled with the tumor-cells especially in the sinuses, and here many
of the syncytial wandering cells appear. In all forms of chorioma infiltra-
tion of the uterine wall by syncytial wandering cells is more marked than in
normal gestation or hydatid mole.

Reactive inflammation occurs about necrosing portions of chorio-
carcinoma and has been interpreted as a sign of local regression.

Metastases in choriocarcinoma are of early occurrence and in advanced
cases are invariably present. Among 455 cases of all types of chorioma
collected by Pollosson and Violet vaginal metastases occurred in 93, pul-
monary in 133, cerebral in 40.

They may appear first in the vaginal veins and prove to be the initial
symptom. On excision these tumors present the usual malignant structure.
In the lungs they form multiple protuberant hemorrhagic nodules, well
circumscribed by the walls of the veins in which they lie. Here the structure
often varies from that of the uterine growth, syncytium is scanty or absent,

FIG. 234. — -Choriocarcinoma invading uterine sinus.

Langhans' cells small and abundant, and the structure may be difficult to
separate from other cellular carcinomas. In liver, brain, spleen andjudney
the tumors resemble those in the lungs.

(3) Syncytioma. Atypical Chorioma of Marchand. Syncytial Endo-
metritis. — In a limited group of cases the uterus fails to present a well-
defined tumor process of the type of chorio-adenoma or choriocarcinoma,
but a portion or the whole of the wall of the cavum is infiltrated by many
large or giant acidophile cells of the general type of syncytial wandering
cells. To this process the term syncytioma is applied. In Schmauch's
list about 5 per cent, of the fatal cases were of this type. The uterus is
usually much enlarged and may contain a bulky mass composed of uterine
stroma infiltrated with the above cells mingled with much fibrin, and necrotic
detritus, and swollen by exudate and hemorrhage. The writer's case 9
illustrates this condition. Or the process may be limited to a small area
of mucosa (v. Velits). Or the entire wall may be thickened, as in Cull en's
case, but a definite intra-uterine tumor is wanting. Rarely the process
extends through the wall into the broad ligament.

The walls of vessels are swollen and infiltrated by large cells. The

556

N EOF LAST 1C DISEASES

stroma contains lymphocytes, plasma-cells, leukocytes, blood and fibrin.
A reactive growth of endothelial cells and fibroblasts may appear. The
muscle-cells develop multiple nuclei and split up into acidophile fragments
which resemble syncytial wandering cells. In three cases I have been unable
to trace any participation of uterine epithelium. The decidual cells probably
participate in the process or form the main element in certain cases in which
the lesion is diffuse. Such a condition is that described by Cullen in which
the uterus, as large as a 5 months' pregnancy, was lined by a thick, irregular,
largely necrotic tissue covering the entire endometrium. Here many areas of
degenerating decidual cells were described. In many cases it is difficult to
distinguish between decidual cells and wandering syncytial cells and this
difficulty is increased when the tissue is degenerating 'and infiltrated by
leukocvtes.

• I ^WT "^l*JPr -PW

*i* •£

').*.•• ' t.f' *¥;i

K'/Mm aMh •'., - " ' • • HP » sit

if/". :<ms

;*•'<*

FIG. 235. — Giant cells in syncytioma.

Progressive metastases are not observed, but Fleischmann described a
vaginal tumor presenting the structure of atypical chorioma, which may
have arisen from deported villi.

The conditions included in the category of syncytioma probably arise
from several antecedent processes, and chiefly from abortion, hydatid mole
and chorio-adenoma. It is unlikely that fully developed choriocarcinoma
ever suffers such extensive regression as to produce this anatomical picture.
Excessive invasion of the uterine muscle by syncytial wandering cells is
observed with retained chorion, hydatid mole, and especially with chorio-
adenoma. After spontaneous expulsion or imperfect curettage of a malignant
mole proliferation of wandering cells may continue, and when hemorrhage and
infection follow, the condition called syncytioma may apparently develop.

CHORIOMA (CHORJONEPIIHELIOMA) 557

When the process has perforated the wall it must have resulted from a
dissecting malignant mole which has undergone the spontaneous regression
which many observations show may overtake this process.

Whatever may be the original conditions which result in excessive
infiltration by syncytial wandering cells, it is clear that the disease is not a
progressive neoplasm but a regressive and inflammatory process appearing
in various stages and after variable antecedents. I have elsewhere considered
at some length the observations supporting this view (S.G.O., 1910).

When the syncytial wandering cells are abundant, well nourished and
form more or less compact sheets, a partial neoplastic quality is suggested
and the term syncytioma may be employed. When the lesion is more diffuse
and complicated by exudative and productive inflammation it appears to be
well designated as syncytial endometritis.

The remarkable extent to which the syncytial wandering cells may invade the uterine
wall in normal gestation has been emphasized by many observers and especially by R.
Meyer. He shows that these cells may be extremely abundant in the superficial portions
of the musculature, often approaching the form of decidual cells, invading the walls and
even the lumen of veins, and extending to the serosa. While normally disappearing shortly
after gestation, in various pathological conditions as carcinoma, myoma, retroversion, or
mole, they persist and multiply by mitotic division, yielding a picture which may readily
be mistaken for sarcoma. Their behavior indicates active ameboid properties. An
imperfect development of decidua favors deep invasion of villi and syncytial cells
(Bauereisen).

Clinical Course of Chorioma. — The different forms of chorioma vary
considerably in their clinical features.

Chorio-adenoma regularly follows hydatid mole, and occurs usually in
multipart over 40 years of age. Of 23 cases collected by Curtis and Oui the
mole was found in situ in 13, and had been expelled in 10. After expulsion
of the mole there may be a period of a few days or a few months in which
the patient is free from symptoms. Hemorrhage, interpreted as profuse
menstruation or metrorrhagia, or more alarming, is the first symptom. In
Pick's doubtful case a vaginal nodule was first noticed. The bleeding
begins uniformly in the third month of a supposed pregnancy or at any period
after expulsion of a mole. The bleedings become more severe and if un-
checked the patient may succumb in 2 to 8 months from exsanguination. In
about 13 per cent, of the cases infection occurs with fatal septicemia. Rup-
ture of the uterus, spontaneous or from curettage, is an occasional fatal
complication.

The treatment commonly employed is hysterectomy. It was followed by
recovery in n of 14 cases, with three deaths (Curtis). Manual extraction of
the mole and curettage were successful in two cases reported by Herz and one
patient subsequently gave birth to a healthy child.

Yet the anatomy of the disease does not encourage the belief that many
of these cases can be completely freed of the infiltrating villi by the curet.
Radium may prove of value in this condition, but the danger of hemorrhage
and infection complicates its use.

Veit emphasizes the necessity of minute examination of all portions
of the placenta extracted after abortion, mole, or normal gestation, as the
best means of prevention of chorioma. He would even extirpate the uterus
when the wall is found to be very thin over the implantation site of a retained
placental remnant, but here microscopical examination of the tissue seems
to be a better guide.

Choriocarcinoma gives less definite clinical manifestations of its onset
than do the other forms of the disease. It follows normal labor promptly
or after a long interval, ectopic pregnancy, retained placenta, hydatid mole,
and abortion. Hemorrhage is again the chief symptom but it is not as

558 N EOF LAST 1C DISEASES

severe as with malignant polyps. The uterus is often only slightly enlarged..
Many cases are first recognized by examination of curettings for hemorrhage.
All pelvic symptoms may be wanting and the illness begins with hemoptysis,
hemiplegia, peritonitis, severe vomiting, or the appearance of a vaginal
tumor. Occasionally the disease masks as puerperal fever (Curtis).

If not interrupted by hysterectomy the disease progresses with hemor-
rhages, anemia, appearance of metastases with their special symptoms,
or septicemia. Death results from cachexia. hemorrhage, pulmonary
embolism, peritonitis, or cerebral invasion.

With or without hysterectomy the disease usually lasts from 6-18 months.
Much more rapid courses are occasionally observed in which death results
from infection or hemorrhage. Schlagenhaufer recorded a fatal issue 34
days after normal birth, with an infected uterine tumor and metastases in
vagina, lungs, kidney and spleen. More prolonged duration with an initial
latent period probably accounts for the late appearance of symptoms in some
of those cases developing years after the last gestation. In advanced stages
the symptoms are dominated by the metastases, cough, hemoptysis, and
dyspnea with pulmonary lesions, and paraplegia, delirium, and convulsions
with cerebral extensions.

Hysterectomy was performed in 181 cases of chorioma of all types col-
lected by Curtis and Oui, 1903-12, with 17 operative deaths. I have been
unable to find any record of operative cure of choriocarcinoma. Schmauch
emphasizes the necessarily fatal character of the process and advises against,
operation as. hastening the fatal issue. When metastases have occurred
operation is certainly contraindicated but it seems impossible to affirm that
the removal of a uterine focus and even of accessible metastases may not in
rare instances affect a cure. On the other hand it seems almost impossible to
avoid displacing intravascular fragments during hysterectomy, and thus
accelerating dissemination.

Syncytioma. — The early symptoms of syncytioma vary widely with the
different antecedent conditions. The disease has followed abortion, hydatid
mole, and placental polyp, but it is notable that a definite history of such re-
lation is often lacking. Until such clinical data are more fully supplied the
exact nature of many of these cases must remain in doubt.

The first symptom is usually irregular and profuse metrorrhagia. The
uterus is then found enlarged, often to considerable dimensions. Infection
of the uterus is readily established and many cases die of sepsis or perito-
nitis after a comparatively brief course. Curettage yields masses of necros-
ing material, or a tumor-tissue which is of uncertain significance and is
often regarded as sarcoma. Many cases, however, recover after curettage,
which Menge recommended as the operation of choice. When the uterus
is extensively damaged, the wall thin, and infection active, hysterectomy has
usually justified itself. Yet the disease has a high mortality. The mortality
from chorioma as a whole is high but decreasing. In Teacher's statistics
of 1 88 cases there were 65 recoveries but some were doubtless reported
prematurely.

Recovery from Chorioma After Curettage or Partial Removal. — Of eight
cases of chorioma collected by v. Velits which recovered after curettage, in
five I find that the tumors were composed chiefly of wandering syncytial
cells and belonged in the group of syncytioma or syncytial endometritis, while
two were proliferating hydatid moles (Risel, Blumreich), and one was inade-
quately described. Even in this group of cases curettage, although followed
promptly by hysterectomy, has a high mortality.

In eight cases recovery followed partial removal of the tumor, metastases

C HO RIO MA (CHORIONEPITHELIOMA )

559

or extensions remaining (Ewing, Lit.). In five of these the tumors were,
wholly or chiefly syncytial. Some of these cases point to a possibility that
an isolated metastasis in the milder forms of chorioma may regress after
removal of the main tumor. For typical choriocarcinoma this possibility
cannot be admitted.

Deportation of Normal Chorionic Elements.— That syncytium frequently
lodges in the pulmonary capillaries has been shown by Schmorl who found
them in 80 per cent, of 158 cases. Dunger has stated that portions of villi
even including stroma may be lodged in pulmonary and pelvic vessels, es-
pecially after violent labor, and he claims that such deported cells may exhibit
transitory proliferation. It must therefore be assumed that benign moles
may give rise to similar metastases and Pick has described such a vaginal

FIG. 236. — Curettings in a case of choriocarcinoma.

metastasis containing several segments of villi with stroma and syncytium
largely necrotic. The occurrence of villi or other chorionic elements in
distant veins should not be regarded necessarily as a sign of malignancy.
Veit states that metastases can be regarded as certainly malignant only
when they occur beyond the usual pelvic depots for deported villi. Pick
claims that the histology of deported villi in cases which recover may not
differ from that in cases which develop malignant tumors. It may readily
be supposed that all emboli from uterine tumors do not succeed in producing
metastatic tumors. Some may regress because of local factors while others
go on growing. I have seen very extensive regression, hyaline change, and

560 NEOPLASTIC DISEASES

fibrin formation in a vaginal metastasis in a case which succumbed to cere-
bral invasion. Yet this vaginal tumor contained scattered small islands
of well-nourished Langhans' cells. Moreover the disease in this patient
developed three years after the last gestation. As a rule the harmless
emboli are found imbedded in fibrin and degenerating, as is sometimes seen
in the veins of the broad ligament in tubal gestation.

The further question arises whether a malignant tumor may arise from
deported normal chorionic cells. Schmorl has reported a case of chorio-
carcinoma in the organs, appearing first in the vagina, 18 weeks after normal
labor, with a normal uterus. Chorioma has frequently arisen after normal
labor at term, and since it is unlikely that a malignant change in the placenta
can escape detection, the suspicion has arisen, and has been entertained by
Marchand, that a malignant tumor may arise from deported normal placental
elements. Strongly against this possibility stand the frequency of partial
hydatid degeneration especially after abortion (80 per cent., Stoerk), the
frequent failure to examine the placenta, and the occurrence of ectopic or
teratomatous chorioma.

After abortion (Schlagenhaufer, Schmidt) and after hydatid mole (Pick,
Schmidt) the uterus was found normal, but vaginal tumors containing syn-
cytiuni and Langhans' cells were excised and the patients recovered. In
these cases it must be held that the vaginal tumors were deported normal
villi or fragments of moles, with, at most, transient proliferation. In three
of them there were marked signs of degeneration in the vaginal tumors,
but in Schmidt's case, which was reported rather soon, the tumor was
depicted as an active chorio-adenoma.

On the other hand, after normal labor (Schmorl), and during gestation
at term (Walthard) vaginal tumors of the type of choriocarcinoma and the
uteri which proved to be normal, were extirpated, but the patients died
with metastases. In Lindfors' case the uterus was found normal at autopsy.
These, and other cases collected by Risel, are very difficult to explain, and
they suggest that deported normal villi or their derivatives may develop into
choriocarcinoma. It should be noted, that in some of the cases the placenta
was not examined, but this objection does not apply to Walthard's
observation.

Ovarian Changes in Chorioma. — In 1895 Marchand pointed out the
notable frequency of ovarian cysts in chorioma, and later (1905) Patellani
found that in 68 fully reported cases at that date 62, or 91 per cent, presented
bilateral cystic changes. This proportion is probably too high unless one
includes marked grades of the small cystic cavities of gestation, but it is quite
evident that pronounced cystic changes in both ovaries are so frequent in
chorioma as to constitute a specific anatomical feature of the disease, and
one which invites explanation. In several cases the cysts have receded after
successful extirpation of the tumor or the mole, but in fatal chorioma they
persist.

The cysts may be very numerous and small, or the ovaries may be bal-
looned out by roomy multilocular chambers to the size of an orange. The
contents are thin, yellowish, serous fluid containing albumens, lipoids, and
a little mucin. The walls of the large cysts are lined by a deep layer of
large overnourished granular polyhedral cells exactly resembling lutein
cells of the early corpus luteum.

The origin of the cysts has not been traced with entire certainty. Most of them
probably arise by distention and overgrowth of corpora lutea of various ages (Jaffe,
Orthmann). The small multiple cysts of gestation are not so clearly traced. Seitz
regards them as arising from the atresic follicles of the ovary, which- begin to hypertrophy

CHORIOMA (CH ORION EP I THELIOMA )

561

in the sixth week of gestation up to term, and he adheres to the view that these follicles
have a different significance from the corpora lutea. Stockel finds that during gestation
the theca cells of the follicles wander out into the ovarian stroma forming lutein cell
groups from which the small cysts arise, and Schaller and Pforinger found such cell groups
so abundant as to suggest a tumor process. Whatever the origin, the structure and be-
havior of the cysts indicates that they have an identical significance in representing a
disorder of lutein secretion.

L. Fraenkel concluded that interference with the lutein function resulted in death of
the ovum and chorioma, since excision of the corpus luteum prevented implantation and
growth of the ovum. L. Pick interpreted the cysts as evidence of hypersecretion leading
to excessive growth of the chorion.

The suggestions that the cysts result from venous congestion (Seitz), that they are

FIG. 237. — Choriocarcinoma of uterus. Cystic ovaries.

equally characteristic of normal pregnancy (Wallert), and that they belong to the ordinary
nutritional changes of pregnancy (Dunger), seem quite inadequate explanations.

Veit considers the possibility that a primary ovarian disease yields a diseased ovum
which degenerates and entails abnormal proliferation in the chorion. Yet normal labor
may be followed by chorioma.

Chorioma after tuba! pregnancy occurred in 12 cases collected by Risel,
to which may be added later reports by Garkisch and Bazy. None was
recognized clinically, all were malignant forms, and all but one fatal. Ova-
rian pregnancy seems to have been the origin of a fatal choriocarcinoma
described by Kleinhaus.

Teratomatous chorioma in the female has been described by Lubarsch,
Pick, and Bock.

CHAPTER XXIX
CYSTS AND EPITHELIAL TUMORS OF THE OVARY

Ovarian Cysts. — Simple cysts form in the ovary under several conditions.
They are often small and bilateral, giving rise to a characteristic appearance
designated as small cystic ovaritis or degeneration. Larger single or multiple
cysts of inflammatory or mechanical origin pass under the term hydrops
follicularis. The first appearance of mild neoplastic processes in dilated
follicles deserves recognition by the term simple cystoma. Both benign and
malignant epithelial tumors of the ovary are usually cystic and thus form a
large and important group of varied and uncertain origin. The corpus
luteum is a frequent source of cysts of peculiar type. A group of combina-
tion cysts includes tubo-ovarian cystoma, dermatocystoma, and combinations
of corpus luteum cysts with other forms. The simple dermoid • regularly
assumes a cystic form, and many teratomas become cystic.

Small multiple cysts (cystic degeneration) represent several different
anatomical processes.

(a) Chronic ovaritis with thickening and fibrosis of the cortex may be
associated with dilatation of many follicles which appear as small translucent
elevations of the surface (Hegar, Bulius). It occurs chiefly in early sexual
life, and is interpreted by Nagel as a premature maturation of follicles.
Yet it is observed also in children and newborn infants. I have observed it.
with general edema of the ovary due to torsion. A moderate and variable
degree of development of small cysts must be regarded as physiological
and occurs especially in infants and in gestation (Felix).

(b) In elderly subjects the deeper portions of the cortex may be the seat
of multiple small follicular cysts lined by overnourished but undifferentiated
epithelium, v. Kahlden regarded these structures as multiple adenomas
and Walthard derived them from superfluous groups of germ epithelium
which have .failed to develop into follicles.

(c) Remnants pf the primitive nephros have been identified in, the ovary
and Babo traces certain multiple small cysts to these structures, v. Franque
describes such cases, the cysts being lined by flat epithelium.

(d) Multiple small or minute translucent cysts may be found over the
surface of ovary and tubes and their ligaments, and are lined by flat, or
ciliated or goblet cells. Their origin is probably not uniform. Some
are referred by Walthard to superfluous undifTerentiated germ epithelium.
Others give evidence of a proliferation of peritoneal epithelium with meta-
plasia of the inclosed cells. Pick regards them as miniature tumors which
reveal the great proliferative capacity of germinal and peritoneal epithelium,
and believes that they may go on to produce cystadenomas. They have
been extensively discussed and variously interpreted by Schickele, v. Franque,
R. Meyer and others.

Simple follicular cysts (hydrops follicularis) arise from distention of
Graafian follicles by an inflammatory serous exudate. These cysts are of
small size, seldom as large as the fist, and when several develop in the same
ovary they may be mutilocular. Occasionally they fuse with lutein or
dermoid cysts. In some cases the condition must be interpreted as an

562

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY 563

exaggeration of the small cystic chronic ovaritis. The contents are serous
albuminous fluid, without pseudomucin, but blood and fatty detritus may
be added. The wall is composed of the distinctly ovarian tissue in a state
of atrophy and fibrosis. Little ovarian stroma may be recognizable and the
epithelial alveoli of cystadenomas are missing. The follicular epithelium
is usually destroyed. Low, warty, fibrous excrescences may appear in the
inner wall. The fairly constant occurrence of inflammation of the pelvic
organs points to the inflammatory origin of these cysts. Single or multiple
cysts are observed in the newborn (Virchow, Klob, Waldeyer).

Simple Serous Cystoma. — This specific form of ovarian cyst is closely
related in structure and identical in origin with the simple follicular cyst,
but differs from it in the greater size, preservation and overgrowth of lining
epithelium, and in the greater vitality of the connective tissue. These fea-

FIG. 238. — Structure of wall of simple cystoma of ovary.

tures justify the view that the process is essentially neoplastic. Although there
are transitional cases between the simple follicular cyst and the serous cyst-
oma there is practical value in distinguishing between them. The forrner loses
its epithelial lining, its walls are acellular and it remains of comparatively
small size. The cystoma grows to bulky dimensions, its walls are cellular
and actively growing, and the lining cells multiply, even forming low papillary
projections. In size the cystoma is usually as large as a child's head and
may reach the dimensions of the bulky cystadenoma. Rarely it is bilateral
(Olshausen, Bulius, Orth). The cavity is usually single. The contents
are serous fluid, free from mucin, but often mingled with blood or with fatty
detritus or crystals. The lining is of cylindrical epithelium, single cells
or syncytium, and these may form low warty projections. The wall is
composed of cellular, vascular connective tissue without epithelial structures,
and it may form nodular or papillary projections with the structure of an

564 N EOF LA STIC DISEASES

active fibroma. The simple cystoma probably arises from ovarian follicles,
but from which form of these structures is not known. Fully formed Graafian
follicles may develop papillary ingrowths (Williams), and it is probable
that some cystomas are of such origin. Hence many authors class these
cysts with follicular hydrops. The occurrence of transition forms leading
to cystadenoma indicates that some are derived in the same manner as
cystadenoma, from misplaced and embryonal cell masses.

Tubo-ovarian Cysts. — The simple ovarian cyst may communicate with
a fusiform dilatation of the tube forming a composite cyst resembling in form a
glass retort. Such cysts may reach considerable dimensions. The walls
are thin and contents usually serous. At the ostium of the tube there
may be one or more folds on the inner surface from which radiate
the elongated fimbrise imbedded in the inner wall. The tubal portion may
present several folds or partial contractions. The lining of the ovarian
compartment is of flat cells, that of the tubal part is of cylindrical and some-
times ciliated epithelium. Corpus luteum cysts may fuse with the tube, in
which case the wall presents the usual feature of such cysts. Shreds of
smooth muscle persist in the wall of the tubal portion, but the ovarian
section is thin and fibrous. The origin of the tubo-ovarian cyst is probably
to be referred to the union of an already formed ovarian cyst with the lumen
of a tube which has become adherent to the cyst wall through chronic pro-
ductive inflammation. Evidences of this inflammatory process are regularly
found in the form of adhesions of the cyst, peritoneal thickenings, salpingitis
and peri-ovaritis (Veit). The communication is established by pressure
atrophy. The occurrence of slight and early dilatation of the tube accords
with this view. Finding the ovarian remnant limited to a segment of the
wall in 12 of 18 cases, Zahn concluded that the composite cyst arises chiefly
in the tube with subsequent involvement of the ovary, but the eccentric
position of the ovarian remnant is common to other ovarian cysts. Moreover
the ovarian portion is usually much the larger (Martin).

Corpus Luteum Cysts. — The corpus luteum is frequently the seat of
dilatation with overgrowth of lutein cells, and gathering of serous fluid,
which produces cysts. In size the cysts are first small and easily recognized
by the yellow layer of lutein tissue. Later they are found as large as an
orange or a child's head, but the larger ones are often complicated by hemor-
rhage or suppuration. While usually single and unilocular, they appear
as bilateral multilocular cysts with hydatid mole. The wall is composed of
atrophic ovarian tissue and is lined by a corrugated layer of yellow lutein
tissue which is often incomplete but seldom absent. The contents are
clear serous fluid, but blood is often extravasated by capillary hemorrhages,
bulky spontaneous bleeding, or by strangulation. Rupture of the cyst
may lead to retro-uterine hematocele simulating extra-uterine gestation
(Lunzer, Lit.). Suppuration, chiefly from gonococcus infection, frequently
occurs, replacing the lutein tissue with granulation tissue, and distending
the cyst with thick muco-pus. A definite group of ovarian abscesses are
of this origin. They are lined by hypertrophic granulation tissue in which
are remnants of lutein tissue, eosinophile leukocytes, plasma-cells, and often
demonstrable gonococci (Langer, E. Fraenkel). Garkisch observed tuber-
culous infection. The lutein-cell layer is early subject to local infarction
and necrosis. The structure reveals notable variations, indicating several
modes of origin of these cysts. All present an outer coat of a cellular con-
nective tissue derived from the external layer of the follicle or the distended
ovary.

(i) Many cysts show an internal lining of hyperplastic lutein-cells

CYSTS AND EPITHELIAL TUMORS OF THE OVARY 565

covered by fibrin. This structure is best explained as a dilatation of the cor-
pus luteum beginning before any regressive changes have set in, and is ob-
served in cysts of all sizes. It is also observed in the multiple cysts arising
from atresic follicles in hydatid moles.

(2) The lining may be composed of hyaline and lamellated tissue beneath
which is a layer of lutein-cells. Such cysts probably arise after pronounced
regressive changes have occurred in the corpus luteum. Many such cysts
contain chiefly blood in various stages of absorption and organization, and
should be interpreted as hematomas in corpora lutea (Fraenkel, Orthmann).

(3) An epithelial lining is occasionally observed, and is composed of
a single layer of cylindrical or flat-cells, which lie either directly upon lutein-
cells as in type (i), or upon the hyaline connective tissue as in type (2).
The origin of this lining is still undetermined. If the cyst arises from an
atresic follicle the epithelium could be derived from the cells of the membrana
granulosa. Ciliated epithelium was found by E. and L. Fraenkel, who
remained in doubt as to its origin, but Pick and Pfannenstiel hold that such
cells must have been derived from the germinal epithelium entering the
cyst at the time of rupture. Connective tissue may appear in the centers
of lutein cysts and the flat character of the lining cells is consistent with
an endothelial origin.

(4) Bilateral multilocular lutein cysts commonly appear with hydatid
mole and chorioma. Kroemer finds them in 59 per cent, of moles and
Patellani in 90 per cent. Since the condition is probably an excessive grade
of the small cystic changes of gestation the estimated frequency will vary
according to the size of the cysts included. I find them by no means constant
in chorioma.

In pronounced cases the cysts reach large dimensions, the walls are thin
and neighboring cysts fuse. The inner lining is of remarkably hypertrophic
and hyperplastic lutein-cells, which may slightly infiltrate the walls. In
small cysts remnants of the granulosa cells may persist (Stoeckel). Lymph-
cysts may appear in the walls.

The natural course of the cysts is regression after removal of the mole.
Albert saw complete disappearance of large bilateral tumors two months
after expulsion of the mole. Yet Pfannenstiel reports two cases of rapid
increase after curettage.

That a true neoplastic process exists in any form of lutein cyst appears
doubtful, although the morphology of some early cysts is suggestive of
unrestrained overgrowth. In the early stages of some cystic corpora lutea
I find o^ernourished alveolar groups of small lutein-cells with hyperchromatic
nuclei and layers of such cells splitting up the ovarian tissue. The ap-
pearance is not distinctive of a true neoplasm. The late course of the lutein
cysts fails to develop the essential features of a neoplasm, as progressive
growth, infiltration or metastases. The most advanced cases retain as a
rule the cystic form and the lutein-cells tend toward atrophy. The process
must be interpreted as a form of overgrowth due to overnutrition, or excessive
function, aided by inflammatory factors. The existence of a true tumor of
lutein-cells is not thereby excluded, but the reported cases of lutein-cell
tumors are not entirely satisfactory.

Lutein-cell Tumors. — The suggestion that the corpus luteum might give
rise to characteristic tumors of the ovary was first made by Rokitansky
in 1859 and later endorsed by Klob and by Klebs. Since that time several
authors with more or less confidence have attributed the origin of certain
tumors to the lutein-cells. Some of these tumors have been described as
sarcoma, others as carcinoma (Kroemer, Lit.). Voight's case was a large

566 N EOF LA STIC DISEASES

solid tumor, grayish yellow on section and showing a perithelial or diffuse
arrangement of large cells resembling lutein-cells. The tumor obstructed
labor. Sante also reported a large tumor appearing in the third month of
pregnancy. It was soft reddish yellow and infiltrated with blood, and the
section showed the structure of alveolar sarcoma with septa inclosing areas
of cells many of which had all the characteristics of lutein-cells. Six months
later the patient succumbed with nodular tumors of omentum. Grousdew
found in the walls of a large cystic tumor numerous groups of polyhedral cells
which he interpreted as lutein-cells. He concluded that the tumor arose
from the cells of one of the corpora albicantia. The patient died with
peritoneal recurrence in the form of spindle-cell sarcoma, at the age of 60.
Michelazzi referred to the corpus luteum a large yellowish tumor in an elderly
subject. Wendeler speaks of an ovarian tumor resembling a giant corpus
luteum the structure of which confirmed the diagnosis of corpus luteum
sarcoma.

I have observed two forms of tumor-like overgrowth of lutein-cells. In
one the cells retain their original characters and the convoluted layer of
the corpus luteum. In the other the cells are smaller, very compact,
and a diffuse growth obliterates the convoluted layer. I have examined a
tumor, with Dr. L. W. Strong, which strongly suggests a lutein-cell origin.
It measured 2^ X 3 J/9 cm., was solid, yellowish, encapsulated in the ovary,
and resembled an enlarged corpus luteum. The structure was that of alveo-
lar sarcoma, the septa and cells merging insensibly. The cells were large and
small, polyhedral, with clear or slightly granular cytoplasm and dense
borders. Many contained hyaline acidophile globules and scanty pigment
particles.

While, as Seitz concludes, the positive proof of the lutein-cell origin has
not been furnished, yet the gross appearance of these rounded yellow tumors
and their peculiar structure render such an origin probable.

Considerable proliferation of lutein-cells often occurs in the cystic ovaries
of hydatid mole and Schaller and Pforringer have 'described a "carcinomatous"
proliferation in such a case.

Adenoma. — Adenomas of the ovary are usually cystic, but there are rare
forms of solid and of superficial papillary tumors. Two main classes of
cystic adenoma are distinguished chiefly on the character of the cyst contents
and on the epithelial structure. These are the serous and the pseudomucin-
ous adenomas. Both these types may show a glandular (pseudopapillary) or
a papillary structure and some authors, as Olshausen and Kaufmann, prefer
to classify the tumors upon this structural peculiarity rather than upon the
character of the cyst contents. Either plan requires the recognition of
transitional cases and the histogenesis is not sufficiently clear to form a basis
of classification. In each class also there are pure benign adenomas, adeno-
carcinomas, and carcinomas, the structure varying in different cases and in
different parts or phases of the same case.

Serous Cystadenoma. — The serous cystadenomas form about one- third of
the cystic tumors of the ovary. In their earliest stages they are probably
identical with tne relatively small multiple cysts of V. Kahlden and some of
them probably begin as simple follicular cysts. When fully developed they
reach large dimensions but never the very great size of the pseudomucinous
tumors. Most of them are pedunculated growths lying in the peritoneal
cavity, but the papillary type especially may be largely intraligamentary,
displacing the pelvic organs in its growth. Most of these tumors are uni-
lateral, but the more actively growing papillary forms frequently (60 per
cent.) affect both ovaries either as primary tumors or through implantation.

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY 567

The wall, at first lobulated, becomes smooth and tense as the tumor increases.
The simple adenomas may be translucent, the more active papillary growths
are opaque, and papillary nodules appear on the surface and vicinity, while
malignant processes are indicated by numerous adhesions and implantations.
In some tumors simple cystic compartments may project in isolated form,
and an exaggeration of this process gives rise to peculiar hydatidiform cystic
adenomas composed of clusters of cysts. The walls of these cysts are thin,
the lining is of ciliated epithelium, and contents are serous (Olshausen).
Of nine cases collected by Jayle and Bender six sprang from the ovary and
three from the posterior surface of the broad ligament. The extra-ovarian
growths probably arise from supernumerary ovaries. Somewhat similar

FIG. 239. — A large papillary cystadenoma of ovary.

tumors lined externally by epithelium occasionally form by myxomatous
degeneration of the stroma of superficial papillary adenomas (Odebrecht).
As might be expected from the position of the epithelium some of these tumors
prove malignant (Hoffmeier). Rarely the superficial papillary growths are
extremely abundant and the intracystic growth much reduced.

On section one large central cavity usually represents the fusion of origi-
nal multiple chambers some of which often persist until the tumor reaches
a large size. The contents are originally yellowish alkaline serous fluid rich
in albumen but free from pseudomucin, but later it may contain increasing
traces of pseudomucin, epithelial detritus, fatty substances and often much

568 N EOF LA STIC DISEASES

blood from rupture of the delicate papillae. Sand grains of calcific deposit
in the wall and papillae may become extremely abundant. When papillae
appear on the surface of the tumor they may give rise to implantation metas-
tases over the adjoining peritoneum. This type of dissemination occurs
in many of these tumors, and its extent and severity accords with the his-
tological signs of malignancy. Ascites regularly accompanies these implan-
tations. In general the serous cyst-adenomas differ from the pseudomucin-
ous, in their smaller size, the greater frequency of. bilateral tumors, the
tendency to produce metastases, the predominance of ciliated epithelium,
and the usual absence of pseudomucin in the contents.

Structure. — The lining cells are cylindrical or cuboidal epithelium which
has a more granular character than the clear cells of the pseudomucinous
adenoma. In the simpler tumors the cell layers are single, lying upon a rich
stroma. In the more active growths the cells increase in number, their form
becomes irregular, secondary papillae develop, the wall is honeycombed,
and sections of the compact papillae may present a glandular appearance.
A papillary structure predominates over the glandular. In more malignant
areas the growth of cells may be more diffuse and less dependent upon the
stroma. In most cases ciliated epithelium may be found and sometimes it
is uniformly present. Calcific granules may appear within or between the
epithelium or stroma-cells (psammoma). They occur at all stages and have
little relation to the vitality of the growth. The stroma forms low, thick
buds or longer cellular and vascular branching twigs. Occasionally it is
finely villous. Very abundant and cellular stroma, suggesting a sarcomatous
property, is limited chiefly to distinctly adenocarcinomatous tumors.

The course of the serous cystadenoma is slow and relatively benign. The
simple tumors are uniformly benign, unilateral, and do not produce local
metastases or recur after extirpation. They may cause pressure symptoms,
but local peritonitis, adhesions, and ascites are rare. The more active tumors
with rich development of papillae are clinically more serious. While slow-
ing, growing and requiring 3 to 15 years to reach bulky dimensions, the
tumor capsule may at any time be perforated and ascites and implantation
metastases follow. Likewise their frequent intraligamentary position and
bilateral occurrence give rise to more severe pressure symptoms. Recur-
rent ascites marks the course of many cases and may require paracentesis
over a period of many years, during which there is progressive anemia and
emaciation. Pyr-Smith records 229 tappings in 9 years, and Peaslee 665
in 13 years. The peritoneum becomes thickened and opaque, adhesions
form and implantation metastases occur in 13 per cent. (Pfannenstiel). In
Peaslee's case they were absent. Rupture of the cyst and discharge of the
serous contents and tumor fragments are rarely observed. It may be fol-
lowed by a slight fever, or by prolonged chronic peritonitis (Werder). As a
rule the implantations develop from papillae on the surface or growing through
the wall without rupture.

Implantation metastases occur early or late and remain localized or extend
over a large portion of the peritoneum. Their course varies with the general
malignancy of the tumor, but their fate cannot always be predicted from the
structure of the original tumor, since some adenomatous tumors have given
rise to carcinomatous implantations. In a well-known group the metastases
disappear after extirpation of the tumor. This favorable outcome occurs
almost exclusively with structures which are comparatively non-malignant
and in which the lining cells of the papillae are but slightly atypical and
appear in single rows. This spontaneous retrogression has been observed by
many writers and is described with anatomical details by Froschel, Bumm,

CYSTS AND EPITHELIAL TUMORS OF THE OVARY 569

H. Freund, E. Fraenkel, Pfannenstiel and others. It seems probable that
regression of tumor fragments disseminated by operation occurs very fre-
quently (Olshausen). Even without the removal of the primary tumor .the
implanted nodules may regress (E. Fraenkel, Werder). Several factors
seem to combine in this result. Chief among them is the low vitality of the
transported cells which tend to atrophy. A chronic inflammatory process
usually incloses the nodule in fibrin, granulation tissue, or multiplying endo-
thelium, which cuts off the nutrition of the tumor-cells. The nodule becomes
flat and fibrous, and finally disappears leaving a slight scar. A constitutional
element is probably at work but the mechanism of the destruction is largely
cellular.

In another group the implanted nodules maintain a low grade of nutrition
or gradually extend over much of the peritoneum, causing adhesions and as-
cites and persisting until the death of the patient from cachexia or inter-
current disease. These cases survive in poor health until the peritoneum
becomes so badly altered that the intestinal functions are gravely disturbed.
The ascites appears to be a less important factor in the cachexia.

In a third group the tumor recurs after extirpation in the form of pap-
illary nodules at the stump, in the wound, or on the peritoneum. Pfannen-
stiel finds that 77 per cent, of the papillary serous adenomas can be pro-
nounced cured by operation after five years, most of the recurrences following
intraligamentary growths. An unusually long period of observation is
required, since recurrences have been observed at the site of the tumor or
in the peritoneum after 13, 15, 20 and 21 years (Malcolm, Opitz, Pozzi,
Holzapfel), and in the line of incision after 21 years (Olshausen). Even after
recurrence the patient may survive many years in fair health (Schroeder).

Finally, the implantations may rapidly or gradually change their type
and become malignant, spreading over the peritoneum, producing more
bulky infiltrating local tumors and causing increasing cachexia. Definite
metastases of papillary cystic type in diaphragmatic and retroperitoneal
nodes, and in subcutaneous tissue are recorded.

The serous cystadenomas show with other cystic ovarian tumors a series
of anatomical peculiarities and accidental complications. The pedicle of
these tumors may become elongated or divided, or it may remain short and
thick. The movable tumors even when benign often form adhesions to
omentum, intestine, appendix, opposite ovary or bladder, and much of their
nutrition may eventually come from such channels. Intraligamentary
tumors on the other hand extend through the pelvic fascias about uterus,
bladder and rectum, which are displaced, compressed or elongated. The
Fallopian tube is usually stretched over the tumor but in some instances the
tube is quite movable. Elevation out of the pelvis is regularly accompanied
by rotation on the pedicle and in the further wandering of tumors with long
pedicles various grades of torsion occur. Martin estimates that 6 per cent,
of all ovarian tumors exhibit this condition. It occurs chiefly in relaxed
abdomens and is especially frequent in pregnancy. The results are edema,
hemorrhage into the tumor, peritoneum or uterus, sometimes fatal, or com-
plete infarction leading to peritonitis or rupture. The symptoms vary with
the intensity of the process, but in slow cases they take the form of cachexia.
Suppuration in ovarian cysts is not infrequent. The microorganisms re-
covered include Bacillus coli, streptococcus, Bacillus typhosus, and the
tubercle bacillus.

Papillary Serous A deno carcinoma.- — The clinical malignancy of many
simple papillary adenomas becomes more pronounced in those tumors in
which the structure reveals the histological signs of malignancy and which

570 N EOF LA STIC DISEASES

must therefore be classed as adenocarcinoma. A considerable proportion
(50 per cent., Pfannenstiel) of papillary cystic tumors reveal adenocarcino-
matous structure in at least some portions of the growth, but most of such
tumors being encapsulated, are successfully removed. The typical malig-
nant tumor is adenocarcinomatous throughout and its variations extend
toward alveolar and diffuse carcinoma. There is little doubt that many of
the former group represent malignant transformations of more typical adeno-
mas. A similar transformation has repeatedly been observed in the recur-
rences of serous adenomas and in their peritoneal implantations. Yet the
majority of adenomas long retain their benign type and there is some ground
for the view that the malignant tumors are usually carcinomatous from the
first. Gebhard takes exactly the opposite view, interpreting every papillary
adenocarcinoma as a degenerated adenoma. He holds that it is never pos-
sible to determine even approximately their duration. Yet unless these
tumors are exceptions to the rule, the transformation often occurs so early as
to constitute a primary adenocarcinoma. The tendency of papillary adeno-
mas in other regions to become carcinomatous, the occasional occurrence
of adenoma in malignant form, the frequent mingling of benign and malig-
nant areas in the same tumor, and the association of adenocarcinoma in one
ovary with adenoma in the other, all indicate that ovarian adenomas are to
some extent specially prone to malignant change.

The papillary adenocarcinoma is usually cystic, but the cysts are smaller
and less numerous than in adenoma, the inverted tumor masses are larger,
and much of the tumor is solid. The finely honeycombed texture of pseudo-
mucinous adenocarcinoma is missing. Some malignant tumors are pedun-
culated and movable, like the adenomas, but a larger proportion are intra-
ligamentary or bound by adhesions. The cyst contents are seldom clear,
since degenerating epithelium is thrown off in large numbers, and small hem-
orrhages discolor the fluid brownish. The capsule is commonly perforated
and papillary growths cover portions of the surface and -invade the perito-
neum. The tumors are frequently bilateral (66 per cent.), and the malignant
structure may be more advanced on one side. Only a small proportion of
these bilateral tumors can be referred to implantation.

In advanced stages metastases appear in the pelvic region and extend over
the peritoneum and even through the diaphragm to the pleura, accompanied
by serous effusions. These secondary carcinomatous growths are more ag-
gressive than the adenomatous, they do not regress, but invade the serosa,
intestinal wall, diaphragm and liver, and produce firm adhesions or fistulous
tracts. From the surface the peritoneal lymphatics may be extensively
invaded. The intestinal functions are severely disturbed.

Intraligamentary growths less frequently produce ascites, but they invade
the ligaments, pelvic tissues, uterus, vagina, rectum, and retroperitoneal and
inguinal nodes, but distant metastases in the^organs rarely occur. Virchow's
observation of the excessive rarity of distant organ metastases in ovarian
carcinoma applies especially to the adenocarcinomas.

The structure varies with the malignancy but regularly presents a pro-
nounced papillary form or at least its traces. A uniform alveolar, medullary,
or tubular structure has not been traced to this origin, although in some
solid portions the growth may be nearly diffuse. Multiplication of cell
layers, cohesion of adjoining papillae, filling of intermediate spaces and of
pseudo-alveoli, are the usual features of malignancy, but the adenocarcinoma-
tous type is commonly preserved. Pfannenstiel, however, finds mixed forms
in which there is solid medullary carcinoma without evidence of glandular
structure. The cells may vary little from those of adenoma, but tend to

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY

571

increase in size, and to become irregular in form, while nuclear hyperchroma-
tism is pronounced. Giant-cells are prominent in some tumors. Calcine
granules forming about capillaries in the stroma or in epithelial masses may be
a very prominent feature (psammocarcinoma). The formation of these
granules is preceded by colloid degeneration.

The stroma forms branching vascular papillary strands; it may be invaded
and split up by tumor alveoli, and in solid alveolar areas it may be reduced
to a trace. Very cellular types of stroma occur, suggesting a neoplastic
process in the connective tissue. These tumors grow with unusual rapidity,
but the stroma always appears to be in a certain relation to the epithelium;
it does not follow the metastases and its designation as sarcoma is hardly
justified. Loeb, however, secured a pure sarcomatous tumor by successive
transplants of such a growth in the rat. Ovarian remnants are rarely pre-
served in the stroma, but in one case I found the abundant septa containing
many groups of large polyhedral cells resembling lutein-cells.

FIG. 240. — Adenocarcinoma of ovary with abundant calcine concretions. Psammoma.

The course of ovarian papillary carcinoma, while slower than that of
other varieties, is unfavorable, because of local recurrence after apparently
complete extirpation, intraligamentary position, early peritoneal implanta-
tions, and later appearance of new tumors in the opposite ovary. Pfannen-
stiel estimates the recurrence of papillary carcinoma at 83.3 per cent., of
other types of carcinoma at 66 per cent. These data are contrasted with
those of papillary adenoma of which 16 per cent, recur. The glandular
type recurs later but more frequently than the papillary (95 per cent.). Ob-
servations on bilateral tumors vary greatly. Glockner's cases all recurred,
while Hoffmeier found only 50 per cent, of recurrences; and there are not a
few bilateral carcinomas of miscellaneous types, which permanently recovered
(Pfannenstiel, Lit.). The removal of both ovaries is probably indicated,
but permanent recovery without this more radical procedure is recorded by
Hoffmeier, Glockner, and Tauffer.

Pseudomucinous Cystadenoma. — Typical pseudomucinous cystadenomas
are distinctly different in gross appearance from the serous tumors. They

572

NEOPLASTIC DISEASES

are usually of larger dimensions, the walls are thin, a multilocular structure is
pronounced and persistent, they are more frequently unilateral and pedun-
culated and the contents are firm or soft gelatinous material or highly mucin-
ous fluid. They form the majority of ovarian cystadenomas. Bilateral
growths occur in 17.7 per cent., and intraligamentary in 9.65 per cent.
(Pfannenstiel). The size of some of these tumors has been remarkable.
Zacharias reports a case in which the tumor contents weighed 132 kg. He
has collected a series of these cases, some of which occurred in young subjects
and most of which were fatal.

On section the cyst presents several roomy compartments with broad,
thin partitions. As the cyst enlarges the partitions rupture, atrophic frag-
ments and strands fall into the fluid, and the cyst is occupied by one large
central and several peripheral cavities. The walls are usually thin but
certain areas may be rather compact with many small cysts, or solid portions

FIG. 241. — Adenocarcinoma of ovary with hyperplasia of interstitial cells.

may appear. Scanty low papillary nodules may usually be found on the
inner surface, and in one group of cases these papillary projections are highly
developed (papillary pseudomucinous cystadenoma). In most tumors the
papillary tendency is not highly developed and the growths belong in the
group of glandular cystadenoma. The pseudomucinous adenoma may
show a very large number of small cysts, honeycombed areas, and exactly
resemble stroma ovarii. In fact Bauer holds that all cases of struma ovarii
are pseudomucinous adenomas derived from superficial ovarian epithelium.
Yet some are associated with other teratoid elements, and the colloid
contains iodine (Pick, R. Meyer). The contents are first clear, thin
gelatinous material, which may become condensed and firmer, or thinner and
fluid. The addition of much cell detritus, fatty matter, cholesterin, serum
or blood alters the color.

CYSTS AND EPITHELIAL TUMORS OF THE OVARY 573

The main ingredient is pseudomucin (Hammersten). This substance is soluble in
water, precipitable by alcohol but not by acetic acid, and when treated with dilute mineral
acid it yields a substance which reduces copper sulphate in alkaline solution. It is, there-
fore, a glycoproteid and on chemical analysis yields small proportions of hydrogen, nitrogen
and sulphur. Iodine is absent (Kretschmar, Bauer). The mucinous substance does not
always occur in the form of typical pseudomucin. In certain cases sometimes called
pseudomyxoma ovarii, the material is much firmer, strongly alkaline, insoluble in water,
but dissolved by strong alkali. This substance, Pfannenstiel's pseudomucin B, has a very
low nitrogen content. A thin mucin, very soluble in water and with high nitrogen con-
tent, is designated by Pfannenstiel as pseudomucin G. Paramucin is a substance obtained
from ovarian cysts by Mitjukoff, which reduces copper without boiling in acid. The pure
pseudomucin occurs only in small cysts containing clear gelatinous material. .It is usually
mixed with albumen, producing the paralbumen which Eichardt wrongly supposed to be
a single substance. In the demonstration of pseudomucin in albuminous mixture the
fluid may be precipitated and washed in alcohol, treated on a water bath for half an hour
with 10 per cent. HC1, and after cooling, the albumen precipitated by phosphotungstic
acid. The filtrate gives Fehling's reaction. True mucin may be separated by chemical
means but does not occur in ovarian tumors. To separate pseudomucin, a part of the
material is extracted in water and another part in i per cent. NaOH for two days. The
filtrates are then treated with increasing amounts of acetic acid. If no precipitate falls
mucin is absent. If present, the precipitated mucin is filtered off and filtrate, heated
with acid, is tested for pseudomucin by Fehling's test. Mucin appears not to occur in
ovarian tumors. Pseudomucin, on the other hand, is not limited to ovarian cysts, but
occurs under many other conditions (E. Herter, Lit.).

The structure presents narrow and slightly vascular septa or partitions,
lined by one layer of high cylindrical cells, in which all stages of secretion
are observed. The nuclei lie at the bases of the cells, the cell bodies are low,
granular and opaque in the resting stage, high and clear in active secretion.
Goblet cells may be abundant and occasionally the cells are ciliated. Pres-
sure of firm secretion may cause flattening or complete atrophy of cells and
septa. The production of mucus is a secretory function and does not usually
entail the degeneration of the cell. In well preserved areas of typical ade-
nomas there is little desquamation of cells, but in more actively growing
tumors the secretion is less abundant, many cells are exfoliated, the cells
become atypical and granular, and the nuclei hyperchromatic. In such
areas the cysts are small and epithelial papillae become very numerous. By
exaggeration of this process adenocarcinoma develops. A false appearance
of malignancy may be produced by compression of many thin septa with
low papillary outgrowths, and this appearance may be exaggerated by the
collapse of any cystic tumor after aspiration.

The two main structural types, glandular and papillary, are designated
by Gebhard as cystadenoma evertens and cystadenoma invertens. No
satisfactory explanation of their different growth tendencies is available.
In the papillary type Waldeyer assumed a primary proliferation of the
connective tissue. Gebhard and Pfannenstiel consider that the primary
factor always resides in the epithelium. Gebhard thinks that the presence
of secretion prevents the growth of papillae in tensely filled cysts, while in
other portions of the same tumor a papillary growth may be observed. It
is possible that the conditions under which the tumor originates determine
the structures. Thus in the alveolar strictly glandular tumor, described
by Bauer, the tumor originated by downward growth of surface epithelium
which early formed^ alveoli. The papillary tumors appear to develop by
growth into preexisting cysts or cavities.

The course of the pseudomucinous tumors is slow and most of them being
unilateral and pedunculated are successfully removed by operation (98 per
cent. Pfannenstiel). When a papillary structure is pronounced the tumors
are most often bilateral, more difficult to eradicate, implantation metastases
may develop, and recovery follows extirpation in a smaller proportion,

574

N EOF LA STIC DISEASES

estimated by Frommel at 85 per cent. Strassmann, however, estimated
the recoveries as low as 44 per cent. Fatalities result from recurrence oi
incompletely extirpated tumors, from later development of a tumor in the
remaining ovary, from implantations in the peritoneum or abdominal
incision, and from progressive pseudomyxomatous changes in the peritoneum.
Ascites is relatively infrequent. The elongated pedicle of many of these
tumors renders them especially susceptible to torsion, which occurred in
14.5 per cent, of Martin's cases. The recurrence usually reproduces the
structure and follows the slow course of the original tumor. A period of

'• FIG. 242. — A type of malignant cystic adenocarcinoma of ovary.

many years (14, 17, Olshausen) may intervene before the recurrent tumor
appears. Rarely the implantation or recurrence assumes a malignant
carcinomatous form (Frank, Olshausen, Pfannenstiel). Recurrence in the
opposite ovary several years after extirpation of the first tumor has been
observed by Martin, Hofmeier and others, and must be interpreted as a new
primary tumor.

Owing to the thin walls of the cysts spontaneous or traumatic rupture not
infrequently occurs, and the contents and cells are discharged into the
peritoneum. When this event occurs at operation and the material is re-
moved no ill effects follow. Spontaneous rupture is followed by prostration,

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY 575

fever and a marked swelling of the abdomen. The further results depend
much on the character of the tumor and its contents, but a condition regularly
follows known as pseudomyxoma peritonei. The first effect is the passage
of the pseudomucinous material into the peritoneal lymphatics. These
spaces become distended and ruptured, the material infiltrates the meshes
of the peritoneum, round-cell infiltration, growth of granulation tissue and
proliferation of endothelium result, and the peritoneum is everywhere thick-
ened by a painless form of chronic peritonitis (Werth, Gunzberger, West-
phalen). When many fragments from papillary tumors are carried along
these may become implanted and produce small papillary outgrowths or
small subserous cysts, but as a rule the organs are found imbedded in ge-
latinous material without any sign of cellular invasion. The large amount
of material produced in some cases has led to the assumption that a true
myxomatou's process becomes established in the peritoneum (Mennig,
Wendeler), but this conception is negated by the complete recovery which
sometimes follows. When the condition progresses steadily and spontaneous
rupture has not occurred the chief factor must be found in a dissemination
of tumor-cells throughout the peritoneum and this process has been fully
described, especially with papillary tumors, by Olshausen, Ackermann and
Pfannenstiel. The passage of mucus apparently without tumor-cells in the
diaphragm, along the portal canals, into the liver and into the appendix has
been reported by Werth and Polano. The prognosis in this condition is
unfavorable. Of 40 cases collected by Gunzberger, 17 were said to have
recovered. Early cleansing of the peritoneum greatly favors recovery and
the final absorption of mucus and tumor-cells. When firm adhesions form
the material cannot be removed and a slowly fatal course is the rule. The
peritoneum becomes thickened, adhesions and fistulous tracts form, and
intestinal paralysis eventually follows. Occasionally a rapid course is
observed with all the signs of a carcinomatous process.

Pseudomucinous A deno carcinoma. — Malignant changes in previously
benign pseudomucinous cystadenoma occur, as previously mentioned, under
several conditions, (a) Implantations from a benign tumor develop in the
stump, peritoneum, abdominal wall, or navel, and pursue a malignant course.
(b) Pseudomyxoma peritonei may develop malignant neoplastic tendencies
and structure, (c) In portions of benign cystadenomas the structure is
malignant but being encapsulated the tumor is completely extirpated. All
of these events are comparatively rare.

In addition there is a group (d) of ovarian adenocarcinomas which repre-
sent malignant forms of the cystadenoma. Some of these evidently represent
a malignant change in an originally benign cystadenoma. The history
reveals the long existence of an ovarian tumor which on examination proves
to be in whole or in part carcinomatous. Gebhard points out that the long
duration of these tumors eliminates the probability that they were malignant
from the first. Others develop more rapidly, present a uniform adenocarcino-
matous structure, and are probably malignant from their inception.

The adenocarcinomas of these types still contain cysts but large portions
of the tumor are solid and present the opaque cellular texture of carcinoma.
The cysts represent natural cavities produced in the growth of the tumor
and spaces of more ragged outline formed by degeneration and necrosis of
central areas. Small hemorrhages frequently occur. The mucus is greatly
reduced in amount but still persists in the small alveoli and spaces of
the tumor. It is seldom clear but more often discolored by cell detritus
and blood. The capsule is often perforated, adhesions form, implantations
develop and metastases occur in pelvic, retroperitoneal, or inguinal nodes.

576

N EOF LA STIC DISEASES

The structure is usually of the glandular type with large and small alveoli
lined by convoluted multiple rows of cells and filled with mucus or occupied
by numerous secondary alveoli. A diffuse growth of cells is unusual, the most
active areas retaining the structure of malignant adenoma. The cells vary
widely from the clear columnar type of simple adenoma. They increase in
number and height, lose most of the features of mucus secretion and become
granular and opaque, while the nuclei are very large and hyperchromatic.

Solid Ovarian Adenoma. — Many cystic pseudomucinous adenomas present
solid areas and when such areas predominate over the cysts the commonest
form of solid adenoma is produced. Stratz estimates that 3 per cent, of all

FIG. 243. — A type of adenocarcinoma of ovary.

epithelial ovarian tumors are solid adenomas. Usually the solid tumor
presents on close inspection a finely honeycombed texture and this tumor
may be designated as the parvilocular ovarian adenoma. It is a pseudo-
mucinous tumor, the small spaces being filled with firm mucus or with mucus
and cell detritus. In accordance with its solid character it is far more
cellular than the cystic growth and the epithelium is usually atypical,
granular and overnourished. Many transitional cases connect this adenoma
with solid and with cystic adenocarcinoma. Yet the typical solid adenoma
reaches a large size without exhibiting malignant characters. Ascites is
common. Pfannenstiel described three cases in which large partly cystic
tumors of the above type were successfully removed and the patient remained

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY 577

well. In a case studied in this laboratory the structure approached adeno-
carcinoma. Glockner describes a large, solid pure adenoma without cystic
tendency, the convoluted alveoli being lined by cylindrical epithelium and
containing little mucus.

The superficial or- everted papillary adenoma forms a distinct variety of
solid tumor. Including the small and early forms this tumor is relatively
frequent. Of the more advanced and bulky growths, J. W. Williams has
collected 15 cases. One or both ovaries present numerous bulky compact
papillary outgrowths which spring from a central core, the altered or disin-
tegrated ovary. The appearance in the advanced stages is extremely
characteristic. Ascites is common and implantation metastases occur early
but the essentially benign character is attested by the successful extirpation
recorded in most cases. An origin from superficial ovarian epithelium is
clearly indicated. Gebhard suggests that an early rupture of a papillary
cystic tumor permits the entire growth to become everted, but some very
early papillomas are superficial from the first. Local inflammatory processes
have apparently contributed to the inception of the tumor process in many
cases.

Adenofibroma. — Epithelial alveoli are occasionally observed in ovarian
fibromas and rarely these epithelial structures increase to such an extent
as to constitute an adenofibroma. Orthmann describes carcinomatous
changes in such a tumor. Cystic dilatation of the alveoli may occur, and
Orthmann describes carcinomatous changes in such cysts.

Adenofibroma colloides designates a rare form of this tumor in which
gelatinous changes are prominent. Amann described a bulky tumor covered
with warty excrescences and containing some small cysts and many alveoli
lined by high cylindrical cells and filled with mucus. Orthmann found
a small tubal metastasis from a bilateral tumor of this same structure.
Another form of superficial fibroma with carcinomatous infiltration by cubical
or flat-cells is interpreted by Orthmann as an invasion from the superficial
ovarian epithelium. In all these tumors the stroma greatly exceeds the
cellular portions.

Carcinoma. — Waldeyer classified ovarian carcinomas according to the
proportions of cells and stroma as simple (alveolar), medullary, and scirrhous.
Gebhard found it more serviceable to distinguish between the malignant
forms of cystadenoma and genuine solid carcinomas of other types, thus
introducing the histogenetic principle. Due consideration of the histology,
histogenesis, and specific anatomical and clinical characters requires the
recognition of several distinct groups of these tumors as follows: Cystic
adenocarcinoma; solid carcinoma; carcinoma mucocellulare, Krukenberg;
carcinoma folliculoides; ovulogenic carcinoma.

There are also rare forms of carcinoma which cannot be grouped with
any of the above classes, as squamous-cell carcinoma, malignant forms of
adenofibroma and melanoma. There is also considerable support for
Rokitansky's belief that certain carcinomas develop from lutein cells.

1. Cystic adenocarcinoma has been discussed with the cystic adenomas
with which it is identical in origin and very similar in course.

2. Solid Carcinoma. — In this, class may be conveniently grouped all the
tumors of large or small alveolar or medullary structure which are not
connected with the cystic adenocarcinomas, and which do not exhibit the
specific structure of Krukenberg's tumor nor of carcinoma folliculoides.
That some of the small alveolar carcinomas are atypical examples of cystic
adenocarcinoma is possible, since the alveoli may contain cylindrical cells,
as in Glockner's cases. Nevertheless their gross appearance and micro-

578 - NEOPLASTIC DISEASES

scopical structure are very different from malignant cystic adenocarcinoma,
of which even the solid forms regularly maintain an adenocarcinomatous
structure. The medullary carcinomas with ova-like cells present a somewhat
distinctive subvariety, but until their histogenesis is much clearer than can
now be claimed a separate classification seems hardly warranted. Until a
more thorough understanding of -the many forms of ovarian carcinoma is
attained no classification can hope to escape revision.

The alveolar and medullary carcinomas produce as a rule solid tumors
maintaining the form of the ovary in the early stages but eventually becoming

FIG. 244. — Solid adenocarcinoma of ovary.

irregular and lobulated. On section many are cystic but the cysts are
chiefly the result of necrosis and liquefaction and not of dilatation of alveoli.
The tumors reach considerable and even large dimensions but rarely beyond
15 to 20 cm. in diameter. They are at first usually unilateral but metastasis
and recurrence in the other ovary are very frequent. If pedunculated they
become bound to the pelvic tissues by adhesions and are held by a broad
short pedicle composed of the ovarian and broad ligaments. Many occupy
the pelvis in a retroligamentary position (Winter). The consistence is firm
or soft in accordance with the cellular character. On section they exhibit

CYSTS AND EPITHELIAL TUMORS OF THE OVARY

579

an opaque uniform texture broken by many lobules, small cysts, areas of
necrosis and hemorrhage, and foci of gelatinous degeneration.

The structure presents a confusing variety of types. Small alveolar
carcinoma presents many small groups of granular polyhedral cells without

FIG. 245. — Structure of a widely metastasizing small alveolar bilateral carcinoma of

ovary.:

FIG. 246. — Carcinoma of ovary with ova-like cells.

definite lumen, supported by scanty cellular stroma. It is characteristic
of this group of tumors that the outlines of alveoli may be lost and the cells
not only grow diffusely but become more difficult to distinguish from stroma-
cells, suggesting myxoma, sarcoma, or a mixed tumor. This tendency toward

580 N EOF LAST 1C DISEASES

diffuse growth and mucoid degeneration of cells and stroma is observed in
many ovarian carcinomas and appears to reach its height in Krukenberg's
tumor. Careful study of such growths usually reveals definite alveolar
areas and supports Heinrich's conclusion that no true mixed carcinoma and
sarcoma of the ovary exists outside the ovulogenic group. Glockner, how-
ever, describes a rapidly growing mixed tumor in a girl of 19 years, which
resembled the parotid cylindroma and for which he suggested an origin
from the Wolman body. I have studied tumors of this general type and
concluded that some belong with the medullary carcinomas with ova-like
cells. Others may very well be true mixed tumors originating from the com-
plex alien tissue masses described by Walthard.

The typical small alveolar carcinoma presents well-defined alveoli.
The early stages are probably represented by v. Kahlden's case, and charac-
teristic examples are described by Glockner, Orthmann, Heinrichs and others.

In the medullary type the cell columns are large, broad and freely anasto-
mosing. The cells are large or small, polyhedral or rounded, opaque,
and granular. Scattered at notably regular intervals may appear large
clear ova-like cells, the significance of which has been much discussed. These
cells are large, spheroidal, with clear cytoplasm, well-marked membrane
and one or more vesicular nuclei. They may be surrounded by a radiating
circle of tumor-cells (Schroeder). They may resemble ova in every detail
(Gebhard) and they have been so interpreted by Emanuel, Kworostansky,
Schroeder, and others. Acconci found them in a cyst adenoma. Some-
what similar structures may be produced by cross-sections of strands of
mucinous stroma, but the cells in question are spheroidal. Very similar
cells may undoubtedly result from mucous degeneration and this origin
of all of them is accepted by the majority of observers. Gebhard, however,
will not deny the possibility that they represent primordial ova, but the more
recent embryological data do not favor such a possibility (c. f. Ingier). Ova-
like cells appear in the epithelial layer of primordial follicles although these
cells are not derived from germ epithelium (W. Nagel).

In a very cellular tumor which probably belongs in this group I found
numerous small pearls composed of flattened cells. Since most of the tumor
was composed of granular polyhedral cells, the squamous characters were
metaplastic. Hansemann has described a squamous epithelial tumor which
he referred to metaplasia of ovarian epithelium.

In a well-defined group the cells are unusually small, and grow in indis-
tinct alveoli or groups which vary greatly in size. Such tumors may present
areas of diffuse growth and when the cells become intimately mingled with
the stroma or appear in rows between stroma fibrils or arranged about
blood-vessels they suggest an endothelial origin. Not a few so-called endo-
theliomas of the ovary are probably of this nature (cf. Pfannenstiel, Figs. 161,

163).

In another group the cell masses are large, circular on section, and com-
posed of large polyhedral, clear, or slightly granular cells. These tumors
have often been described as endothelioma. Yet this structure is occasion-
ally seen in distinctly alveolar and epithelial tumors and there is no necessity
of assuming an endothelial origin. Polano divides the pseudo-endotheliomas
among (i) alveolar carcinoma, (2) adenocarcinoma, and (3) sarcoma. To
these may be added the peritheliomatous structure which is often assumed by
epithelial tumors.

In young subjects there occurs a form of solid ovarian carcinoma which is
bilateral, of rapid growth, producing widespread local invasions, and numer-
ous bulky metastases, while presenting a structure of diffuse growth of small

CYSTS AND EPITHELIAL TUMORS OF THE OVARY

581

rounded cells resembling lymphosarcoma. Stone has described such a case
in which a large metastasis in the breast first attracted attention, and the
ovarian tumors were overlooked. In the ovary the supposed sarcomatous

FIG. 247. — Structure of a peculiar carcinoma of ovary, presenting anastomosing cords of

small polyhedral cells.

FIG. 248. — Structure of a highly malignant small-cell carcinoma of both ovaries in a
young subject. There were metastases in breast and other organs, in which the structure
suggested lymphosarcoma.

growth revealed its primary alveolar structure. I have seen other very
similar cases.

A distinctly scirrhus carcinoma of the ovary is rare and is observed
chiefly in elderly subjects.

582

N EOF LA STIC DISEASES

Carcinoma develops in fibromas either from the downward growth of
surface epithelium (Orthmann), or from the proliferation of glands in a fibro-
adenoma. In either case the connective- tissue areas are predominant and
the tumor usually presents the gross appearance of the original fibroma.

Folliculoma malignum ovarii is a term employed by S. Gottschalk in de-
scribing a peculiar small alveolar carcinoma of the ovary. Several apparently
related but structurally somewhat different tumors have been grouped
under this term, and while their origin and significance are not clear, the
tumors are peculiar in many respects and deserve separate consideration.
Their chief characters are a comparatively small size, honeycombed texture,
small alveolar structure, embryonal cell character, and slight malignancy.
Metastases are absent. In Ingier's cases the tumors were bilateral. Ascites
may occur. In Gottschalk's case the tumor, 10 X 8 X 3H cm-> maintained
the form of the ovary, presented numerous small and minute cysts, inter-
stitial hemorrhages, and a tumor process affecting chiefly the ovarian cortex.
The structure resembled struma ovarii and presented many small alveoli
lined by small cubical epithelium with prominent nuclei and surrounded by

FIG. 249. — Structure of granulosa cell carcinoma of ovary. (After Werdt, Z. B. 59.)

many small groups of cells. The small cysts contained mucinous material.
Very similar tumors have been described by M. Voight, Lonnberg and Ingier.
Other cases sometimes included in this group seem to belong rather with the
medullary carcinomas with ova-like cells (Mengershausen, Schroeder).
The presence of ova-like cells led some to assume an origin from primary
follicles. Voight derived his tumor from downgrowth of superficial ovarian
epithelium. L. Pick regarded Gottschalk's case as struma ovarii. Ingier
attacks the whole group because the follicular origin is not demonstrable.
Yet Bauer has shown that a form of struma ovarii may develop from the
superficial ovarial epithelium, and since the early stages of his tumor were
practically identical with Gottschalk's, one is led to believe that folliculoma
malignum is a form of ovarian tumor in which the alveoli resemble thyroid
structures, while the secretion of mucus is scanty. These tumors must, there-
fore, be distinguished from very similar growths of teratoid origin. In the
latter group other teratoid elements are usually demonstrable and iodin may
be present in traces. Among the tumors which produce multiple small cysts

CYSTS AND EPITHELIAL TUMORS OF THE OVARY 583

in an enlarged ovary are the granulosa cell carcinoma of Werdt, and the
oophoroma folliculare of Brenner.

The term folliculoma malignum seems applicable also to a group of tumors
resembling in many respects those described by Voight and Ingier, of which
I have studied four examples. In the gross these tumors are of moderate
size, preserve the form of the ovary, and present a finely honeycomb or solid
texture. In structure they are glandular adenocarcinomas and carcinomas.
The alveoli are small and compact, or larger with a free lumen. The cells
are unusually large and polygonal. The cytoplasm is clear and the borders
very distinct. The stroma is abundant and consists of hyperplastic ovarian
tissue. An origin from undeveloped follicles is indicated by a diffuse neo-
plastic overgrowth of the lining cells of the small cortical follicles.

Carcinomatous tumors of this class present an alveolar, diffuse or scirrhus
structure. The cells are very large, giant-cells are abundant and the cyto-

FIG. 250. — Oophoroma folliculare. A rare ovarian tumor arising from multiple Graaffian

follicles. (Brenner.)

plasm is clear or granular. The structure differs in these particulars from
other forms of ovarian carcinoma.

Fibrosarcoma Muco cellular e Carcinomatodes (Krunkenberg). — Under this
term Krunkenberg in 1896 described a peculiar malignant tumor of the ovary,
usually bilateral, of considerable dimensions, maintaining the form of the
ovary, of myxomatous appearance, occurring in young or old subjects, grow-
ing slowly, usually with ascites sometimes chylous, and eventually fatal by
extension and recurrence. The structure presented small groups or a
diffuse growth of large polyhedral or rounded cells with mucoid contents
compressing the nucleus into a signet ring form. In the diffuse areas the
cells were intimately mingled with the stroma so as to suggest an origin from
stroma cells or endothelium. Krunkenberg's first case presented a large
cyst with carcinomatous wall in one side, a solid tumor on the other, while
there was extensive invasion of lymphatics of abdomen, stomach, pleura,
and bronchial and axillary nodes, a condition not commonly observed in
other ovarian carcinomas. Krunkenberg failed to point out the close resem-
blance of his tumors to secondary carcinoma of the ovary and he was unable

584

N EOF LA STIC DISEASES

to determine from which ovarian element the tumors arose. These deficien-
cies were soon supplied by Wagner, Romer, Schlagenhaufer, and Glockner,
with the demonstration that this peculiar tumor may be exactly reproduced
by secondary carcinoma from stomach and other abdominal organs, and that
the great majority of such growths are secondary to tumors in other organs.
It is still generally admitted that there are primary tumors of the ovary
of the Krunkenberg type, and cases reported by Glockner, Schenk, and Rost-
horn are regarded as examples. It is obvious that cases without autopsy,
as that of Outerbridge, are unavailable in the discussion. In Glockner's
case both ovaries were much enlarged and extensions from one had eroded
the spinal column. The entire tumor had a myxomatous texture and there
were liquefaction cysts. One portion presented diffuse myxomatous tissue,
while in another the structure was distinctly alveolar. Schenk described

•p^ ..*.

•%'

-v

V*|

FIG. 251. — Follicular carcinoma of ovary.

bilateral tumors in a subject of 27 years of age, one weighing 2300 gr. and
presenting the typical structure.

Although Marchand and Chiari were unable to find any primary tumors
in the cases of Krunkenberg and Schenk, and doubtless no such tumors were
demonstrable, it. still seems uncertain that the typical structure of secondary
mucoid carcinomas can be exactly duplicated by primary carcinoma of the
ovary. It is not always possible to demonstrate the primary focus in cases
of widespread carcinoma of the abdomen with involvement of the ovary,
although the structure is not always that of Krunkenberg's tumor.

Glockner states that the typical structure may be seen in portions of
alveolar carcinoma of the ovary, but the typical cases show little or no alveo-
lar structure. I have studied five secondary ovarian tumors of this type
and one primary carcinoma with myxomatoid areas. The structures while
similar were far from identical, the primary tumor containing distinctly
alveolar areas. None of these tumors gave evidence that the stroma reaction
was neoplastic or sarcomatous, or that the large cells were derived from the

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY

585

stroma. I am inclined to believe, therefore, that the pure Krunkenberg
tumor is always secondary, and that primary carcinomas presenting this
structure regularly yield areas of a different type.

The clinical course of ovarian carcinoma varies greatly. The clinical
features of the adenocarcinomas have been considered under the cystic
tumors. The alveolar and medullary carcinomas are uniformly malignant,
but statistical reports of this group are wanting. The majority of these
tumors are originally bilateral or soon become so. When pedunculated
they may remain movable for some time, even after general metastases have
occurred. After extirpation local recurrence in the stump or in the opposite
ovary is common. Peritoneal metastases are less common than with cystic
adenocarcinoma, but through the lymph- and blood-vessels there may be

FIG. 252. — Structure of a Krunkenberg tumor of ovary, secondary to gastric carcinoma.

general dissemination in the early stages of growth. In such cases the gen-
eral condition of the patient may long remain remarkably good, but cachexia
eventually supervenes. That the prognosis in this group of tumors is not
wholly unfavorable is shown by Glockner's report of five survivals out of 18
cases after three years. Yet some of his tumors were adenocarcinomas.

In Martin's table of 41 cases of various types only one solid carcinoma
failed to prove fatal.

The Krunkenberg tumors, both primary and secondary, are uniformly fatal.
Tumors of the type of carcinoma folliculoides are of slow growth and offer
a better prognosis, a fact which commends the retention of this tumor as a
special form of ovarian carcinoma. The so-called endotheliomas of the ovary
are not distinguished from carcinomas by any clinical peculiarities but are
usually malignant (Apelt, Pfannenstiel).

586 N EOF LAST 1C DISEASES

General Etiology. —In view of the remarkable embryological history, the
complex structure, and the series of functional changes which the organ suf-
fers, tumors of the ovary are not notably frequent. Dippert refers to 58,787
female clinic patients of all types among whom were 941 ovarian tumors,
1.6 per cent. Gurlt collected 947 ovarian tumors, 8.5 per cent., among
11,140 women with tumors of all types.

Hereditary influence is suggested only in isolated instances such as are
mentioned by J. Simpson, Lohlein and others. Trauma is a negligible
factor, owing to the protected position of the organs. Inflammatory changes
are held to influence the development only of the fibromas and simple cysts
(Pfannenstiel).

Single women, furnishing 18 per cent, of ovarian tumors, are relatively
more susceptible than the married, especially for dermoids (32 per cent.),
and parovarian cysts (26.19 per cent.), (Olshausen, J. Williams, Lippert
Wedekind). Childbirth seemed to entail less liability in Martin's 1005 cases,
of which 554 were nulliparae. Yet. Lippert found that 73.6 per cent, of his
638 cases had borne children.

Age. — All ages are susceptible, from birth to senility, but the period
of sexual activity, 25-35 years, is most, prominent. A fetal cystadenoma and
sarcoma are described by Doran, and a bilateral sarcoma by Lonnberg. Wiel
collected 24 cases under 5 years and 60 under 10 years of age, and Hubert
175 cases in children. The predominance of cysts, dermoids, and sarcomas
and of malignant tumors in early life is notable. Kelly emphasizes the
high operative mortality in children, in a collection of 55 cystic, 47 dermoid,
and 24 solid tumors. Many cases, chiefly cystic, occur also after 70 years.
Most of the carcinomas occur between 40 and 50 years (Martin).

The relative frequency of the different forms of tumors I have calculated
from the reports of Martin and Libbert, over 200 cases, as follows: Cystade-
noma, 55 per cent., carcinoma, 22 per cent.embryoma,9.2 per cent., parovarial,
8.4 per cent., sarcoma, 2.9 per cent., fibroma, 2.5 per cent. Pick emphasizes
the relative frequency of ovarian tumors in pseudohermaphrodites.

From the above data it appears that the effective causes of ovarian tumors
are quite as obscure as with other organs. Neither predisposing nor exciting
factors can be accurately defined, but it may be assumed that chronic
hyperemia exaggerating the natural regenerative processes in the organ figures
in most cases. The studies of histogenesis, on the other hand, indicate that
developmental anomalies are essential conditions in the growth of the great
majority of ovarian tumors.

Histogenesis. — Virchow and the older pathologists held that the
Graafian follicle produces only simple cysts and that some other source must
be sought for the cystic tumors. Waldeyer (Eierstock u., Ei, 1870) traced the
origin of the tumors to Pfliiger's tubes, which he held were either fetal rem-
nants or newly formed in later life by the ingrowth of superficial ovarial
epithelium. Olshausen contrasted the papillary serous tumors with the
pseudomucinous and chiefly because of the prominence of ciliated cells
in the former he derived them from the Wolffian medullary cords of Kolliker.
This view he later abandoned but it long received support from Fischel,
Coblentz, Doran, and others. Marchand, 1878, studied an ovary the cortex
of which was filled with minute cysts containing papillae of ciliated epithe-
lium, and he thus showed that the presence of ciliated cells did not require
an origin from medullary Wolffian tubes. He was inclined to refer them to
included portions of tubal epithelium or to Graafian follicles.

In a similar cystic ovary Malassez and Sinety traced the origin of these
small cysts to the superficial ovarian epithelium, finding the cysts often

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY 587

connected by cords of cells with the surface. Ciliated columnar epithelium
they found on the surface in the closed tubes (Pfliiger's) and in the cysts.
Flaischlen also traced the downward growth of surface epithelium forming
tubes which developed into cysts with ciliated cells, in the intact portions of a
cystomatous ovary.

Elaborate confirmation of these observations has been furnished by
Walthard who in serial sections of many ovaries of all ages demonstrated
the downward growth of surface epithelium forming cords, tubes and cysts
lined by cubical, columnar, ciliated and even flat epithelium. He describes
the formation of granulosa cells of the primitive follicles by downgrowths
of surface epithelium, chiefly in the fetus and during the first year of life. A
somewhat similar downgrowth occurs up to old age, but without relation to
follicles and these cell groups may produce small cysts. Several varieties
of ciliated cell groups are found in the cortex and connected with surface
epithelium. Most of these undergo atrophy, but others in which there is a
row of supporting cells and the stroma is very cellular, go on to develop
cystomas of various types. Larger areas of this type with cellular stroma
he regarded as misplaced tubal mucosa. All the tumor-bearing areas give
the impression of alien tissue. Mesonephric (Wolffian) rests are commonly
found in the hilus and penetrate the zona vasculosa, rarely the zona paren-
chymatosa (v. Franque), in the form of compact groups of cubical cylindrical
or ciliated cells surrounded by connective tissue and smooth muscle. They
appear not to develop beyond small cysts or minute cystic adenomas.

Many of the structures observed by Walthard had been described by
Pfliiger and Kolliker, both of whom demonstrated a postembryonal and
periodically recurring formation of ovarial tubes. It appears from Wal-
thard's study that the probable sources of tumors are not to be identified
with Pfliiger's tubes, which are connected with the formation of granulosa
cells, but with congenitally misplaced groups of goblet, ciliated or squamous-
cells with which a portion of cellular stroma is associated. It should be
noted that while these alien tissue masses exhibit many of the elements
regarded as essential to tumor growth, the actual development of the tumors
from these sources, although highly probable, is still unproven.

The superficial ovarian epithelium has been clearly shown to give origin
to the superficial papillomas of the ovary (Malassez, de Sinety, Flaischlen,
Pick). Recently Bauer has shown that pseudostruma ovarii is derived by
downward growth of surface epithelium. Since the papillary serous cystoma
is identical in structure with the papilloma and since downward growth of
this epithelium is commonly seen at various ages there is considerable ground
for assuming that this form of cystoma is derived from embryonal or adult
surface epithelium. When one considers that these same cells may secrete
much mucus and assume the goblet form (Walthard), the same origin is
Indicated for the pseudomucinous tumors. The direct transformation of
these cells into alveolar or solid carcinoma is described by Glockner, Linnell,
and Bauer.

The follicular origin of ovarian cystomas has long been a popular theory
but still lacks definite proof. Wendeler erroneously assumes the embryonic
origin of the granulosa cells from the connective tissue of the Wolffian body,
which might eliminate them as sources of epithelial tumors. That the super-
ficial ovarian epithelium as well as that of the follicles may be ciliated has
been shown by v. Velits, who also found an ill-defined ovum in such a follicle.
Lateral sprouts from primitive follicles have also been observed by Steffeck,
Hoffmeier and v. Franque, but these may represent the granulosa cords of
Walthard, which tend to atrophy. Low and even branching papillary out-

588

NEOPLASTIC DISEASES

,v \

growths into follicles have been described by W. Williams but it is not clear
that these slight grades of proliferation go on to produce definite tumors.
They are seen in simple follicular cysts, v. Miiller and Pozzi traced ovarian
carcinomas to altered follicles in which they identified ova. Yet it is doubt-
ful if the identity of these structures was established.

The presence of ova-like cells in early cystoma does not prove their
follicular origin, since these cells are probably not true ova and the granulosa
cells are not sex cells or capable of producing such. Pfannenstiel holds the
frequent association of cystoma with dermoids as an argument in favor of
the follicular origin of the cystoma.

It is commonly assumed that ovarian tumors arise from a narrowly defined
tissue segment or single follicle. Yet the early stages of many tumors

suggest that considerable areas of
superficial epithelium or many
follicles are successively involved
in the origin of the growth. This
mode of origin has been proven
for the pseudostruma of Bauer,
is strongly indicated by those
tumors which preserve the form of
the ovary, and by those which
present multiple cysts throughout
the cortex, and is suggested by the
hyperplasia in remaining follicles
observed in many cases of cyst-
adenoma.

The Wolfiian remnants in hilus
and body have been urged as the
source of pseudomucinous and
serous tumors by Rokitansky,
Kossmann, Nagel and others.
The intraligamentary position ac-
cords with this origin, and Wal-
thard found on? small adenoma in
a mesonephric tubule.

The occasional presence of
smooth muscle-cells, the associa-
tion with struma ovarii or der-
moids, and the striking resem-
blance of the columnar and mucus
cells to intestinal epithelium led Ribbert to propose a teratoid origin for
pseudomucinous cystoma. Misplaced portions of tubal mucosa or of ac-
cessory Fallopian tubes have been held by Marchand and by Kossmann
as sources of papillary tumors with ciliated cells. Walthard identified some
of his alien tissue masses as tubal remnants.

It thus appears that moderate proliferation of epithelium has been ob-
served in primitive and adult follicles, in the superficial epithelium and its
various invaginations in embryonal and adult life, and in the Wolffian tubules
of the hilus, but that only the surface epithelium has been fully traced into
tumor growth. That the proliferating cells are not the normal surface
epithelium but are misplaced and embryonal is strongly suggested by many
features of ovarian tumors. Wendeler would combine the views of March-
and, Walthard, Kossmann and others by assuming that the originating cells
are misplaced Mullerian epithelium, which in its upper segments goes to

PIG. 253. — Development of pseudostruma
ovarii from superficial epithelium. (After
Bauer, Z. G. G. 75.)

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY 589

form the Fallopian tube. This theory would seem consistent with most of
the observed facts and may for the present be accepted. That ovarian
tumors may also arise from other structures is not thereby excluded. It is
highly probable that tumors of adult type are derived from adult epithelium.
The ovulogenic origin of certain atypical adult and embryonal carcinomas,
sarcomas and mixed tumors should be entertained for the ovary as for the
testis. The search for elements demonstrating the tridermal composition
has not been pursued as actively in ovarian tumors as in testicular growths
but there appears to be no reason why the one-sided development of tera-
tomas should be less frequent in one organ than in the other. It is especially
in tumors of bizarre and varying structure, which do not fall distinctly in the
recognized classes of intrinsic ovarian neoplasms, that the ovulogenic origin
should be considered.

Tumors of the Parovarium (Epoophoron). — The parovarium is the rem-
nant of the sexual portion of the Wolman body. It lies in the membrane
connecting ovary and tube and consists of a main channel running close to
the tube, and of 10 to 18 lateral branches arranged like the teeth of a comb.
The main channel ends in a blind pouch which may be dilated into a small
cyst, the hydatid of Morgagni. Portions of these tubules may be found in
the wall of the tube, where they may be confused with secondary Fallopian
canals, and in the hilus of the ovary. The tubules are small, lined by low
cylindrical cells and walled by circular and longitudinal muscle-fibers.
Slight dilatation of the tubules is common and has been interpreted as an
evidence of functional activity (Bucura).

Cysts of the parovarium are observed in about n per cent, of ovariot-
omies (Olshausen). They commonly reach the size of the fist, but very
large cysts weighing 42 pounds, or containing 33 liters of fluid, are recorded
by Kummel and Nagel. Kossmann holds that only the small multiple or
multilocular cysts rise from the parovarium. The large cysts he refers to
dilatation of accessory Fallopian tubes, hydroparasalpinx. Favoring this
view are the presence of muscle-tissue in the wall, the preservation of par-
ovarian tissue noted in some cases, the unilocular character, the difficulty of
deriving a single large cyst from the tubules of the parovarium, and the
close contact of the cyst with the tube wall. Orth states that the cysts
which show parovarian tubules in their walls are derived from the
par-epoophoron.

Parovarian cysts are characterized by their elliptical form, thin walls,
close contact with an elongated tube, a movable serous covering, and the
presence of an intact ovary. The parovarian cysts are subserous, so that the
peritoneal coat is movable over the tumor. The tube is intimately adherent
and stretches over the cyst wall in greatly elongated form, measuring in
Payer's case 76 cm., the fimbriae n cm. The ovary may be stretched to a
flat plate. The chamber is usually single. While commonly pedunculated
and subject to torsion, these cysts may be extraperitoneal and displace the
elongated uterus out of the pelvis. The thin wall easily ruptures. The cyst
wall is composed of connective tissue and blood-vessels, and muscle-fibers
are occasionally seen. Elastic fibers may be abundant and to their contrac-
tion or that of the muscle-fibers is attributed the numerous foldings of the
inner surface. The lining is of low cylindrical and ciliated epithelium
which is often degenerated and desquamated. The contents when clear are
of thin, opalescent alkaline fluid of low gravity, 1005. Mucin and pseudo-
mucin are absent or present in traces only, and albumen is scanty. Urea
may occur in considerable traces, and a reducing substance is usually demon-
strable. The salts are chiefly chlorides and sulphates. Hemorrhage and

590 N EOF LAST 1C DISEASES

fatty degeneration often alter the character of the fluid. Papillary fibro-
epithelial growths from the cyst wall occur in a considerable proportion of
cases and Pf annenstiel refers to an extensive cauliflower growth with invasion
of the wall.

A variety of other forms of tumors has also been referred to the par-
ovarium, on account of their structure and location. These include adeno-
myomas (Pick), multilocular hydatidiform cystoma, adenosarcoma (Werth),
nbro-adenoma, fibrosarcoma, and carcinoma (Pick, R. Meyer).

Mesonephric Tumors. — While most observers find that the WolfHan
tubules (epoophoron) often found in the hilus of the ovary show little tend-
ency to develop tumor growth, a small group of cystic tumors have been
referred to this origin. Usually they produce harmless cysts of small size
lying in the hilus or medulla (v. Franque, Walthard). Other tumors are
solid and composed of tubules presenting the comb-like arrangement of the
epoophoron (Schickele, Lit.). The cells are high and cylindrical and they
may show moderate proliferation.

A peculiar malignant tumor of mixed structure, containing myxosarco-
matous and gland-like structures, somewhat resembling the embryonal ade-
nomyosarcoma of the kidney, is described by Glockner and referred to a
mesonephric origin.

Adenomyoma of Ovary. — A rare form of ovarian tumor reproduces
exactly the structure of Recklinghausen's adenomyoma. They are small,
multicystic, and benign. They present tubules with dichotomous branching
and ampullary sacs lying in a very cellular stroma. Such cases have been
described by Babo, Aschoff, Neumann and Vassmer, and referred to a meso-
nephric origin, but since they are usually associated with adenomyoma of
uterus or tubes it is probable that Russell's interpretation of his case as of
Miillerian origin is correct. The mesonephric tubules are free from a very
cellular stroma (Schickele, Lit.).

Adrenal tumors of the ovary occur in typical form and present the usual
variations in structure of adenoma, adenocarcinoma, and perithelioma.
They commonly reach a large size, are of yellowish color, and prove malig-
nant. They arise from the broad ligament, hilus, or body of the ovary, where
adrenal tissue is often present. Typical tumors of the hilus or broad liga-
ment are described by Weiss, L. Pick and Peham, and in the body of the
ovary by Peham, Sternberg and Pf annenstiel. It would seem difficult to
distinguish between, such tumors in the body of the ovary and tumors of
the corpus luteum.

Testicular Adenoma of Ovary.— L. Pick has described a peculiar adenoma
of the ovary and brought forward satisfactory evidence to show that it is
derived from a testicular element in the ovary of the hermaphrodite subject.
The tumor is a well circumscribed, yellowish, solid growth of moderate dimen-
sions and lobular conformation. The structure presents regular elongated
tubules about 35 m. in diameter, lined and filled by uniform cuboidal epithe-
lium. The stroma is slightly developed and may contain cells resembling
the interstitial cells of the testis. The tubules resemble those of the sweat-
glands vand are exactly similar to the tubular adenomas of undescended
testes.

[CARCINOMA OF THE FALLOPIAN TUBE

Since Orthmann's first description of primary carcinoma of the tube
(1886) about 1 20 cases have been reported (Doran, Fromme, Heynemann,
Lit.). It occurs chiefly between 43-50 years, but cases have been observed
as early as the 2yth year (Norris). In its etiology the influence of chronic

CYSTS AXD EPITHELIAL TUMORS OF THE OVARY 591

inflammation is of first importance. Many cases begin as multiple papillary
outgrowths of the mucosa such as arise on inflamed mucous membranes.
Sterility, which may also be referred to inflammation, was noted by Kerhrer
in 14 and a single birth in 20, of 52 cases. Association with tubo-ovarian
cysts and uterine myoma is often observed (Orthmann), and various abnor-
malities in the position and structure of the tube may serve as predisposing
factors to tumor growth.

In gross appearance the tumors are solid and nodular, or more diffuse
and papillary. They arise from the middle and outer portions of the tube,
the uterine end usually being free. Very early tumors have been found in
the form of small superficial excrescences, while the advanced carcinomas
may reach the size of a child's head. Distention of the tube with fluid may
add to the bulk and lead to perforation with peritonitis (Kiwisch).

The tumors were bilateral in about one-third of the cases. Stolz collected
10 such cases which had the structure of malignant adenoma and I have
recorded one other. In a recent case studied by L'Esperance in this labora-
tory the mucosa of uterus and both tubes was the seat of diffuse adeno-
carcinoma and co-extensive tuberculosis.

FIG. 254. — Double primary adenocarcinoma of Fallopian tubes.

The papillary forms of the tumor long remain benign but others invade
the wall, cause adhesions, perforate the peritoneum and cause local and
distant metastases. Extensions have often been observed in the ovary,
uterus, opposite tube, and pelvic nodes (Stolz). in omentum, stomach and,
intestine (Amann), rectum (Cullen), and inguinal nodes (Rosthorn). Tubo-
ovarian carcinoma is difficult to trace to its exact origin on account of the
resemblance of the epithelial tumors of these organs. In three reported cases
this condition was bilateral (Dittrich, Edebohls, Sanger). Ascites and
ovarian abscess are occasional complications of tubal carcinoma.

Structure. — The earliest cases observed have appeared as numerous low
papillary outgrowths of the tubal folds, covered with a single layer of cuboidal
cells, and resembling ovarian papilloma. Some tumors retain this distinctly
papillary structure with increase in the cell layers. Others exhibit an al-
veolar structure, probably from fusion of adjacent papillae, and resemble
uterine adenocarcinoma. Sanger and Earth believe that the latter develop
from the former by a gradual change in structure and malignancy.

Orthmann describes a diffuse acanthoma of the tube with hornification
and pearl formation, and the transformation of cylindrical cells into squamous.

592 NEOPLASTIC DISEASES

For some tumors apparently originating in the wall, an origin from an
accessory tube or from Gartner's duct has been suggested (Friedenheim,
Doran).

Secondary carcinoma of the tube is relatively frequent, especially from
the uterus and ovary (Sanger). Direct extension of corpus carcinoma into
both tubes was described by Lancereaux and three cases of tubal metastases
from corpus carcinoma were collected by Kundrat. Primary carcinomas of
both tube and uterus are recorded by Hofbauer and by Novy. The prognosis
of tubal carcinoma is no better than that of cervical carcinoma and after
infiltration of the wall it is distinctlv unfavorable (Doran, Stotz).

Miscellaneous Tumors of the Fallopian Tube. — Extensive proliferation
of peritoneal and vascular endothelium of inflammatory origin is described
by Kworostansky. A peculiar tumor composed of carcinoma arising from
the mucosa, sarcoma of the wall, and endothelioma of the blood-vessels is
described by v. Franque. A teratoid chondrosarcocarcinoma, is reported
by Amann.

Primary sarcomas and myxosarcomas are described by Janvrin, Jacobs,
Sanger, and v. Kahlden. They were of variable and uncertain structure
and origin.

CHAPTER XXX
THE OVARIAN TERATOMA

The commonly recognized varieties of this tumor, the cystic dermoid
and the solid teratoma, represent adult and embryonal types of the same
growth. Although varying greatly in gross anatomy and clinical course
they are probably identical in origin and many intermediate forms connect
the extremes of either type in one nearly continuous series. The chief
distinction is the clinical malignancy of the solid teratoma, the simple der-
moid being relatively benign.

Clinical Course. — Dermoids constitute about 10 per cent, of all ovarian
tumors, while solid teratomas are much less frequent in occurrence (Kroemer,
Lit.). They appear at all ages, often in childhood, most frequently between
30 and 40 years, the malignant growths occurring rather earlier than the
dermoids. The early growth of both varieties is rapid, but after attaining a
certain development the dermoid reaches its limit and may remain stationary
for many years, its later course being determined by accumulating secretion
in the accompanying fystoma, or by malignant changes, or other complica-
tions. The dermoid may migrate from the ovary and become implanted
elsewhere or perforate the hollow viscera. Extensive calcification may lead
to complete arrest of growth. Rupture of the cyst and discharge of its con-
tents if sterile lead to a low grade of peritonitis, with encapsulation of
discharged detritus or to multiple implantation cysts. Purulent peritonitis
results if the cyst is infected. Malignant processes develop in about 3 per
cent, of dermoids and commonly lead to invasion of the peritoneum. These
secondary processes take the form of pseudomyxoma peritonei, or numerous
cellular nodules, or more diffuse pelvic growths of sarcomatous type.

The solid embryonal tumors develop rapidly and are malignant from the
first. They soon reach considerable dimensions, become adherent to sur-
rounding structures, perforate the capsule and become implanted in the
pelvis, on opposite ovary, abdominal wall, or over the diaphragm and omen-
turn, with ascites and peritonitis. Later, distant metastases occur in retro-
peritoneal nodes, lungs, and liver.

The prognosis of simple ovarian dermoids is favorable, as the tumors
are well circumscribed, often pedunculated, and readily extirpated. The
various complications alter this prognosis and with malignant changes
the operative mortality is considerable and recurrence is the rule. With
bilateral dermoids malignant processes appear to be comparatively frequent
(Hohne).

The solid malignant tumors are usually fatal, directly, or from operation,
or recurrence. Yet when the tumor is circumscribed or pedunculated and
early, it may be successfully removed. Neuhauser estimates the cured cases
at 27 per cent. Struma ovarii is usually benign, but many give recurrence
and metastases. Chorioma ovarii is uniformly fatal.

Gross Anatomy. — The ovarian dermoid is a cystic tumor of globular

outline and smooth surface and varies in size from a small nodule to a bulky

cyst. It arises within the ovary, destroying the organ, or leaving a small

nodule lying upon the cyst. It may be attached to the ovary by a pedicle

38 593

594

N EOF LAST 1C DISEASES

which may break from torsion leaving the tumor attached to surrounding
tissues. The polypoid form has been referred to a superficial position of the
follicle supposed to give origin to the dermoid. They may develop in the
broad ligament or in the retroperitoneal space, and both ovaries may be
normal when the tumor arises from a supernumerary organ, traces of which
are found in these extra-ovarian growths. The solid embryonal and malig-
nant teratomas exhibit the same variations in position, they often contain
many small cysts and they may reach very large dimensions, Falk's tumor
weighing 25 kg.

FIG. 255. — Dermatocystoma of ovary. Simple cystoma above. Dermoid with hair in
center. Thyroid-like tissue below.

Both dermoids and solid teratomas are frequently (14 per cent. Arnsper-
ger) combined with ovarian cystomas, either serous or pseudomucinous
or lined by ciliated epithelium. A corpus luteum cyst may also be
associated with the dermoid and Schottlander believes such cysts are often
overlooked. In these cases the dermoid portion is limited to a segment
of the wall of a large cyst, or the dermoid projects as a finger-like protrusion
at one point of the cyst (Rokitansky's protuberance), or two partly or com-
pletely separate cysts, dermoid and adenoid, are in apposition or show various
stages of fusion. The dermoid portion may be represented also by an em-

THE OVARIAN TERATOMA 595

bryonal teratoma. In not a few cases the dermoid is found in one ovary, a
cystadenoma in the other.

Dermoid cysts usually contain hair and teeth. The hair is very long
like that of the head, or short and fine as lanugo, or curled and stiff as of the
pubes, and it is often silvery in tumors in young subjects. Sebaceous or
oily material is mingled with the hair. It may be condensed in the form of
firm globules, or in a large mass consisting of fatty crystals forming about
hair, or in epidermal concretions. The occurrence of these masses has been
referred to albuminous bloody exudate following torsion, to mixture with
secretion from sweat-glands, or to a sort of butter formation. Bonney
counted 4000 small globules in one case and Opitz reports their appearance
in the stool through an intestinal fistula.

In the combined cystomas the mucinous material mingles with the fatty,
and when blood is added, the dermoid element may be obscured and require
careful identification on the cleansed interior. A small tuft of hair or a
pigmented spot, or a bony plate, often mark the dermoid area. Calcification
transformed the entire mass into a stone in Pfannenstiel's case. Teeth
occur in about half the dermoids and in many solid tumors. They lie loosely
on the surface or firmly fixed in a rudimentary maxilla, or deeply imbedded
in dental follicles. The teeth are well formed and may be identified as in-
cisors or molars, etc. The embryonal tumors usually contain only small
milk teeth, while those of the dermoid are more adult. Rokitansky observed
the eruption of permanent after the discharge of milk teeth which fall into
the cyst contents and become absorbed. Saxer's dermoid consisted of a
single well-formed tooth, while Schnabel and Plouquet counted from 100 to
300 or more.

The maxillae have resembled the lower jaw with coronoid process or the
upper with antrum Highmori. Other bony masses have been interpreted
as sternum (Wilms), skull (Grechen), ribs (Schramm), or pelvis (Kuster).
Portions of long bones connected by joints are described by Kappeler. Well-
formed extremities have occasionally been observed, as a finger with three
phalanges and nail (Amor), several fingers (Reverdin), short extremity with
long nails (Thornton). Axel Key identified two lower limbs with toes,
skull, brain and jaw. Even more complete rudimentary fetuses are described
by Repin, Askanazy, Shattock, and Goffe, who identified such structures
as skull, cystic brain vesicles, pigmented optic cups, complete extremities,
pelvis with hairy pubes, vulva, clitoris, spinal cord, and blind coil of intestine.
The development of these structures, however, falls considerably below that
of the epignathi. In the embryonal tumors the complex structure usually
renders the gross identification of organ rudiments impossible.

Glandular organs may occasionally be detected. Areas of thyroid tissue
are rather frequently present, as small colloid foci, or large masses of typical
gland tissue, or the entire tumor may be composed of thyroid tissue, constitut-
ing the wrell-known " struma ovarii." Salivary glands lying near a maxillary
bone are described by Axel Key and Flaischlen.

Brain tissue appears in the form of convolutions of soft gray tissue
(Baumgarten). It is often the seat of hemorrhage. A portion of cerebellum
was observed by Askanazy. Pigmented optic cups have been found em-
bedded within or lying near the brain tissue. Baumgarten described
double rudimentary eyes, one of which exhibited a cornea-like structure.
Kordi recognized a lens and eyelid, and Graves found eyelid with lashes.

The embryonal teratomas may usually be distinguished from the more
adult dermoids by the absence of any large cystic cavities with hair or seba-
ceous material, or definite Climbs, or organs. The solid tumors usually

596

NEOPLASTIC DISEASES

contain many small cysts and close inspection may reveal islands of bone or
cartilage, rudimentary teeth, minute dermoids with fine hair, pigmented
retinal structures, and in general the cellular structure of an embryonal
tumor. Transitional cases between the main types occur, and overgrowth
of one element, as in struma ovarii, gives rise to peculiar forms requiring
special consideration.

Microscopical study reveals the extensive details of the structure of
ovarian teratomas, strengthens the interpretation of the various forms
of fetal mimicry, and reveals the essential tridermal nature of these growths.

The hairy dermal papilla is covered with a thin epidermis and a corium
of normal structure which contains many sebaceous, sweat, and hair glands
and presents an almost exact duplicate of the scalp. Retention in the glands
often produces comedones and small sebaceous cysts. The epidermis may
be traced into the mucous membrane which covers the maxillae and the

* \ Jk -«

FIG. 256. — Salivary gland alveoli in a small ovarian dermoid.

tissues in which teeth are found. This point may be indicated by a shallow
depression or deep pocket suggesting a buccal cavity. All stages of the
development of teeth have been traced, from a simple enamel organ to a
perfectly formed adult tooth. Here have been found the rudiments of buccal
and salivary glands. The subcutaneous tissue contains embryonal fat,
connective, and blood-vessels. Beneath this layer one commonly finds
plates of bone or cartilage which may be interpreted as fragments of skull,
since brain tissue, medullary canal, spinal cord and ganglia may sometimes
be identified in this region (Kroemer). Here also small cysts may present
an ependymal lining. Cerebral elements may be reduced to pigment streaks,
ependymal tufts or concretions (brain sand). Askanazy points out that
the nerve tissues of ovarian dermoids include the central, peripheral, and
sympathetic, as well as special sense organs, as of eye and ear. The dominant
system is the sympathetic. The adult forms of these tissues are represented

THE OVARIAN T ERATO MA

597

by brain cortex, ganglia and nerve trunks, the embryonal by neuro-epithelial
cell groups. The chromatophores of the central nervous system are often
abundant. The respiratory tract is represented by canals lined by columnar
or ciliated epithelium in a cellular lymphoid mucosa walled by cartilaginous
rings and strands of smooth muscle. Mucous glands, islands of thyroid
tissue, and occasionally striated muscle bundles complete the resemblance
to the fetal trachea. Kroemer interprets certain sharp infoldings of this
mucosa, with change to squamous lining, as vocal cords, and he identifies
the nares by ciliated epithelium lying on curv.ed cartilaginous plates. Wilms
describes a rudiment of lung connected with trachea by a bronchus. Mam-
mary gland tissue is described by Sutton and Reverdin. Gastro-intestinal
tract appears in segments which resemble stomach, ileum, or colon. A
single layer of low columnar epithelium, lining a flat mucosa with many glands
without lymphoid tissue or valvulae, but backed by layers of smooth muscle,
recalls more or less definitely the stomach. In the portions of small intestine
valvulae, villi, crypts and simple or agminated lymphoid follicles are found,

£* **

ffltim&wiM

FIG. 257. — Ependymal structure in brain tissue in a small ovarian dermoid.

the'lymphoid tissue being frequently present in abundance. Segments of
colon are often observed. Pommer described cecum and appendix. Colon
with meconium has been described by Perls, Repin, and others. Arnsperger
identified a portion of esophagus, but Askanazy finds that the esophageal
remnant is commonly missing, and that the intestinal tract opens directly
into the respiratory, constituting a condition which is characteristic of tera-
tomas. Kroemer identified a Miillerian duct with cervical and uterine
glands, myometrium, and vaginal mucosa. In the embryonal tumors the
respiratory and intestinal structures are reduced to short canals or small
cysts in which one type of epithelium often changes sharply into another.
The ocular structures vary from rudimentary eyes with retina, choroid,
lens, and cornea, which have appeared separately, although not all in the same
case, down to isolated groups of pigmented choroid or retinal cells. The
most frequent structure is a layer of pigmented cells lying upon a vascular
membrane which incloses an optic vesicle. The pigmented cells resemble

598 NEOPLASTIC DISEASES

those of the choroid, or they are hexagonal plates reproducing the mosaic
of the retinal epithelium. These structures may be bilateral and lie near
or within areas of brain tissue with which no definite connection by an
optic nerve-trunk has yet been observed.

Mesodermal elements, besides those recognized in the gross, appear in
many forms. Islands of hyaline or elastic cartilage occur in both adult and
embryonal tumors and in the latter they may grade into myxomatous or sar-
comatous tissue. Spongy bone masses may contain lymphoid marrow but
without giant-cells (Coe, Kroemer). Muscle-fibers are usually smooth, but
scanty striated cells have been observed, as well as heart-muscle cells (Wilms,
Askanazy, Katsurada).

The outer wall of a dermoid cyst varies greatly in structure and probably
passes through certain transformations. Any ovarian tissue remaining
is confined to a small, often cystic, mass of tissue located at one point or
distributed along the wall. When the original dermoid sac is preserved
the lining is of cuboidal or columnar epithelium and is derived by many from
the cells of the Graafian follicle. This membrane with low epithelial lining
has been interpreted as a form of amnion. An extension of squamous
epithelium from the dermoid papilla over much of this sac is regarded by
Kroemer as a late and secondary change. Erosion of this lining epithelium
is accompanied by formation of giant-cells lying on granulation tissue.
Fat crystals and fragments of hair may be imbedded in this tissue and
considerable calcification of the wall may occur, especially after separation.
The gradual absorption of the oily contents of the cyst may result in honey-
combing of the wall, the fat passing into dilated lymphatics lined by pro-
liferating endothelium.

Schottlander traces the large serous cysts accompanying some dermoids
to dilated lymphatics. The gradual absorption of the thin wall of the
original dermoid chamber leads to communication with surrounding cavities
which include corpora lutea, serous cysts, and adenomatous cysts. As these
communications widen, the wall of the cyst changes and its lining varies
in different portions and at different periods.

Metastases develop from dermoids in which malignant changes have
become established and more frequently from the solid and embryonal
teratomas.

Local dissemination of the tumor elements over the peritoneum follows
rupture of the cyst wall or tumor capsule. These implantation metastases
are of very variable structure. Lazarus found nodules on diaphragm and
in Douglas' pouch, the latter containing cartilage and cysts with cylindrical
cells. In several cases multiple epidermoid and dermoid cysts have re-
sulted. Neuhauser described multiple miliary nodules of glia-tissue along
the vessels of a portion of omentum removed at operation on a patient who
recovered. Falk demonstrated at autopsy complete regression of peritoneal
metastases three years after laparotomy in an inoperable tumor.

Through the lymph-vessels the retroperitoneal nodes are involved by
metastases which are of simple or complex type. Many of these are of
ectodermal and neuro-epithelial nature. Ewald found ectodermal and ento-
dermal cysts and cartilage in a large recurrent retroperitoneal tumor. Pick
demonstrated a long bone with marrow cavity, lying in a retroperitoneal
node. Falk described a complex metastasis in the abdominal wall contain-
ing brain tissue, and intestinal canal with musculature. All of the complex
secondary tumors are probably the result of direct extensions or implantations.

Through the blood-vessels metastases have appeared in lungs, liver, and
kidney, and are usually of sarcomatous or indifferent embryonal type.

THE OVARIAN TERATOMA 599

It is evident from these observations that several types of differentiated
cells may be detached from ovarian teratomas and give rise to metastatic
tumors. That undifTerentiated cells capable of developing tridermal struc-
tures may be dislodged from the ovarian tumors is as yet unproven. All the
tridermal secondary growths appear to be local recurrences or implantations
in or about the peritoneum. The various cells of the original tumor appear
to become separated by the embolic process and to develop only their
particular kind in metastatic tumors. Yet it must be admitted that the
embolic cells or cell groups are capable of developing organoid structures,
such as brain tissue and dermoid cysts (cf. Saxer).

Atypical Forms of Ovarian Dermoids. — Not all ovarian dermoids exhibit
the tridermal and complex structures of the fully developed tumor. Sup-
pression of one germ layer, overgrowth of single elements, and secondary
changes, give rise to several well-defined subvarieties.

(1) Bidermal A trophic Teratomas. — Simple dermoid cysts without de-
monstrable elements of a third germ layer constitute about 5 per cent, of all
ovarian teratomas (Wilms). The ectodermal lining presents the usual fea-
tures of a typical dermoid and the wall contains dermal glands, teeth, connec-
tive, fat, smooth muscle and bone or cartilage, but entodermal structures
are missing. While only a very thorough study can determine the absence
of entoderm, there is little doubt that this layer is the least vigorous of the
three in this as in other teratomas. Askanazy saw complete loss of ento-
dermal structures in a petrified dermoid containing teeth. Kroemer ob-
served partial separation and beginning atrophy of the entire dermoidal area,
which hung by a narrow pedicle to the cyst wall. It seems possible that the
entire dermoid might be destroyed in this way, especially when associated
with a large adenocystoma. Kroemer pictures a very large multilocular cys-
toma in which the dermoid was reduced to a diminutive hairy nodule. These
observations, as well as the occurrence of a dermoid in one ovary and a sepa-
rate adenocystoma in the same or the other ovary, led Hanan, Ribbert, Lan-
dau, Pick and others to conclude that the pseudomucinous cystadenoma is a
one-sided entodermal development of a teratoma. Askanazy includes among
typical dermoids some which seem to consist exclusively of epidermis.
Saxer's dermoid consisting of 'a single tooth must have resulted from early
suppression of other elements. Portions of the main dermoid, including
epidermis and hair or even bone (Wilms), may be transplanted into adjoining
cysts, giving a false impression of multiplicity of dermoids. After rupture of
ovarian dermoids multiple implantation dermoids may appear over the
peritoneum.

(2) Multiple dermoids in one or both ovaries have repeatedly been
observed (Novak, Lit.). Schroeder reported seven isolated dermoids
in one tumor and Pfannenstiel saw five, all of uniform size. Wulkow found
two dermoids in one cystoma and four in a similar tumor of the other ovary.
Some of these may have been the result of transplantation, but Heinsius
described five complete dermoids in four separate compartments. Hoffmeier
found four in one ovary and seven in the other. The largest number observed
was by Novak who found ten in one ovary and eleven in the other. Keitler
observed in one ovary a dermoid cyst with hair and teeth, in the other two
dermoids and a cyst enclosing a solid teratoma. The genesis of the true
multiple dermoids may be referred either to the simultaneous growth of
separate ova (oocytes), or to the separation of blastomeres of one original
ovum.

Retroperitoneal and intraligamentary dermoids containing portions of
ovarian tissue have been reported by Coen, Dunnwald, and others. Rarely

600

NEOPLASTIC DISEASES

this location may be referred to the separation from the ovary and secondary
implantation elsewhere (Reinprecht). More often a supernumerary ovary
is the probable source (Herrmann, Wilms).

An elongated pedicle may permit unusual migration and attachments of
the dermoid. I have examined a complex dermoid, showing epithelioma of
the skin, hanging in the cecum. Perforations of bladder, rectum or ileum
are recorded.

(3) Secondary changes may greatly alter the appearance and structure
of dermoids. Torsion leads to hemorrhagic infiltration and necrosis, and
this may be followed by extensive calcification or by suppuration. All

FIG. 258. — Atypical epidermal growth in an ovarian dermoid.

traces of the original dermoid structure may thus be lost and the tumor
becomes a solid calculus (Busse, Askanazy).

(4) Malignant characters in the dermoid itself or in the associated cys-
toma are important features of many cases.

The epidermis may develop epithelioma invading the other tissues of
the dermoid, of which Bab has collected 37 cases. A mammary carcinoma
in a dermoid is reported by Yamagiva, and adenoma of the sweat-glands by
Friedlander. Seeger observed bilateral carcinomatous dermoids. Sarcoma-
tous changes occur in dermoids, while in many teratomas much of the tissue
may be of embryonal and sarcomatous character (Ludwig, Lit.). Pigmented
sarcoma arising in the cyst wall is recorded by Amann and by Lorrain.

THE OVARIAN TERATOMA 601

Round-cell sarcoma in the wall and in hepatic metastases is recorded by
Litten. Bierman described a large spindle-cell sarcoma and Neumann a
perithelial alveolar tumor, arising from the corium of dermoids. The wall of
the associated cystoma appeared to be the source of spindle-cell sarcomas in
the cases of Flaischlen and Ludwig. A typical perivascular and alveolar
sarcoma is described and pictured by Schwertassek. Kroemer traced an
alveolar sarcoma of the cyst wall to the vascular endothelium, and the endo-
thelial origin of many of these tumors is also maintained by Mirabeau and
Schottlander. The ovarian tissue is believed to furnish some of the dermoid
sarcomas, as in the cases of Geyer and Thornton. It would appear that the
tumor process is incited in some way by the dermoid, according to Kroemer
in some cases by the absorption of oily material.

These malignant processes extend beyond the dermoid with rupture of
the cyst and produce metastases in peritoneum and liver. The rupture of
the cyst may also be followed by multiple dermoidal implantations or by
encapsulation of fatty material which lodges on the peritoneum.

(5) Struma Ovarii. — The occurrence of thyroid tissue in ovarian tumors
has long been recognized and variously interpreted (Bell). It is relatively
frequent in ovarian while very rare in testicular teratomas. An origin from
metastatic thyroid cells or from mucous degeneration of a carcinoma (Kretsch-
mar, Voight) has now fully yielded to the view that these tumors represent
one-sided growths of a teratoma. This view was strongly supported by
Walthard and others who found in several such growths islands of cartilage,
bone, epidermis and acinous glands. Moreover Pick in 21 dermoids found
islands of thyroid tissue. Both these observations are frequently verified
(Trapl, Lit.).

The tumors occur in both benign and malignant forms. The benign
tumors may reproduce almost exactly the structure of the normal adult
thyroid gland. Meyer demonstrated iodin in the tissues. They produce
rather bulky tumors resembling a colloid goiter in the gross and they are
subject to hemorrhage, cyst formation, and regressive changes. Trapl brings
evidence to show that the ovarian struma may functionate vicariously for
the thyroid gland.

The malignant tumors are more cellular, invade the surrounding tissues
and produce metastases (Polano, Katsurada). To what extent the malignant
cellular tumors may lose their structural resemblance to thyroid tissue is
not yet clear but it appears not unlikely that some solid carcinomas of the
ovary are derivatives of teratoid thyroid tissue.

That the typical structure of struma ovarii may be produced by a tumor
originating from downgrowth of superficial epithelium is clearly shown by
Bauer, but his claim that all ovarian strumas originate in this manner cannot
be entertained.

(6) Chorioma Ovarii. — While chorioma testis is comparatively frequent,
the ovary has furnished only rare or uncertain examples of this type of
atypical teratomas.

A notable example is described by L. Pick in which both microscopical
and gross features were complete reproductions of the primary uterine
chorioma. Small polyhedral Langhans' cells rich in glycogen and with many
mitoses were combined with large vacuolated syncytial masses. The
syncytium appeared to spring from neuro-epithelial cell groaps, invaded the
vessels, and added a hemorrhagic character to the tumor. In addition there
was a sarcomatous framework holding epidermis and glands lined by mucous
cells.

The occurrence of choriomatous tumors of the pelvis and liver without

602 NEOPLASTIC DISEASES

demonstrated involvement of the ovary leaves a well-founded suspicion
that an ovarian teratoma may have been suppressed or overlooked. Kroe-
mer described a pure chorioma of the ovary in a woman of 51 years,
without other teratoid elements. A typical malignant chorioma ovarii was
also described by Glinski and Rosner. Lubarsch examined- a large tumor
mass in the pelvis of a 1 3-year virgin, which consisted of polyhedral vacuolated
cells and syncytium. He concluded that this structure might be duplicated
by tumors arising from various epithelial structures of the genito-urinary
tract.

In several instances it has been shown that epithelial tumors of ordinary
type may in metastases yield a structure much resembling chorioma. Hence
Risel discards many of the reported choriomas of tubes, ovary, and other
organs, as spurious imitations derived from other than teratomatous sources
or gestation products. Monckberg considers many of these growths to be
derived from endothelium. Not a few of the so-called choriomas of the
liver appear to me to be derived from primary carcinomas of the liver-cells.
L'Esperance, in this laboratory, has described such a spurious hepatic chori-
oma and pointed out its notable distinctions from true chorioma.

Nevertheless the gross and microscopical features of a group of heterotopic
choriomas in both sexes exactly reproduce those of uterine chorioma. On
the other hand the secondary chorioma-like structure occurring with carci-
noma and other tumors fails to yield such complete reproductions of the true
chorioma. Hence I am disposed to think that many of the above tumors
are true teratomas derived originally from ovary or testis and that the
original tumor is suppressed or overlooked, or that such tumors arise from
deported chorionic structures from uterine gestation. For the diagnosis
of such true heterotopic choriomas it is necessary to insist on complete
identity in gross characters including pulmonary metastases and not to rely
merely on occasional microscopical resemblances.

(7) The Relation of Simple Ovarian Tumors to Teratoma.— The demonstra-
tion that one element of an ovarian teratoma may suppress the others raises
the question how far the apparently simple tumors of the ovary may prove
to be of teratomatous origin.

Under the term epithelioma chorio-ectodermale, L. Pick would include
certain embryonal ovarian tumors resembling adenoma, carcinoma, and
endothelioma. He describes five cases of cystic or solid growths in which
the cells were rich in glycogen, and were arranged in cystic adenomatous or
solid carcinomatous structure. The main tumor-cell he identifies as the
Langhans' cell, while syncytium-like masses were often present.

Pick's interpretations of these tumors has not been supported. Kroemer
did not find a convincing resemblance of the tumor-cells to chorionic epithe-
lium, and Risel notes the absence of a vasodestructive property in the tumor-
cells. In seems probable that the tumors described by Pick were embryonal
growths in which the syncytial masses were developed from the main tumor-
cells of ordinary ectodermal or entodermal origin and that they were not of
chorionic nature. This conclusion, however, does not dispose of the possible
teratomatous origin of many apparently simple embryonal tumors of the
ovary. Especially for the extensive group of sarcomas of the ovary, round-
and spindle-cell, perivascular, alveolar, and "endothelial," the observations
by many authors of identical structures arising from dermoids and teratomas,
strongly suggest a teratomatous relation. This question must, however,
await further observations.

Chondroma of the ovary is described by Reiss and Jung as a mesodermal
teratoma, and Meyer accepts this interpretation. The chondrosarcomas

THE OVARIAN T ERATO MA 603

being embryonal tumors should from this point of view be regarded as
teratomatous. Ovarian melanoma may also be interpreted as of terato-
matous origin.

In all of these cases further observations are necessary before a teratoma-
tous element can be accepted. While the observations on tumors of the
testis point by analogy to the simple origin of many ovarian tumors, the
conditions in the ovary are much more complex than in the testis.

Etiology. — The origin of ovarian dermoids and teratomas is now referred
by the great majority of observers to the sex cell or ovum. The essentially
tridermal character of these tumors requires that the originating material
be totipotent. Only two possible sources of such material have been seri-
ously considered, the isolated blastomere of Marchand-Bonnet, and the
primitive unfertilized ovum. Bandler constructed an elaborate argument for
the Wolffian origin of ovarian dermoids but this view has not met with favor.
Several considerations speak against the theory of an isolated blastomere.
Chief among these is the frequency of such tumors in the sex glands, both
ovary and testis. While it is not necessary to regard all tridermal tumors
from the same viewpoint, those of the sex glands find a direct and obvious
explanation in the autonomous growth of a totipotent cell which is constantly
present in these organs in considerable numbers. On the other hand it is
almost impossible to conceive how isolated blastomeres can gather in suffi-
cient numbers to explain the incidence of dermoids. The occurrence of as
many as seven dermoids in one ovary and 21 in both organs practically elimi-
nates the blastomere or polar body as a possible source. The field of the
isolated blastomere lies with the parasitic implantations, and its extension
to the teratomas of the sex glands is unwarranted.

The direct evidence in favor of the origin from sex cells is considerable.
Ovarian dermoids occur during the period of functional activity of the
ovary. They are excessively rare in the fetus and they are practically
unknown as a tumor arising after the climacteric. The multiplicity is readily
explained by the abundance of ova in the organ. The spontaneous growth
of the unfertilized ovum is a reasonable hypothesis, in view of the very
numerous factors which are known to incite the growth of ova in lower ani-
mals. It is a matter of little consequence whether this growth be designated
as parthenogenetic or otherwise. No one has traced the dermoid to an ovum,
but the frequent association of cystoma with dermoids suggests, as Kroemer
holds, that the cystoma arises from the epithelium of the Graafian follicle
and the dermoid from the contained ovum. The occasional combination
with a corpus luteum cyst finds a parallel explanation. Malformation of
the genitals has been observed with ovarian dermoids but not with sufficient
frequency to indicate a definite relation of such gross anomalies with the
tendency to teratomatous growths (Freund). These anomalies have in-
cluded pseudohermaphroditism, infantilism, supernumerary ovaries, elon-
gated cervix with cysts of Wolifian duct (Amann), and myomas in many cases.

That the dermoid and the teratoma have an identical origin is indicated
by the occurrence of intermediate types of- tumors, and by the association
of both embryonal and adult tissues in the same tumor. Yet the difference
in the structure of the dermoid and the teratoma has not been satisfactorily
explained. Askanazy assumes that the adult tissues of the dermoid are of
equal age with those of the host and the tumors are congenital, while the
teratoma arises later in life and yields embryonal tissues. Yet congenital
dermoids are excessively rare, and since their initial stages are never seen the
early growth must be rather rapid. After attaining a certain size they
may remain stationary, so that the age of a dermoid extirpated after the cli-

604 NEOPLASTIC DISEASES

macteric is difficult to determine. Hence it is probable that both dermoids
and teratomas arise chiefly in young adults, especially about the 2oth year
(Kroemer). It is possible that the varying structure depends upon the
degree of differentiation of the originating sex cell. Back of the mature
ovum are the oocytes, the oogonia, and the primary sex blastomere, each
of which may be assumed to give origin to tumors. From this point of view
the two theories of origin, from sex cell and from isolated blastomere, approxi-
mate each other. The embryonal tumors may thus be assumed to develop
from early members of the sex cell series, the dermoids from late members.
Yet the localization in the ovary requires that all the tumors must arise from
cells included within this organ, a condition which the isolated blastomere
does not readily meet. It seems probable therefore that the varying struc-
ture is determined by local factors, still undefined, acting upon cells of a uni-
form character.

CHAPTER XXXI
CARCINOMA OF STOMACH

Statistical. — The stomach is probably the most frequent seat of cancer in
males as is the uterus in females. The exact proportions of these two forms
of cancer are matters awaiting expert statistical study. Welch, 1885, from an
analysis of 31,482 cases of cancer in cities found the proportions; stomach,
21.4 per cent.; uterus, 29.5 per cent. These figures include Gurlt's Vienna
statistics, which are much too low for the stomach, 10 per cent, in 4131 cases.
I should be inclined to balance Gurlt's data with Haberlin's figures for
Switzerland, which are much too high for most localities, 41.5 per cent, in
27,511 cancers. Intermediate but high ratios are recorded by Reiche (Ham-
burg) 35.5 per cent.; Virchow (Wurzburg, 1855), 34.9 per cent.; Martin (com-
piled from 70,000 cases) 33 per cent. The U. S. Census, 1912, reports 46,534
deaths from cancer, 18,517 of stomach and liver, 39.75 per cent., 7089 of
female genital organs, 4431 of breast, indicating a distinct predominance of
gastric cancer. This census also shows a more rapid increase of reported
gastric cases than of uterus or breast cancer during the past decade. Marked
variations in different countries and cities and slight relative immunity of
negroes and in the tropics, appear in various studies.

Males are slightly more often affected than females (5-4 Welch, 3-2
Haberlin, 65-35 Kaufmann, 588-412 Friedenwald). Of deaths from all
causes gastric cancer gives i per cent. (Brinton); ij^ per cent. (Gussenbauer,
v. Winniwarter, Vienna); 3^2 per cent. (Welch, Prague); 2 per cent. (U. S.
Census, 1911, stomach and liver).

Etiology. Age. — The average age of incidence is 61.2 years (U. S. Census,
1911). The distribution is indicated in the following table.

Decade o 10 20 30 40 50 60 70 80

io; 20 30 40 50 60 70 80 100
Total — !

Welch, 1885 2038 .1 2.713.3 24.530.4 216.851.15

Reiche, 1900 2000 .04 .87 5. 85 14. 15 25. 932.1 18.1 2. 76

Martin, 1908 7000 .08 1.5 8.8 18.0 28 28 14 2.0

U. S. Census, 1911. . . .Stomach and liver

17,365 .261.15 4 13.225.5 3020.8 5.5

U. S. Census, 1914 Stomach alone

11,733 ,12 6 92 457 1345285735872647 725

The average age for carcinoma of liver is 47.2 years (Rolleston).

While the disease is distinctly one of advanced age its rather frequent
occurrence between 30 and 40 years, and even between 20 and 30, is note-
worthy. A high proportion of the early cases appear to be adenocarcinomas.
A congenital adenoma of the pylorus in an infant 5 weeks old was reported
by Cullingworth. Of several other cases under io years, collected by R.
Williams, none appeared to be true carcinoma of the stomach. In the second

605

606 N EOF LA STIC DISEASES

decade Osier and McCrae collected 13 cases, illustrating ulcerating and fung-
ating carcinomas of caidia and pylorus (Moore, Dock, Glynn, Wilde),
scirrhus of the pylorus (Koster, Dittrick, Landouzy), and encephaloid
cancer (Scheffer). Carcinoma developing on an ulcer in a girl of 18 years is
described by Bernoulli. In the third decade the usual forms of the disease
are not infrequently represented, and they tend to run a rapid course (Osier,
McCrae, Matthieu).

Heredity. — From a study of 1744 gastric cases from various authors
Welch found that in about 14 per cent, other members of the family
suffered from cancer. Napoleon I, his father, brother and two sisters died of
gastric cancer. Twenty-three families known to Manishon included 69
cancerous members of which in 57 the disease was in the stomach. In
these and other cases collected by R. Williams it is possible to assume a
tissue predisposition. The rarity of these observations emphasizes the
usual absence of any element of heredity in gastric cancer. Yet this group
of cases seems to be a particularly favorable field for the clinical study of
heredity in cancer.

Trauma. — Many observers have endeavored to establish a definite
relation between trauma and gastric cancer. Menne cites a series of cases
designed to illustrate a direct or indirect relation to trauma, and concludes
that the trauma may be the effective etiological factor, or may excite
malignant growth in a latent and quiescent focus, or may accelerate the
growth of an existing carcinoma. He also describes various traumatic
lesions of the stomach of benign course which might serve as sources of
carcinoma. The legal verdict in these cases strongly favored the victim,
on the ground that the evidence created a probability approaching certainty
that the carcinoma resulted from the trauma. Although the violence was
sufficient to injure the stomach and gastric symptoms began within a rea-
sonable time, there was in the history and anatomical findings in these cases
insufficient data from the pathological standpoint to prove the traumatic
origin. Boas reported a traumatic history in six gastric carcinomas, but holds
that trauma never produces carcinoma in a healthy stomach. Most ob-
servers fail to find any traumatic history in their experience with gastric
cancer. With the exception of rare cases following ulcer, the known begin-
ning of the disease is inconsistent with a traumatic origin.

Idiosyncrasy.— R. Schmidt describes two types of subjects who develop
gastric carcinoma, the dynamic and the adynamic. The former are well-
nourished individuals whose parents were long lived and whose digestion
has always been so good that they may be designated as "gastric athletes."
They develop the disease in adult or later life. The latter are poorly
nourished, present a phthisical habit, a low pilosity, and suffer from epistaxis,
gastric ulcer or achylia. They develop the disease early.

Alcoholism was noted in the majority of cases of gastric carcinoma in
adults, by Martin, and R. Schmidt, but Friedenwald found it in only 15
per cent.

Location. — -Three-fifths of all gastric cancers originate in the pyloric
region, another 20 per cent, arise along the lesser curvature and cardia, and
the remainder from the walls of the greater curvature. The fundus is
rarely involved. Welch's table from 1300 cases exhibits this distribution—
pyloric region, 60.8 per cent.; lesser curvature, 11.4 per cent.; cardia, 8 per
cent.; posterior wall, 5.2 per cent.; diffuse, 4. 7 per cent.; multiple tumors, 3.5
per cent.; greater curvature, 2.6 per cent.; anterior wall, 2.3 per cent.;
fundus, 1.5 per cent.

By more minute distinction between the pylorus proper and the vicin-

CARCINOMA OF STOMACH 607

ity of the pylorus, Boas in 125 cases located 27.2 per cent, in the pylorus,
and 26.4 per cent, in the lesser curvature, and in 40 later cases he found 25
of the lesser curvature and 6 in the pylorus. Mathieu in 234 cases locates 56
per cent, at pylorus, 12 per cent, at cardia, 4 per cent, on lesser curvature,
1.2 per cent, on greater curvature, 23.5 per cent, on the lateral walls.

Tabora connects the occurrence of cancer at the pylorus and on the lesser
curvature with varying physiological conditions in the stomach. Cancer
of the lesser curvature is usually associated with achylia, pyloric cancer
with hypersecretion. In achylia the pyloric region is relaxed, the stomach
is promptly emptied, in J^ to % hour after a test meal, and motor insuffi-
ciency develops late. Hence the pyloric region escapes irritation, while
the fixed and vascular lesser curvature is chiefly exposed. With hypersecre-
tion the lesser curvature is equally exposed, but the long closure of the
pyloric ring (Pawlow) exposes unduly the prepyloric mucosa where primary
cancer chiefly develops.

Gross Anatomy. — Gastric carcinoma appears in several characteristic
anatomical forms. A classification of these forms may be reached on
strictly histological data as done by Kaufmann. Yet the location and gross
form of the tumor determine very marked differences in the symptoms and
course of the disease, which it seems desirable to emphasize by a classification
according to etiology, gross .anatomy, and structure. From this point of
view one may recognize the following types:

(1) Bulky adenocarcinoma.

(2) Gelatinous carcinoma.

(3) Carcinoma following ulcer. Ulcerocancer.

(4) .Carcinoma simplex.

(5) Scirrhus carcinoma.

(6) Stenosing fibrocarcinoma. Linitis plastica.

Of 1 22 1 cases reviewed by Welch, 791 (64.8 per cent.) were medullary,
399 (32.7 per cent.) scirrhus; 31 (2.5 per cent.) colloid. Adenocarcinoma is
the most frequent variety in my material.

(i) Adenocarcinoma. — The distinguishing features of this group depend
upon a relatively benign adenocarcinomatous structure, which presents a
circumscribed polypoid or fungating and eventually ulcerating growth.
This tumor is the gastric counterpart of adenoma destruens of the colon and
uterus. As in other situations it may reach large dimensions before invad-
ing the lymph-nodes, but it is rather more malignant in the stomach than
elsewhere.

The location is chiefly near the pylorus, less frequently at the cardia,
in both of which situations it soon ulcerates. Or it may develop from the
lesser or greater curvatures where it tends to reach large dimensions.
This type of carcinoma may be multiple in the stomach and similar tumors
may appear in the colon (Hauser). In the early stages, as described by
Verse, it appears as a flat, warty thickening of the mucosa, which may develop
into a polypoid outgrowth, but more frequently, especially at the pylorus,
it early ulcerates, infiltrates the wall, and runs the course of an ulcerating
carcinoma. These cases are sometimes difficult to distinguish from second-
ary carcinoma developing on a peptic ulcer. Their broad base, markedly
overhanging edges, and histological structure usually serve to separate them
from the secondary carcinomas arising from ulcers.

A second mode of origin is through the carcinomatous transformation
of an adenomatous polyp, all stages of which are described by Hauser and
Verse. It appears probable that most of the bulky, polypoid and fungating
adenocarcinomas develop from such preliminary lesions. It is characteristic

608 NEOPLASTIC DISEASES

of these bulky tumors that they grow to large size without prominent gastric
symptoms or invasion of lymph-nodes. Ulceration becoming established
rapidly transforms the clinical picture, adding hemorrhage, pain, vomiting,
and cachexia. The excavation of such tumors may be extensive and deep
and lead to fatal hemorrhage or perforation.

All of these growths are comparatively solid on section, resembling
medullary carcinoma, but some show accumulation of mucus, and areas of
fatty degeneration, hemorrhage and necrosis. In a small subgroup the
gross structure is distinctly villous, resembling the coarser tumors of the

FIG. 259. — Bulky ulcerating adenocarcinoma of stomach.

bladder. Their structure shows well-developed branching, vascular, papillae
covered with multiple layers of atypical cylindrical cells which may infiltrate
the wall and have been known to produce hepatic metastases (Matsuoka)
(Matti). In a case of empyema Verse found six carcinomas in the stomach,
some of which were of elongated papillary or villous type.

The adenocarcinomas are regularly embedded in the submucosa which
may be widely infiltrated and in the muscularis which is usually perforated,
but extensions to the lymph-nodes may be long delayed. Yet the nodes,
liver, and other organs are eventually invaded by growths which reach
considerable dimensions, and precocious metastases in distant localities
have been observed. Finlay found multiple subcutaneous metastases, the
structure of which led to the diagnosis of a latent cancer of stomach, verified

CARCINOMA OF STOMACH 609

at autopsy. I have seen a similar case in which a single nodule excised from
the midscapular region presented the typical structure of malignant
adenoma of the stomach, which was later found at autopsy. Roseler's
multiple ulcerating carcinomas of the skin, although not examined micro-
scopically were probably of this type. A metastatic growth in the humerus
was the first sign of gastric cancer in a case of Tilling's.

The structure of gastric adenocarcinoma presents somewhat orderly imi-
tations of the gastric tubule. The originating tubes become much elongated,
bifurcated and sacculated and the tumors are composed of such alveoli com-
pactly grouped with little stroma. The cells are cylindrical or cubical, the
cytoplasm clear and the nuclei hyperchromatic. It is notable that in many
gastric tumors the infiltrating and metastasizing alveoli are lined by single
rows of cells, and that multiple layers of very large cells are less common than
in tumors of the colon. Hence the structure often suggests a benign adenoma.
The lumina of the alveoli are usually small, or they may be distended with
mucus and exudate, or secondary alveoli may form within the acinus.

Carcinoma cylindrocellulare micro scysticum is a type described by Hauser
and presenting many large or cystic alveoli distended with thin mucus and
serum.

The gastric mucosa is often the seat of glandular and polypoid over-
growths and in the neighborhood of the tumor the hyperplastic glands may
gradually pass into carcinomatous structures (Hauser, Verse). Kulbs de-
scribed an infiltrating adenocarcinoma with ciliated cells in original tumor
and in metastases in adrenals and lung.

Adenocarcinomas of the pylorus, with scanty groups of squamous cells more
abundant in metastases, are described by Herxheimer and Lubarsch. The
squamous-cells were probably of metaplastic origin. Primary squamous-cell
carcinoma of the cardiac region, probably derived from esophageal epithelium,
is described by Kaufmann, Ziegler and Borst.

Simple adenoma of the stomach occurs in single or multiple polypoid form.
Rarely this tumor is submucous. The single tumors usually remain of small
size and give no symptoms unless located near the orifices. Others become
the seat of adenocarcinoma. Rarely they reach large dimensions while
retaining an, adenomatous structure. Chaput described a pedunciilated
tumor of the fundus as large as a child's head, which was free f rom ulceration
and presented a pure adenomatous structure. Multiple adenomas usually
form a part of the lesions of gastritis polyposa.

(2) Gelatinous Carcinoma. — Mucous changes are a frequent microscopic
feature of most forms of gastric cancer, but when this change becomes very
pronounced it greatly alters the gross appearance and course of the tumor,
which in structure is usually an adenocarcinoma.

The characteristic gelatinous carcinoma usually begins in the pyloric
region and infiltrates all coats 'of the stomach wall which may measure 2 to
3 cm. in thickness. The organ may be reduced in size but not so markedly as
with true scirrhus. The gelatinous material infiltrates and largely replaces
the tissues of mucosa, submucosa, and muscularis, and appears in translucent
nodules on the serosa. Advanced cases of this type are described by Storer,
Amidon, Verse, and others. In Amidon's case the stomach measured 7 in.
in length, the wall J-g inch in thickness. The pylorus was but slightly
thickened. The mucosa was everywhere replaced by nodules of gelatinous
carcinoma, and the peritoneum was extensively invaded. Verse's tumor (64)
was a bulky mass encircling the pylorus and infiltrating the vicinity. In
Hauser's case (32) the secondary hepatic tumors were pure adenocarcinoma
without colloid. Adhesions to neighboring organs are frequent with this

610 NEOPLASTIC DISEASES

type of growth. Invasion of lymph-nodes while frequent is usually late and
colloid visceral metastases are rare.

In an important group of cases the gastric wall is penetrated early and
while the original tumor may remain comparatively small there are numer-
ous and bulky extensions over a portion or the whole of the peritoneum, with
ascites. The stomach outranks the colon and gall-bladder as a source of col-
loid carcinoma of the peritoneum (Kaufmann).

The structure of gelatinous carcinoma in the stomach is very similar to
that of simple adenocarcinoma, with the addition of extensive formation of
thin mucus. This material fills all but the youngest alveoli to distension and
after rupture it infiltrates the supporting tissues and invades lymphatics and
the sheaths of vessels and nerves. The lining cells of the alveoli present all
stages of its formation and many cells are desquamated and dissolved in the
mucus. Complete disappearance of all traces of epithelium may occur in
large areas of such tumors, which thereby reach a standstill while growth pro-
ceeds in other areas. A partial absorption of this mucus may follow.

In infiltrating portions of mucous carcinoma the diffusely growing cells
become ballooned with mucus and the nuclei are compressed into signet-ring
forms. These cells are commonly present both in this and other anatomical
forms of gastric cancer, either actively growing or regressing and their pres-
ence is an important aid in diagnosis between chronic inflammation and can-
cer of the stomach.

(3) Carcinoma Following Peptic Ulcer. — The relation of gastric ulcer to
carcinoma has long been an actively debated question. Rokitansky, 1840,
recognized that cancer might develop from ulcer. Dittrich, 1848, among 160
cancers found six developing near ulcers, and two in which the carcinoma was
limited to portions of ulcers. Lebert, 1878, calculated that 9 per cent, of can-
cer arise from ulcers, while Zenker, 1882, went so far as to conclude that all
gastric cancers are secondary to some form of ulceration. He noted the per-
sistence of free HC1 with cancers following peptic ulcer. In 1890 Hauser
described several cases of cancer of characteristic anatomical form following
ulcer. G. Futterer, 1902, concluded that ulcers in the pyloric region fre-
quently give rise to cancer, especially in those portions of the edges most
exposed to irritation. The onset of cancer may be marked by increasing
pain, anemia, and emaciation. The free HC1 steadily diminishes (Riegel).
Mayo Robson finds a history suggestive of ulcer in 59.3 per cent, of his cases
of gastric cancer but reports only one specific case with microscopic evidence.
Recently the Mayo clinic reports that 71 per cent, of their gastric cancers
were associated with ulcer and 68 per cent, of ulcers were complicated with
carcinoma.

In determining the relation of gastric ulcer to cancer, statistical, clinical,
gross anatomical, and microscopic data are available (Ewing, Lit.). Statis-
tics show that ulcer is much more common and cancer much less common in
women than in men, and this conclusion is not seriously altered by distin-
guishing between simple and chronic ulcer. The clinical history of precedent
ulcer and of persistent free HC1, while suggestive and important as corrobora-
tive evidence, cannot demonstrate a direct connection between ulcer and
cancer.

The gross anatomy, however, furnishes very strong evidence. In charac-
teristic cases, as described by Hauser, there is a deep crater-like ulcer with
thick and very dense base free from cancer, indurated and undermined or
everted edges, exactly reproducing the chronic peptic ulcer. In addition
there are marked contracture of the wall, swelling and induration of lymph-
nodes and occasionally visceral metastases. Secondary ulceration of primary

CARCINOMA OF STOMACH

611

carcinoma does not often produce such a lesion and these cases must be
regarded as probably carcinoma following ulcer. In most cases of this
type microscopical evidence is required and when it appears in unequivocal
form there can be no doubt that a carcinoma has been engrafted upon a pep-
tic ulcer.

The uncertain territory in this field includes (i) certain superficial ulcera-
tive processes which the microscope shows are clearly carcinomatous and
(2) certain characteristic chronic peptic ulcers which have been classed as
carcinomatous on less definite microscopical structure.

(i) That localized superficial carcinomas of the stomach may early be-
come ulcerated has long been known and is most clearly demonstrated by
Verse's descriptions of such early cases. These lesions are chiefly located
in the pyloric region and lesser curvature, they are comparatively super-

FIG. 260. — Hauser's figure of peptic ulcer with secondary carcinoma of stomach. Note iso-
lated polypoid outgrowths on edge of ulcer and elsewhere.

ficial and usually lack the deep funnel form and extensively indurated base
and borders of the carcinomatous peptic ulcer. They may eventually
closely simulate the latter.

Microscopically they present pronounced adenocarcinoma, or alveolar
gelatinous carcinoma in both base and edges and the surrounding mucosa is
hyperplastic. Verse finds that the glands on the edges of such ulcers may
show a gradual transformation into carcinomatous structures.

(2) Peptic ulcers exhibit many transitional stages of carcinomatous
change. Some, and in the experience of most observers the majority, fail
to show any evidence whatever, of carcinoma. In Vienna, 2 per cent., in
Copenhagen, 20 per cent, of the subjects coming to autopsy show scars of old
healed ulcers (Hirschfeld). Others show suspicious or pronounced precan-
cerous changes in a portion or the whole of the edges. The proportion of

612 NEOPLASTIC DISEASES

ulcers classed as carcinomatous depends on the criteria employed by the
observer. Hirschf eld places the proportion of ulcers which become cancerous
at 5 to 6 per cent, and he summarizes clinical and statistical data indicating
that the proportion is small. Futterer, however, places the proportion very
much higher and holds that the tendency toward carcinomatous change
greatly influences the prognosis of gastric ulcer. Hauser emphasizes the
inflammatory overgrowth of glands in the edges of ulcers but interprets as
carcinoma only very advanced stages of the process. Recently Wilson and
MacCarty in the Mayo clinic report that 68 per cent, of their gastric ulcers
were associated with carcinoma. They secure this high proportion by inter-
preting as carcinomatous many appearances which it is difficult to separate
from chronic inflammatory overgrowth and heterotopia of gland tissue.
They recognize many cases in which it is impossible to determine whether
the ulcer or the carcinoma was the primary lesion. Boekelmann collects a
series of estimates varying from 3 to 50 per cent. In France opinions are

FIG. 261. — Atypical proliferation of gastric glands on edge of peptic ulcer. A precancerous

lesion.

widely at variance. Moutier in 35 cases from operation and autopsy found
19 simple ulcers, 15 distinctly cancerous, and one cancerous duodenal ulcer.
I believe that the figures of Wilson and MacCarty indicate too high an
average for the carcinomatous transformation of ulcers. Where definite
carcinomatous alveoli are present throughout the base of an ulcer, especially
if early, the condition is probably better regarded as primary carcinoma.
MacCarty states that where irregular epithelial structures occur in the
submucosa one is surely dealing with carcinoma. Yet heterotopia of
epithelium may be of inflammatory origin and it would seem better to
designate many of these uncertain lesions as at most precancerous. In
my own material I find it very difficult to trace the development of cancer
in the edges of peptic ulcers. The cases seem to fall distinctly into the group
of ulcerating adenocarcinomas or among simple ulcers without any trace of
cancer. The structure of the malignant cases varies greatly, indicating that

CARCINOMA OF STOMACH

613

there are several histological types of early ulcerating cancers. The mucosa
surrounding simple ulcers is sometimes extensively altered, the glands
hypertrophied, the cells enlarged, nuclei hyperchromatic, and alveoli occa-
sionally misplaced, but definite precancerous changes in cases of undoubted
simple ulcer I have rarely found. It has appeared, however, that the digest-
ive fluids may completely excavate a superficial carcinoma leaving the
base free but a submucous ring of cancer encircling the ulcer. More often
islands of carcinoma remain throughout the base. The complete destruction
of all traces of carcinoma is probably not possible, but the presence of small
areas of carcinoma in the edges of an ulcer does not necessarily mean a car-
cinomatous change in a simple ulcer.

FIG. 262. — Hypertrophic gastritis in a stomach the seat of peptic ulcer.

It is at least evident that quite specific criteria must be employed in the
diagnosis of cancer following ulcer, since the conditions surrounding this
process in the stomach are peculiar.

Against a very great frequency of carcinomatous change of peptic ulcer
stand several general considerations emphasized by R. Williams. Sixty
per cent, of gastric cancers, he finds, are located at the pylorus, while only
12 per cent, of ulcers occur in this situation. The commonest seat of ulcer
is the lesser curvature (36.3 per cent., Welch), whereas only 12.2 per cent, of
cancers occur in this situation. Ulcer of the duodenum very rarely gives
rise to cancer. The age incidence of the two diseases is very different. Yet

614

NEOPLASTIC DISEASES

I cannot agree with Williams that such evidence is conclusive. It is much
too general and uncertain. Thus Boas found 27.2 per cent, of his cancers at
the pylorus, but a later series of 40 cases gave only 15 per cent, at this location.
Bamberger reports that after 1025 gastro-enterostomies for ulcer observed
for some time cancer developed in 22 (2.1 per cent.). Among 152 cases in
which ulcer was treated by excision cancer developed in 1.9 per cent. These
results are hardly compatible with a frequent origin of cancer from peptic
ulcer.

Experimental production of adenocarcinoma by irritation of artificial
ulcers in animals is reported by Hemmeter, Futterer, and Maniscalio, but

PIG. 263. — Edge of ulcerating carcinoma of stomach. The carcinoma was limited to a
narrow ring encircling the ulcer.

the supposed malignant process although interesting in itself, lacked the
progressive character of cancer.

Gross Anatomy. — Carcinoma following peptic ulcer presents in its early
stages the same appearance as the uncomplicated peptic ulcer and it may be
impossible to detect the malignant change except by microscopical study.
The carcinoma usually begins on the pyloric side of the ulcer and causes
increased swelling and density of the borders and fixation of the ulcer to
the muscularis and serosa. No great change in the density of the base can
be expected since this portion of ulcers is always very firm and carcinoma can
invade the base only from below. The shortening of the curvature, thicken-
ing of serosa, and cicatricial contraction drawing up the lymph-nodes, seen

CARCINOMA OF STOMACH

615

in old ulcers, are increased in carcinoma, and the swollen lymph-nodes become
more dense. These changes observed in surgical cases are usually somewhat
aggravated in subjects coming to autopsy. The vicinity of the ulcer then
shows more extensive thickening from invasion of all coats of the organ,
the lymph-nodes are larger, and there may be extensions to liver, gall-
bladder and peritoneum, but extensive metastases are rare and in many fatal
cases the disease is localized to stomach and adjacent nodes. Although
pyloric stenosis is frequently established, the tendency to dilatation of the
stomach is usually counteracted by cicatricial contraction of the lesser
curvature. Perforation of the ulcer occasionally terminates the progress.

The structural type of carcinoma
following ulcer is usually a small
alveolar or adenocarcinoma and this
type was exclusively represented in
Hauser's cases. From the hyper-
plastic glands on the edges of the
ulcer, there is a downward growth 'of
atypical glands which soon break up
into irregular alveoli lined by atypi-
cal, cylindrical or cubical cells. From
these structures solid cell groups
commonly develop and extend later-
ally in the wall and through the
lymphatics into the lymph-nodes.

(4) Carcinoma Simplex. Medul-
lary and Diffuse Carcinoma. — The
more malignant types of gastric car-
cinoma are composed of more atypi-
cal cells arranged in alveoli or grow-
ing diffusely. These tumors produce
two well-defined gross anatomical
forms.

(1) Soft, often ulcerating, round-
ed, more or less circumscribed tumors
of considerable extent occur chiefly
in the cardia and fundus. They are
often vascular (carcinoma telangiec-
tatica) and subject to severe hemor-
rhages. Fatty degeneration and
necrosis lead to ulceration of wide
extent, to erosion of large arteries and

to perforation. The neighboring organs, liver, pancreas, colon, duodenum,
may be involved by continuity of growth. The lymph-nodes are early in-
vaded and metastases are very frequently seen in liver, lungs, peritoneum,
and distant organs. This is the most aggressive and rapidly progressive
form of gastric carcinoma.

(2) Diffuse carcinoma may arise from any portion of the mucosa, usually
near the pylorus and maintain an infiltrating tendency from the first. The
original tumor may then be difficult to locate and a large segment of the
wall may show diffuse thickening of all coats with little ulceration or only
superficial erosion of the mucosa. Early invasion of lymph-nodes and
widespread metastases occur as in the preceding form. Occasionally there
is deep ulceration at the pylorus and diffuse infiltration over a wide area.
Most of the perforations in gastric cancer occur in this type. Among 507

FIG. 264. — Ulcerating gastric cancer.
Groups of tumor cells and cellular connec-
tive tissue forming base of ulcer.

616

NEOPLASTIC DISEASES

cases of cancer Brinton found perforation into the peritoneum in 17, into
colon, ii. Mislowitzer collected 17 cases of perforation of the abdominal
wall. Lang in 210 cases reports peritoneal perforation in 12.

The structure presents small or large alveoli or a diffuse growth of
atypical cells, which are usually small, polyhedral or round, and with relatively
large hyperchromatic nuclei. A desmoplastic quality may be entirely lack-
ing, and some of these carcinomas are readily mistaken for lymphosarcoma.
The cell form may vary considerably and in different portions of the same
tumor one may find large alveoli, small alveoli or diffuse growth. Giant-
cells may occur in considerable numbers and when they appear with round-
cells of various sizes in a tumor lacking alveolar structure the resemblance to

r •?•> •

FIG. 265. — Section of mucosa in diffuse superficial carcinoma of stomach.

sarcoma may be pronounced (cf. Kaufmann). The invasion of muscular
wall, nerve-trunks and lymph-vessels is remarkably free. In less active
foci mucous globules appear in many cells. In metastases an alveolar
structure is apt to reappear or the structure may be even more atypical than
the original.

(5) Diffuse scirrhus carcinoma is a slowly progressive type of the disease
which differs from carcinoma simplex in its slow course, desmoplastic proper-
ties, absence of ulceration, prominence of pyloric stenosis, and in the peculiari-
ties of its metastases. It differs from sclerosing pyloric fibrocarcinoma in
its wider extent, more cellular character, and frequent metastases.

The gross appearance is characteristic. A considerable portion of the
wall beginning at the pylorus shows smooth thickening of all coats, especially
of the submucosa and muscularis. The entire organ may be involved and
greatly reduced in size by cicatricial contraction. The pyloric and other

CARCINOMA OF STOMACH

617

areas of mucosa may be eroded over a wide extent, but there is seldom destruc-
tive ulceration. The serosa is opaque, fibrous and covered with small
nodules from invaded lymphatics. There may be a remarkable freedom from
adhesions, but usually the pylorus is fixed to neighboring tissues and much
contracted.

The lymph-nodes are regularly involved and in these structures and in the
liver and other organs bulky tumors, often much larger than the original,
develop from a freer growth of tumor-cells. The peritoneal lymphatics
may be extensively involved with constriction and adhesions of the intestine.

FIG. 266. — Diffuse superficial carcinoma of stomach. The ducts of the mucous glands are
intact, the bases are breaking up into small carcinomatous alveoli.

The omentum may be drawn up into a small cancerous mass attached to
the lower border of the stomach.

In a well-defined group of cases the original tumor is small and poorly
defined, but bulky metastatic tumors develop, especially in liver and ovary,
and the disease runs its course as a primary tumor of these organs. Twenty-
four per cent, of secondary carcinomas of the liver are derived from the
stomach (Rolleston) and not a few develop from relatively small and usually
fibrous cancers of the stomach. In the ovary the metastases are often
bilateral. A scirrhus tendency may be associated with adenocarcinoma,
and in the pyloric region this tendency is frequent and pronounced, so much
so that Hauser describes a special variety of scirrhus adenocarcinoma.

618

NEOPLASTIC DISEASES

FIG. 267. — Diffuse carcinoma of pylorus with three secondary peptic ulcers, one at pyloric
ring, one 3 cm. and another 5 cm. from ring.

FIG. 268.— Cross-section of secondary peptic ulcer arising on diffuse carcinoma of pylorus.

CARCINOMA OF STOMACH 619

The great majority of scirrhus tumors present small or large solid groups
•of polyhedral cells which are easily recognized as carcinomatous. As the
fibrosis increases the tumor-cells diminish in number, and in wide areas they
may be reduced to small groups of degenerating cells with mucous globules,
or to small granular opaque cells which resemble plasma-cells. In the nerve-
trunks, lymphatics, and capillaries about such tumors much larger and more
typical cells are usually found, while in the lymph_ nodes and peritoneal
nodules the growth may be quite typical.

FIG. 269. — Diffuse carcinoma of entire stomach. Gastroenterostomy.

(6) Sclerosing Pyloric and Diffuse Fibrocarcinoma. Linitis Plastica. —

The usual form of scirrhus carcinoma of the stomach is easily recognized
by the diffuse thickening of all the coats, the contraction of the organ often
to a rigid tube, the frequent presence of metastases, and especially by the
microscopic evidence of round-cell, or alveolar or gelatinous carcinoma. It
has long been known and is specifically mentioned by Rokitansky and by
Kaufmann, that the epithelial cells in scirrhus cancer of the stomach may be
reduced to a minimum or may largely disappear, so that a very careful
microscopical examination is required to detect the traces of carcinoma.
Indeed the last traces of epithelial structures may completely disappear over
considerable areas of thickened submucosa and muscularis, so that no suspi-
cion of malignant process past or present may be suggested.

620

N EOF LA STIC DISEASES

Neglect of this fact has led to the accumulation in the literature of a
large number of cases of supposed benign cirrhosis and contraction of the
pyloric region or the entire stomach, which have appeared under various
terms and interpretations (Lyle, Lit.). Cruveilhier first described the condi-
tion as benign hypertrophic pyloric stenosis. It is commonly known under
Brinton's term "linitis plastica." Brinton was by no means certain that the
process was not cancerous.

Although the existence of miscellaneous forms of purely inflammatory
gastric and pyloric sclerosis cannot be denied, it now appears, largely through
the critical analyses of Bret and Paviot, Meinel, Krompecher and Makai and

others, that the great majority if not all the
cases of linitis plastica are atypical cicatrizing
fibrocarcinoma.

Of 130 cases collected by Lyle 60 maybe
disposed of as carcinomas belonging with
scirrhus cancer, or in the present group of
atypical fibrocarcinoma. The remaining 70
occurred under various circumstances.

A considerable group appear to be ex-
amples of chronic gastritis with marked con-
tracture and thickening of the whole or
much of the stomach. In these cases there
appears to be hypertrophy, chiefly of the
muscular coat, while the submucosa lacks
the extensive overgrowth of linitis plastica.
In the case of Schoch and Nauwerck the
stomach was much dilated from a lesion
limited to the pylorus. In many others the
gross appearance closely resembled scirrhus
carcinoma (Schmidt, Viti, Rosenheim, Deguy,
Marcy and Griffith). In Sheldon's case gas-
tric symptoms antedated operation 15 years
and the patient was well three and one-half
years later, v. Eiselberg's patient was well
five years after gastro-enterostomy.

In several cases there were signs of old
superficial ulcers (Formad, Allbutt, Turner,
Meinel). Nothnagel's case ran the course
of pernicious anemia. Many cases would

FIG. 270.— Characteristic atypi- SUprprest classification with polyserositis and

showed multiple thickenings throughout the
nuclei infiltrating peritoneum, intestine, colon and rectum
(Lebert, Marignac, Wilks, Henrot, v. Kahl-
den, Gabbi). Yet very similar cases are re-

ported by Bret and Paviot, who point out that the intestinal lesion is chiefly
subserous and that extensions readily pass from the stomach to omentum
and colon.

Krompecher, under the term gastro-intestinal sclerostenosis, emphasized
a group of benign cases which he attributed to cardiac disease, chronic con-
gestion, edema and fibrosis, but he later abandoned the idea that these cases
were not probably carcinomatous. Leith describes a case of this type as
non-cancerous cirrhosis. The lesion involved stomach, ileum, and colon f
but the microscopic report is somewhat lacking in details although the author
positively excludes carcinoma.

hyperchromatic
muscuiaris.

CARCINOMA OF STOMACH

621

FIG. 271. — Sclerosing fibrocarcinoma of pylorus. Linitis plastica. Erosion of mucosa.
Small groups of tumor cells with mucous contents limited to serosa.

FIG. 272. — Diffuse sclerosing fibrocarcinoma of stomach.

stomach.

Linitis plastica. Leather-bottle

622 NEOPLASTIC DISEASES

In dealing with such an extensive collection of anomalous conditions it is
obviously impossible to urge that any uniform process is represented. It
appears quite possible that rare cases of chronic gastritis, the scarring of
ulcers, late syphilis, peculiar traumas, and atrophying fibrous processes may
simulate fibrocarcinoma, but it may be claimed that no well-defined group
of cases exists apart from fibrocarcinoma. As Krompecher points out, the
microscopic study of older cases and even of the latest reports is open to
serious criticism, since the histology of regressing fibrocarcinoma of the
stomach is seldom fully recognized. Thus Tilger wrote an elaborate descrip-
tion, completely excluding traces of carcinoma, in a case which on subsequent
study Meinel found to be carcinomatous.

In a series of 17 cases of linitis plastica Krompecher andMakai found nine
which they recognize as disseminated fibrocarcinoma, by the discovery of

FIG. 273. — Diffuse pyloric carcinoma with erosion.

islands of atypical epithelium, or scanty acini of adenocarcinoma, or groups
of cells with mucous degeneration and typical signet-ring nuclei. In other
portions of these same tissues they find only cellular granulation tissue or
hyaline areas and cells of undetermined origin, all of which made up the bulk
of the sclerotic areas in the remaining eight cases in which no definite signs of
carcinoma were present. In the peritoneal placques and thickenings of intes-
tinal wall, and peritoneum similar structures were present. They therefore
conclude that all their cases are of identical nature and belong in a group of
atypical disseminated sclerosing carcinoma. They also incline to agree with
Meinel that a benign acquired cirrhosis of pylorus and stomach of the type
of linitis plastica probably does not exist. The interpretation of these cases
as endothelioma, offered by Jungmann, Szobolew, v. Hansemann, Fick,
Cignozzi, Aldegarmann, and Donath, they also discard. Yet of the cases
reported as endothelioma, only those of Fick and Cignozzi bore any gross
resemblance to linitis plastica.

CARCINOMA OF STOMACH 623

My own study of a group of these cases has led to the same conclusions,
modified as above stated, because of the very miscellaneous nature of the
reported cases.

I find every gradation from small-cell diffuse and scirrhus carcinoma, with
pronounced signs of malignancy, down to overcellular granulation tissue con-
taining isolated cells with mucous globules, to vascular tissue with over-
growing capillaries suggesting endothelioma, or hyaline connective tissue with
scanty cells of undetermined origin, and even to connective tissue without
a trace of atypical cells of any type. As a rule extensive search reveals some
foci of characteristic mucous cells in submucosa or muscularis. The nerve-
trunks sometimes show infiltration by polyhedral cells with hyperchromatic
nuclei, when the surrounding tissue is free. The last traces of epithelial
cell groups may appear as foci of mucus lying in fibrous tissue. Single
rows of cells in fibrous tissue may resemble plasma-cells. In four cases re-
garded as benign pyloric stenosis, and narrowly limited to this orifice, I found
none of the usual signs of carcinoma but only such atypical regressing cell
groups. It therefore seems necessary to conclude that all cases of hyper-
trophic pyloric stenosis and diffuse cirrhosis of the stomach in adults are
atypical fibrocarcinoma. Miscellaneous cases of apparently benign character
must be regarded with suspicion.

From this point of view the origin and significance of this type of carcinoma
becomes of great interest. The atypical cells may safely be traced to the
disordered glands in the mucosa. This structure commonly shows advanced
chronic inflammation with hypertrophy or erosion, rarely with atrophy
and replacement by granulation tissue covered by flat epithelium. The
presence of scars of old superficial ulcers in many cases suggests that the
cells may be derived from the heterotopic glands in the edges of these lesions.
Meinel argues for the derivation of the cells from the endothelium or lymph
spaces and uses the term lymph-epithelioma. I find it often difficult to
distinguish atypical epithelium from the hyperplastic endothelium in these
tissues but have not observed any definite indications that the atypical
cells are of endothelial origin. Most of the cases described as endothelioma
of the stomach are quite different in gross appearance from linitis plastica.
G. Hayem derives the tumor from the granular acidophile peptic cells.
In a case of linitis plastica extending from the cardia to the prepyloric
region he found an intact muscularis mucosa but a diffuse infiltration with
large, irregular, granular, acidophile, vacuolated cells with large nuclei, which
he would trace to a diffuse breaking down of the peptic glands.

The movements of the stomach provide unusual facilities for the
mechanical transfer of proliferating epithelial cells which might otherwise
be quite unable to disseminate themselves over such wide areas. It seems
necessary to assume that the growth capacity of these cells is much less than
that of frank carcinoma. Hence the course of the disease is slow, fibrosis
and mucous degeneration overtake most of the cell colonies and in many
areas the carcinomatous element disappears entirely. The wide dissemina-
tion over duodenum, peritoneum, and colon suggests that the process was at
one time more active but eventually regressed with fibrosis. A final stand-
still of the entire process may thus be assumed in the cases which appear
to recover after gastroenterostomy.

In linitis plastica there appears to exist a peculiar form of gastric
carcinoma probably occurring in resistant subjects and originating from
cells of limited growth capacity, which pursues a chronic course and tends
to spontaneous regression of the tumor process but to the death of the
patient. The occurrence only in adults, 20 to 80 years, clearly separates the

624 N EOF LAST 1C DISEASES

condition from congenital stenosis. Yet congenital cancer of the stomach
is reported by Mathieu. Danosky described in a ten weeks' old infant a
diffuse and very dense thickening of the submucosa with pyloric stenosis.
Torkel attributes the benign congenital stenosis of the pylorus to a congenital
malformation with inclusion of islands of Brunner's glands in the pyloric
muscle. It is possible that some later cases of pyloric stenosis may develop
from this same anomaly and that a malignant process may originate in these
aberrant glands.

In the typical condition of linitis plastica the stomach is much thickened
and contracted (leather bottle stomach). The lesion begins in the pylorus
and may be confined to this region or to the curvatures, from which it ex-
tends over a part or the whole of the stomach and occasionally to the
duodenum. The pyloric orifice projects into the duodenum as the cervix
uteri into the vagina. The stomach wall is four to eight times the normal
thickness. The new tissue is chiefly in the submucosa, while the muscularis
is also much thickened and traversed by opaque bands of fibrous tissue. The
tissue is very dense, resisting incision almost like cartilage. The mucosa
is usually thrown into folds or nodular elevations, or it is thin, eroded or
ulcerated. The pylorus may be movable when the disease is limited to the
stomach, but is often fixed by adhesions. The pyloric lymph-nodes are
usually moderately enlarged. Extensions to the peritoneum give rise to
fibrous thickenings constricting the intestine and causing marked cicatricial
contraction of the omentum. Fibrous areas may be seen over the liver
and spleen. Hanot and Gombault found the portal vein converted into a
rigid tube. The microscopical structure is indicated in the preceding
discussion.

The Gastric Mucosa in Cancer of the Stomach.- — The condition of the
gastric mucosa varies widely, depending on the type and progress of the
tumor and the previous condition of the mucous membrane. There is a
constant tendency toward diminished functional capacity, associated with
atrophy of peptic cells and a metaplastic transformation of gastric into an
intestinal type of cell lining, with marked increase of goblet cells (J. E.
Schmidt, Lit.). An increased secretion of alkaline mucus tends to neutralize
acid. This change begins in the pyloric region where it may become very
marked and simulate heterotopia of duodenal glands. Observing it in marked
degrees Gosset and Masson were led to believe that all pyloric cancers might
be derived from heterotopic duodenal glands.

Throughout the altered mucosa many large eosinophile cells and hyaline
globules often appear, about the nature of which there has been much dis-
cussion. They appear also in the stroma of cancers. They have been
regarded as capillary red-cell thrombi (Saltykow), degenerated fibroblasts
(Marchand, Lubarsch), or epithelium (Thorel), altered plasma-cells
(Schridde, Fabian), or englobed secretion (Verse). Very marked polypoid
outgrowths are observed in cases developing on gastritis polyposa. A
relatively intact mucosa often persists in cancer following ulcer. Thus in
15 cases examined by Rosenheim, Hammerschlag, Lenek and Boekelmann,
the mucosa was intact in 12 and showed slight increase of peptic cells in
three. In some cases an adenocarcinoma is associated with general hyper-
trophic gastritis. Chronic productive interstitial gastritis with atrophy
is the most frequent condition, as was early shown by Fenwick. In all of 14
cases Rosenheim found catarrhal, interstitial, and atrophic gastritis, most
marked near the tumor but appearing in foci throughout the fundus.
Similar results were obtained by Mathieu and Cohnheim. In 17 cases
Boekelmann found interstitial gastritis in all, focal lesions in seven, diffuse ad-

CARCIXOMA OF STOMACH 625

vanced changes in eight, and early complete loss of glands in two. In diffuse
carcinoma the mucosa has been found atrophic, with or without extensive
erosion. In diffuse colloid cancer the gelatinous nodules may be widely
distributed over the mucosa. The various changes in the production
of HC1 and ferments depend closely upon the state of the mucosa, but
portions of the fundus may be nearly intact in cases with loss of HC1
(A. Schmidt, Kokubo). Hence function may be restored after partial
gastrectomy.

The relation of the gastritis to the carcinomatous process varies.
Fenwick pointed out that atrophy is most marked with scirrhus cancer which
occurs in subjects with general fibroid changes. Here the atrophy must
be more or less independent of the carcinoma. There is little ground for
the assumption that gastric atrophy itself leads to carcinoma, although
the disease may rarely arise in atrophic mucosae (Riegel). Gastric atrophy
occurs with carcinoma of other organs, as observed by Fenwick in 16 of 50
cases. Schneider also found an acidity in 22 of 29 cases of extragastric
cancer. It is therefore necessary to assume that carcinoma affects the
gastric mucosa chiefly through a deleterious influence on the organism as a
whole. To a considerable extent the two conditions must be regarded as
coordinate.

Extensions of Gastric Cancer. — The carcinomatous focus having become
established, the mode and rate of extension are determined chiefly by the
growth energies of the cells. Hence there are very wide variations in the
behavior of different tumors.

Adenocarcinomas first remain localized in the mucosa but early perforate
the muscularis mucosae, invade the lymphatics of submucosa and muscularis,
and thus reach the lymph-nodes. They also penetrate the blood-vessels
of the stomach wall, as is indicated by the distant subcutaneous metastases
observed in some early cases. A wide superficial extension in the mucosa
is less common than in the colon, but occasionally one finds a large portion
of the fundus covered by a superficial adenocarcinomatous ulcer.

The diffuse and seirrhus tumors not only penetrate the lymph-vessels
early but extend widely through all coats of the stomach. The entire
pyloric region may be the seat of a diffuse infiltration of the mucosa and
submucosa with superficial erosion, giving a characteristic form of pyloric
carcinoma with stenosis but without ulceration or early metastases. Many
cases of linitis plastica arise in this way. All forms of diffuse and scirrhus
cancer invade the submucosa by preference and extend widely through the
large and small lymphatics. Submucous invasion is said to extend usually
i to 2 cm. beyond the superficial lesion, so that this amount of tissue requires
excision (Carle, Fontino, Terrier, Hartman). Yet no general rule can
apply to all tumors. Through this coat the pylorus may be passed and the
duodenum invaded for i or 2 cm. Carle and Fontino had three pyloric
cancers which extended i to 3 cm. beneath Brunner's glands, while Brinton
in 210 cases found 15 invasions of the duodenum. More distant sub-
mucous metastases in ileum and colon mentioned by Welch (Lit.),
Kaufmann, and others, suggest that embolic cells may be propelled long
distances before finding lodgment. Rectal metastases described by
Bensaude probably travel outside the intestinal wall. Passage through the
ventral lymphatics of the muscularis is readily accomplished, usually with
thickening and fibrosis of this tissue. In the subserous lymphatics permea-
tion becomes much freer. As a rule the serosa backing a carcinoma is
thickened, contracted and adherent to neighboring tissues, with approxima-
tion of the contiguous lymph-nodes, and it is not unusual to find the

626

NEOPLASTIC DISEASES

lymphatics leading from such a focus clearly outlined by infiltrating growth
over a considerable area or even over much of the serous surface. This
process has much influence over the form and motility of the stomach, tends
to limit dilatation of the organ and contributes to the hour-glass contractions.
Extension to the peritoneum occurs directly from the serosa or from
secondary foci in other organs. It is facilitated especially by mucous changes
in the tumor.

The Lymphatics of the Stomach.— Cuneo describes three main groups of
perigastric lymph-nodes, (i) Nodes of the cardia and lesser curvature. The
coronary nodes are two to six in number and are closely applied to the coro-
nary artery. The nodes of the lesser curvature form two groups. One group
lies in the lesser omentum in front and behind the vertical portion of the
cardiac orifice. These nodes may be absent. The other group is constant

FIG. 274. — Carcinoma of stomach.

X-ray after injection of vessels with bismuth.
(Schmidt.)

and lies closely applied to the stomach wall in the course of the coronary
artery and contiguous to the vagi. The upper surface of the pyloric region
is free of nodes. When invaded by carcinoma this group of nodes is often
contracted and bound to the stomach wall.

(2) The hepatic (pyloric) chain drains the lower two- thirds of the greater
curvature and the pyloric region. The nodes form a subpyloric and a retro-
pyloric group. The former lie between the vessels and the stomach but not
in direct contact with the organ. Some may be distinctly aberrant and lie
5 to 6 cm. from the stomach in the gastrocolic ligament. They receive the
lymph-flow from most of the greater curvature and unite with the retro-
pyloric group or directly with nodes along the hepatic artery.

The retropyloric nodes lie with the gastroduodenal artery and are in
relation with the posterior surface of the pylorus and behind with the pan-
creas. They receive lymph from the posterior surface and upper border
of the pylorus and from the first portion of the duodenum and unite with
the main hepatic chain.

CARCINOMA OF STOMACH

627

(3) The splenic group lies along the splenic artery from stomach to hilus
of spleen, in the pancreatic-splenic omental fold. They drain the fundus ot
the stomach.

The lymphatics of the gastric mucosa are very rich but fine. Passage of
lymph to the submucosa is somewhat restricted by the muscularis mucosa,
through which small vessels pass to larger sinuses in the submucosa. Thence
narrow vessels pass between the muscle bundles to larger subserous spaces.
The submucous and subserous plexuses communicate freely with those of
the esophagus, but only the submucous plexus joins freely with that of the
duodenum. The subserous vessels encircle the pylorus but do not freely

FIG. 275. — Diagram of lymphatics of stomach. (After Cuneo.)

join with those of the duodenum. While the above descriptions indicate
the general course of lymphatic flow yet there are notable variations in the
lymphatic vessels and still further anomalies in the distribution of lymphatic
metastases (Lengeman, Mayo).

Lymphatic invasion usually begins as an embolic process with secondary
growth which may fill the lymphatics in all directions (Lengemann, Renner).
Yet in slowly growing carcinoma Borrmann's view of continuous permeation
may be correct.

General statements regarding the frequency of lymph-node invasion have

628 NEOPLASTIC DISEASES

little value, since this event varies so greatly in different forms of tumors.
In post-mortem material it is rare to find the lymph-nodes free and this con-
dition may be expected only in slow scirrhus cancer and linitis plastica. In
none of Verse's 12 early carcinomas, accidentally found at autopsy, were the
nodes invaded, although several were of considerable dimensions and ulcer-
ated and one was recognized during life. There is therefore a considerable
period when the therapeutic problem is purely local.

Operative material includes chiefly tumors of pylorus or lesser curvature.
When a sufficient number of nodes are carefully searched few cases will be
found free from some invasion. Cuneo in eight autopsies found lymphatic
invasion in all, but in 13 gastrectomies the nodes were invaded in only two.
Lengemann, however, made a very thorough study of gastrectomies rinding
all nodes free in only one, an extensive adenocarcinoma of pylorus with areas
of carcinoma solidum. In 20 cases no of 189 nodes examined (58 per cent.)
were free. The retropyloric nodes and those of the lesser curvature were
more often involved than the subpyloric. The invasions was rarely continu-
ous and hence must have occurred by embolism. The size of the nodes
gives uncertain indications of their condition. Kausch believes that lympha-
tic invasion is practically constant in operative cases. In resected ulcerating
carcinomas, I find invasion of accompanying nodes practically constant, but
careful search of the nodes may be required to detect small groups of embolic
cells in the sinuses. Practically it must be assumed that all accessible
nodes should be removed in gastric resections for carcinoma.

Observations on the occurrence of extragastric metastases concern autopsy
material. In such cases Cuneo found invasion of perigastric, diaphragmatic,
or retroperitoneal nodes in 85 per cent. Extensions to the thoracic nodes
are not uncommon. The subhepatic and pancreatic nodes are among the
first involved. Mesenteric nodes were invaded in 41 cases and the lumbar
and aortic in 106 of 603 cases collected by Gussenbauer and Winiwarter.
From these trunks the inguinal nodes may be affected (Belin). After
pleural invasion the axillary nodes may suffer.

The importance of enlargement of supradavicular nodes in the diagnosis
of abdominal cancer was first emphasized by Troisier, and of these cases
gastric cancer furnishes the largest proportion (Tarchetti). An inflam-
matory swelling of these nodes is quite as frequent as carcinomatous invasion.
Thus Hechler found swelling in 25 per cent, of 70 abdominal cancers but the
clinical observations were not followed by microscopical. The left nodes
are usually the ones affected but either or both sides may be involved ac-
cording to the anastomoses of the thoracic duct. The course of the invasion
is through the thoracic duct, which in several cases has been found completely
infiltrated (Hosch, Lit.). Chylous ascites may accompany the thrombosis
(Leydecker, Hektoen). From the supradavicular nodes the breast may be
involved (Moutier, Marcy). Extensions to the thoracic duct are discussed
at length by Piat. In rare cases there are widespread metastases strictly
limited to the lymph-nodes after the manner of lymphosarcoma and in these
cases the cells may be small and round (Israel, Hosch). Multiple cutaneous
metastases may be the chief or even the sole form of secondary tumors. The
liver is invaded in about 33 per cent, of autopsy cases (Kaufmann) either by
direct extension across the adherent peritoneum, or backward from the
subhepatic nodes, or by embolism from perforated portal vein (Spaeth,
Acker). Very large tumors may then form in the liver and the disease may
simulate hepatic carcinoma.

Along the splenic lymphatics or through the splenic vein the spleen may
be involved and drawn toward the stomach.

CARCINOMA OF STOMACH 629

The pleura and lungs were involved in 7.3 per cent., the pancreas in 7.6
per cent., and the peritoneum and intestines in 27.6 per cent, of 2156 cases
collected by Martin.

Ovarian metastases occur in 2.3 per cent, of the cases of gastric carcinoma
(Borrmann) and form an interesting feature of the disease. Characteristic
cases are described by Schlagenhaufer, Glockner, and others. The original
tumor is usually scirrhus, less frequently a small, diffuse or gelatinous car-
cinoma. The ovarian growths are generally bilateral and of such size that
they have often been regarded as primary ovarian growths. Kaufmann
found two ovarian tumors weighing 16 pounds. Their structure varies
greatly and may reproduce an alveolar or diffuse carcinoma or adenocar-
cinoma with mucous changes. In one variety the cells are large, contain
mucous globules, and are distributed in small groups or diffusely in the
hyperplastic ovarian stroma. This structure is nearly identical with that
described by Krukenberg as fibrosarcoma mucocellulare. It has been shown
by Schlagenhaufer and others that many of the Krukenberg tumors are
secondary carcinomas from mammary, gastric, intestinal and uterine growths.
That some of the so-called endotheliomas of the ovary are secondary growths
is claimed by Polano and by Papaioannou. Bilateral ovarian tumors and
even unilateral growths of this type are so frequently secondary as to call for
a careful search for a primary growth and the removal of both ovaries if
one is to be resected. The mode of extension to the ovaries is by peritoneal
implantation, permeation through abdominal lymphatics, and probably also
through the blood-stream. When the peritoneum is extensively invaded
implantation on the ovary readily follows. Kraus argues that this is the
most frequent method and Sitzenfrey found cancer-cells implanted between
the germinal epithelium. In several of the scirrhus cases the abdominal
nodes have been extensively involved to the exclusion of other organs and the
permeation to the pelvis and ovary has been traced. In some cases the origi-
nal tumor is small and metastases are practically limited to the ovary. Here
it has been assumed that tumor-cells have passed the pulmonary blood-vessels
and found a peculiarly favorable soil in the ovary, but the possibility that the
ovarian growth is primary must be considered (Stickel, Pfannenstiel).

Of the miscellaneous locations of metastatic growths may be mentioned
brain, bones, kidney, and adrenal, and spinal cord or membranes.

Direct extensions may also pass far beyond the adjacent organs, pene-
trating the diaphragm, the spinal column and abdominal wall. In 48 cases
of umbilical cancer collected by Longuet and Quenu, 14 originated in the
stomach and passed along the umbilical lymphatics.

Histogenesis.— The origin of gastric cancer has been traced satisfactorily
to altered but previously normal gastric tubules. Only in certain rare cases
is there ground for assuming an origin from congenitally misplaced or em-
bryonal cell groups. Waldeyer described in detail the hypertrophy, cellular
overgrowth, and downward extension of small groups of gastric tubules with
the development of carcinomatous alveoli and invasion of lymphatics.
Hauser describes early adenocarcinomatous changes in small areas of the
gastric mucosa. These changes consist in elongation of a group of glands
which become very narrow or occasionally dilated and joined to one another
by numerous lateral outgrowths, so that they form a network of communi-
cating acini in the thickened mucosa. The epithelial cells become more
opaque and the nuclei hyperchromatic but they long remain confined to a
single layer. The stroma is usually thinned and while rich in nuclei of con-
nective-tissue cells, is poorer in lymphocytes then the normal mucosa.

These changes affect a small area, i to 3 cm. of the mucosa, which on

630 N EOF LA STIC DISEASES

microscopic examination reveals multiple foci of altered glands separated
by normal mucosa. From these early foci develop flat adenomatous thicken-
ings and papillomatous elevations which form a relatively brief transitional
stage to adenocarcinoma.

Verse describes 12 cases of beginning carcinoma of the stomach (/. c., 31-
42). The lesions consisted of flat or papillary or polypoid thickenings of
the mucosa, from i to 5 cm. in diameter. They occurred in subjects suc-
cumbing to other diseases, and in several there were general hyperplastic
or atrophic gastritis and a history of alcoholism. The structure presented
elongated, branched and anastomosing tubules, lined with one or more rows
of hypertrophic cylindrical or cubical epithelium with hyperchromatic
nuclei. Many of these tubules had perforated the muscularis mucosae.
At the edges the gradual transformation of normal into neoplastic tubules
could often be followed. In some areas the line of separation was sharp,
or single tubules of neoplastic type lay among normal tubules. These small
lesions were often the seat of purulent inflammation and superficial ulceration
sometimes resulted. While the stroma was at times overcellular, Verse
points out that the initial change was in the glands and often existed with-
out any proliferation of stroma.

From these observations it seems thoroughly well attested that carcinoma
of the stomach arises from the previously normal glands through a process
beginning as localized overgrowth and that the process is located primarily
in the epithelial cells which usually show preliminary disturbances of over-
nutrition and excessive function.' There is, however, a considerable gap
between the ordinary condition of inflammatory overgrowth and definite
adenocarcinoma in the stomach and this gap appears to be bridged, if at
all, by a rather sharp morphological change which is established rapidly.
Thus single glands and minute groups of glands exhibit a pronounced altera-
tion while surrounded by normal or slightly altered tubules. The original
cancerous area may be single or composed of multiple foci which later fuse.
From this area of origin the tumor tends to grow from its own elements.
Yet during the formation of the original focus and to a variable extent
thereafter, normal glands continue to be transformed into neoplastic struc-
tures. This lateral extension is more pronounced in the colon than in the
stomach.

G. Hayem describes the development of a diffuse scirrhus cancer from
a diffuse parenchymatous gastritis in which the peptic glands seemed to
break down and the granular acidophile peptic cells spread through the
stroma giving origin to the tumor. I have seen one early ulcerating tumor
which recalls this description.

While the majority of gastric carcinomas probably arise from such focal
lesions as are described by Verse, another group originates from more ad-
vanced, polypoid or adenomatous structures. The progress of carcinom-
atous changes in gastric polyps has been followed in detail by Verse. In
gastritis polyposa a large portion of all of the mucosa may be the seat of
multiple outgrowths and from one or several of these carcinoma may
develop As shown by Hause and by Doering the natural termination
of this condition is death from carcinoma.

In the development of carcinoma from peptic ulcer the usual preliminary
changes may be traversed, including hypertrophy and hyperplasia of lining
cells, enlargement of alveoli, stratification of cell layers, and elongation and
lateral sacculation of tubules. Or the cells of slightly hyperplastic tubules
may at once break up into small groups of atypical cells which from the
first grow more or less diffusely in the mucosa (cf. Hayem). The former

CARCINOMA OF STOMACH

631

method yields adenocarcinomas which later become more atypical, the
latter produces small alveolar and diffuse carcinoma.

The importance of developmental anomalies in the genesis .of gastric
carcinoma appears to be slight. Torkel describes aberrant Brunner's
glands in the pyloric mucosa and finds a connection between them and
congenital stenosis, but they do not appear to give origin to malignant
tumors. Islands of intestinal mucosa are frequently found in the pyloric
region and it is possible that they give origin to certain carcinomas, especially
those of the cylindrical cell type. Such islands are difficult to distinguish
from the local or general metaplasia with assumption of intestinal characters
occurring in chronic gastritis, ulcer and cancer (^Sachs, Lubarsch, A. Schmidt,
Kukubo, J. E. Schmidt).

FlG. 276. — Gastritis polyposa.

Symptomatology.- — For a more detailed discussion of this subject consult
Welch, Martin, Riegel and Mathieu, /. c.

Onset. — The inital symptoms of gastric cancer may be as vague and
variable as their early recognition is important. Except in cases following
ulcer the previous digestive or gastric history is almost wholly unknown.
Two groups of incipient cases present themselves for diagnosis, one in which
there has been a definite history of gastric disturbance, and another in which
the disease appears to arise in a perfectly healthy subject. The spontaneous
development of the disease in the ''athletic stomach" without demonstrable
exciting factors must be doubted, yet many patients date their illness from
a specific dietetic error or a trauma, or some acute disease (Hammerschlag).
Long-continued abuse of the stomach is commonly overlooked until the
disease reaches a certain stage, when it produces symptoms which when once
established are usually persistent.

Oppression after eating is a very early sign. Its persistence after an acute
onset distinguishes it from simple functional disturbance. Pain is a very
important early symptom which is influenced by diet, appears one or two
hours after eating, or when the stomach is empty, often worse at night, and
aggravated by exertion. Chronic gastritis does not as a rule give persistent
pain. Loss of flesh is an early significant symptom in_many_cases, especially

632 NEOPLASTIC DISEASES

with disturbed motility, but is often long delayed. Regurgitation appears
early and may soon be succeeded by vomiting. When pain and indigestion
persist, a systematic search for definite signs of carcinoma is indicated.
The first of these definite signs is usually the presence of occult blood in
stomach washings or stools. Repeated radiographs of the stomach may be of
much value in early cases, especially of pyloric tumors (Cole). Gastroscopy
may locate very early lesions of the cardia and curvature and a portion of a
suspicious ulcer may be successfully removed for examination (Janeway).
Early loss of HC1 maybe expected only in cases preceded by chronic gastritis.
Gluzinski's test of relative deficiency of free HC1 is highly recommended by
Tabora. Detection of tumor fragments in vomitus or in wash water and

FIG. 277. — X-ray photograph of an extensive gastric carcinoma, involving whole"orpyloric

region, without stenosis.

especially^ in blood-clots, is always worth attempting. Reineboth found
such fragments in five of eight cases. Zoeppitz points out the nearly
constant occurrence of ulceration or erosion in early lesions and estimates
the frequency of early symptoms as follows: occult blood, 94.5 per cent.;
emaciation, 89.9 per cent.; anacidity, 88.9 per cent.; lactic acid, 67.3 percent.;
long bacilli, 64.4 per cent.; palpable tumor, 63.4 per cent.

Complete loss of free HC1 and pepsin, presence of lactic acid and Boas-
Oppler bacilli, marked vomiting, hematemesis and a palpable tumor, belong
to the established disease, but may appear as early symptoms. In all
cases accurate determination of the secretory and motor powers of the
stomach should form a basis for the interpretation of symptoms.

General Patho genesis. — The relation of the symptoms and course to the
anatomical character of the tumor is not always distinct so that clinical

CARCINOMA OF STOMACH 633

conceptions of the disease are not constructed from the anatomical stand-
point. While it is desirable to emphasize such relations wherever they exist,
clinical records are not usually available for such analysis.

Several factors widen the discrepancy between clinical records • and
anatomical type. Chief of these is the necessary period which is clinically
unobserved. It is extremely difficult to accurately determine the duration
of gastric carcinoma. Thus Osier and McCrea classify as clinically acute
carcinoma lesions which gave observed symptoms for one month but which
must have existed very much longer. It seems probable that the use of
the a--ray will eliminate many uncertainties regarding the duration of gastric
cancer. The studies of Rieder, Fraenkel, Holzknecht, Jonas, Haudek,

FIG. 278. — X-ray photograph of localized carcinoma causing complete obstruction of
pylorus and dilatation of stomach.

v. Schmieden, Cole, and others, show that it is possible to locate and even
to outline the lesion in gastric carcinoma and to follow certain physiological
peculiarities of the cancerous stomach, so that when other data confirm
the diagnosis, attention may be directed to the anatomical character of the
tumor, its operability and prognosis. By serial radiographs Cole has been
able to recognize 90 per cent, of gastric carcinomas. The increasing atten-
tion of surgeons to the operative possibilities on these cases also bids fair to
throw much light on the early stages of carcinoma. Hence there are some
indications that it will soon be possible to construct a clinical classification
of gastric carcinoma with close reference to its anatomical types.

The location of the tumor determines to a large extent its course and
symptoms. Pyloric cancer is rather sharply distinguishable from lesions

634 NEOPLASTIC DISEASES

of the lesser curvature. Ulcero-cancer of the pyloric region is usually
associated with hypersecretion which tends to cause spasmodic contraction
of the pylorus and severe pain. Motor insufficiency develops early and pro-
fuse hemorrhages are more frequent with this type of carcinoma than with any
other. Primary carcinoma of the pylorus is not associated with hypersecre-
tion, but even in its early stages there is relative or pronounced acid
insufficiency (Gluzinski, Tabora). Pain is less severe, motor insufficiency
occurs early and small bleedings are the rule.

Carcinoma of the lesser curvature usually arises in cases with established
achylia. The pylorus being open, insufficiency is delayed. Pain, hemorrhage
and cachexia are not prominent, and the disease may run the course of
chronic gastritis for one or more years. Periods ofjmarked improvement with
gain in weight are not infrequently observed.

FIG. 279. — X-ray photograph of a bulky adenocarcinoma arising from lesser curvature,
occupying much of the fundus, without pyloric stenosis or dilatation.

Cachexia, in gastric carcinoma, is a complex condition in which two
main factors are usually combined, (i) General dyscrasia referable to
infection, ulceration, hemorrhage, anemia, pain, and loss of digestive capac-
ity, and (2) the more specific terminal cachexia of carcinoma. The latter
is rarely observed, while the former group of factors dominate the clinical
history throughout. In the absence of such complicating conditions cancer
of the stomach often produces no effect upon health. In fact a specific
cachexia of cancer may be practically eliminated from the symptomatology
of the gastric disease. Even the toxic destruction of protein reported by
F. Miiller and Klemperer may be separated with difficulty from non-specific
influences. A similar phenomenon occurs in starvation. Hence some
patients remain in fair health until a late period and even the digestion may

CARCINOMA OF STOMACH 635

be little affected (Boas). For the same reason marked temporary improve-
ment with gain in weight and relief of gastric symptoms may occur
(Friedenwald).

From the hematological standpoint the cachexia is marantic or anemic.
In the marantic cases the blood is concentrated often to a remarkable degree
by vomiting and defective absorption, so that the patient may succumb
with over 100 per cent, of Hb and polycythemia.

Anemia in cancer of the stomach is usually secondary and of the chlorotic
type but it often becomes so severe as to suggest a progressive pernicious
type. Yet a low Hb index and leukocytosis are commonly present. In
these cases malnutrition and repeated losses of blood from ulcerating tumors
are the chief factors. Progressive pernicious anemia is occasionally as-
sociated with gastric carcinoma. In one group of cases the anemia develops
as a sequel of the gastric disease and is preceded by hemorrhages and mal-

FIG. 280. — X-ray photograph of chronic indurated ulcer of lesser curvature of stomach.
Note the deep pocket outlined by dotted line, leading into ulcer. On greater curvature is a
normal peristaltic constriction.

nutrition and occasionally by metastases in the bone-marrow (Frese).
The tumor is then extensive and ulcerating, but in Israel's case it was small
but bleeding. I have seen three cases, all ulcerating. In another group the
gastric tumor is small and ulceration is missing. Ehrlich and Lazarus refer
to three cases of this type, one a ring-shaped growth of the pylorus. In a
third group the carcinoma arises in an atrophic mucosa and the anemia
may be referred chiefly to the gastric atrophy. All these relations illustrate
the peculiar susceptibility of the bone-marrow in predisposed subjects to
functional disturbances of the stomach.

Acidemic coma was first observed in gastric cancer by v. Jaksch and
later by Senator, Riess, Klemperer, Osier, and others. The usual symptoms
are present and the urine contains acetone bodies in moderate amount.
Klemperer noted a reduction in the total urinary nitrogen in cases previously
showing an increase, and concluded that the coma was referable to toxic
derivatives of protein destruction. The tumors are usually large and ulcerat-

636 NEOPLASTIC DISEASES

ing but the stomach is not as a rule dilated. In Osier's case there was a small
ulcerating pyloric growth. Tetany is occasionally observed with dilatation of
the stomach from carcinoma (Leube). Progressive degenerative neuritis
has been described by Miura and Klippel. Sudden blindness from toxic
amaurosis is reported by Deutschmann.

Relation to Anatomical Varieties. — (i) Adenocarcinoma occurs at rela-
tively early ages. It is the chief tumor observed in the second decade,
becomes less prominent in the third decade, while one group of cases follows
gastritis polyposa, and miscellaneous cases occur at any period. Its course
is chiefly determined by the stage at which ulceration is established and this
complication again depends much on the location. It is the usual type of
tumor occurring at the cardia, in which situation it produces unusually

FIG. 281. — Carcinoma of pylorus with pyloric stenosis, and invasion of subpyloric nodes,

severe pain, dysphagia, and obstruction to the esophageal bougie, while a
palpable tumor is absent.

(a) At the pyloric or cardiac orifice it ulcerates early and this destructive
process yields most of the pronounced gastric symptoms, as pain, hemorrhage,
vomiting, and a local tumor, followed by progressive cachexia. When
obstructing tumors at the pylorus break down the event is often indicated
by hemorrhage, some relief of vomiting, increased pain, and diarrhea replacing
constipation. The onset of symptoms, which may be abrupt, is doubtless
preceded by a latent period, but the active course is usually severe and
relatively rapid, but surgically considered this class of patients is more favor-
able than the general condition might indicate.

Gastric carcinoma occurring at early ages is usually of rapid course
and since adenocarcinoma is the usual type in young subjects the age of
incidence rather than any peculiarity in the growth seems to determine
its active progress. Yet in adults adenocarcinoma is occasionally very rap-
idly fatal. Rohrer's adult patient lived only three months with a rapidly

CARCINOMA OF STOMACH 637

enlarging epigastric tumor and fracture of femur from metastatic
adenocarcinoma.

(b) When ulceration is long delayed these tumors may reach large
dimensions which are readily palpable and when located away from the
orifices or even near them, they may long remain latent. Ulceration becom-
ing established leads to rapid excavation and at once transforms the clinical
picture. Martin describes such a case with duration of symptoms of five
weeks, with a bulky tumor at the pylorus and extensive metastases in the
liver. They form a well-defined group of cases seen at autopsy and the
clinical history can usually be reconstructed from the gross appearance of
the tumor. There are of course many variations due chiefly to factors
which control the progress of ulceration, infection and metastases. Oc-
casionally after a severe initial period the course becomes chronic. Pro-
nounced anemia is common and may take a pernicious type.

(2) Carcinoma following ulcer is the best defined clinical group but the
certainty with which this type of tumor may be distinguished from ulcerating
primary carcinoma is often overestimated. Mathieu considers the condition
so distinctive that he describes it as a separate clinical entity under the term
"ulcerocancer. " Characteristic cases are preceded by a variable period,
months or years, of symptoms of ulcer. The development of carcinoma
is marked by gradual diminution of free HC1, which, however, may persist
to the end; by increasing anemia; an advancing cachexia; and the develop-
ment of a tumor which is usually small and fixed. As a rule the pain becomes
more severe and constant, and the vomiting may be aggravated. Many
authors mention a selective anorexia against meats. The later course of
the disease varies extensively and is determined chiefly by the location.
Apart from the previous history it is not as a rule to be distinguished from
other forms of advanced ulcerating carcinoma.

The total duration of the disease including the period of simple ulcer is
much longer than that of ulcerating primary carcinoma. Boekelmann
observed cases for 15, 20, and 29 years. Yet as a rule after the establish-
ment of cancer the course is steadily progressive and rather rapid (Mathieu).

(3) Gelatinous carcinoma is one of the more chronic types of the disease
but it presents few distinctive clinical features. Certain adenocarcinomas
undergo mucoid degeneration and the history of these cases is similar to
that of the original tumor. The diffuse infiltrating types of gelatinous
carcinoma usually cause contraction of the stomach and great thickening
of the walls which may be demonstrated by #-ray examination. Ulceration
and hemorrhage are less pronounced than with many other types of the
disease. Many cases pursue a "latent" course. Storers case was remark-
able for the slight disturbance of digestion, and in Amdion's case gastric
symptoms appear to have attracted little attention. In a case reported by
Osier and McCrae no marked gastric symptoms were noted, the patients
presenting chiefly nervous and mental symptoms. In another case the
symptoms began with bloody ascites and the only gastric symptom was
occasional vomiting of mucus. Extension to the peritoneum with ascites
is relatively common but occurs also with carcinoma simplex, and scirrhus.

(4) Carcinoma simplex is characterized clinically by its steadily pro-
gressive course and relatively short duration. The localized form of this
tumor yields severe gastric symptoms, among which hemorrhage and pain
are prominent. Deep ulceration may lead to fatal hemorrhage as an early
symptom. In the diffuse form of carcinoma simplex the gastric symptoms
are less marked. The metastases which develop in peritoneum, liver, lungs,

638 N EOF LAS TIC DISEASES

ovary, nervous system, and elsewhere produce appropriate symptoms which
may divert attention from the stomach.

A characteristic case originating in the cardial region is that of Hosch:
age 62 years, initial symptoms, vomiting, dysphagia, loss of flesh for four
weeks, then ascites, supraclavicular nodes enlarged in sixth week, epigastric
tumor in fourteenth week. Autopsy revealed a contracted stomach dif-
fusely infiltrated from cardia nearly to pylorus, with extensive metastases
limited to lymphatic system.

(5) Scirrhus carcinoma is regularly of slow development but the early
stages are often latent and the period of observed symptoms may be brief.
The clinical characters vary greatly and depend on the location of the growth.

Pyloric scirrhus is one of the more characteristic clinical types of the
disease. It frequently but not always produces pyloric stenosis and dilata-
tion of the stomach with characteristic symptoms of this condition.
Defective motility, constant presence of lactic acid, and absence of free HC1,
are prominent, while hemorrhage is slight or absent. Since stenosis may
be produced by any type of tumor of the pyloric region these symptoms have
only limited diagnostic value.

Diffuse scirrhus carcinoma tends almost invariably to contract the
stomach, so that its capacity is small. Ulceration is absent or superficial
and hemorrhages are reduced to a minimum. When the stomach is
very small it may refuse to retain even small quantities of fluid.

(6) Sclerosing Fibro carcinoma. Linitis Plastica. — The clinical features
of this condition resemble the scirrhus carcinoma to which it is closely related
anatomically. The course of the disease is always prolonged, but the
observed symptoms may be brief. It usually begins with a period of months
or years marked by dyspepsia. Later there is pronounced anorexia, pain,
tenderness, and frequent vomiting. A transverse elongated tumor may be
demonstrated. Owing to the integrity of the mucosa, hemorrhage is usually
absent. Free HC1 is diminished or absent. The #-ray reveals a contracted
organ especially at the pylorus (Jonas). In the later stages peritoneal
extensions fix the pylorus, increase the gastric symptoms, and cause ascites.
Pernicious anemia may dominate the picture. The terminal stages are
marked by persistent vomiting, emaciation and cachexia. Yet in several
instances the gastric condition was masked by other diseases (Viti, v.
Sury).

The duration in 43 benign cases was found by Lyle to average 49 months,
the shortest course being three months, the longest 20 years. In 37 definitely
malignant cases the average duration was 23.9 months.

The lethal tendencies of the disease have long been noted. The apparent
recoveries three and five years after gastro-enterostomy do not affect the
conceptions of the nature of the process, since long survival after this opera-
tion has occurred with ordinary scirrhus cancer (Le Count).

Surgical Treatment.- — Oper ability. — When the disease is recognized early,
is confined to the stomach wall, inflammatory adhesions limited, and lymph-
nodes not invaded, the prognosis from resection may be regarded as good.
In such cases much depends on the type of growth and the probability of
discontinuous metastases. Most cases are encountered late, with infected ad-
hesions and involved lymph-nodes, and require extensive resection of gastric
tissue and all accessible nodes. Even here results are encouraging. Exten-
sive adhesions and invasion of nodes and surrounding tissue preclude resec-
tion, but Petersen calculates that average life is prolonged five months by
gastro-enterostomy. Le Count's case indicates that the prolongation may be

CARCINOMA OF STOMACH 639

much greater in slowly advancing tumors which may be induced to undergo
fibrosis.

Operative Mortality. — Has steadily diminished. Matti, 1905, collected
rates from German clinics from 68 to 17 per cent. Petersen at Heidelberg
saw the mortality from resection fall from 35 to 18 per cent., and from gastro-
enterostomy from 35 to 17 per cent. From 1366 resections Martin derived a
mortality of 25 per cent. Kocher's mortality was 17.7 per cent., Mayo's
13 per cent.

Curability. — Leriche collected 89 resections for cancer well after three
years. H. J. Paterson calculated that about 8 per cent, of resections for
carcinoma were surgically cured. Of 101 resections by Kocher up to 1905,
Matti reported 71 leaving the hospital, of whom 72 per cent, died in one month
to six years, average life 18 months, while 20 patients remained well. Of 252
pyloric resections by the Mayos the condition of 191 was known, of whom 39
(20 per cent.) were well after three years. Other similar statistics are avail-
able, indicating that of selected operable cases about 20 per cent, may be
surgically cured. Many of the cured cases appear to have been very early
and possibly doubtful ulcerocarcinomas. Even with recurrence Petersen
ventured to calculate that resection prolongs life an average of seven months.
Against this result it appears necessary to charge up the natural duration of
the disease, the operative mortality, and certain accelerations of course in
unfortunately chosen cases. On the other hand many cases, eventually
fatal, enjoy freedom from gastric symptoms and the stomach is found free
from the disease (Matti). Recurrences are chiefly in liver, peritoneum, and
retroperitoneal nodes.

Over against this encouraging outlook based upon carefully selected
material, it would appear from Peck's study that the average case of gastric
cancer has little to hope from surgery. This author collected 527 cases of
gastric cancer in the New York hospitals, which gave 480 operations, 143
exploratory, 167 gastro-enterostomies, 98 radical extirpations with an opera-
tive mortality of 28 per cent., 33 patients traced, 23 recoveries for a variable
period, and 8 known to be alive after three to four years. Friedenwald reports
from 1000 cases 266 operations, 138 exploratory, 9 gastrectomies, i living
over 1 8 months, but all dying of the disease.

The study of individual cases is more significant than combined statistics.
Rapidly growing diffuse carcinoma carries a fatal prognosis even with early
resection. Not a few cases surviving three years eventually succumb. The
permanent cures observed up to 1 6 years at Kocher's clinic appear to have
been adenocarcinomas, sometimes bulky and ulcerating but confined to the
wall, and ulcerocarcinomas.

The surgical results support the view that certain gastric carcinomas, as a
rule, are not among the very malignant tumors. A more careful analysis
of operative results with reference to anatomical condition is highly desirable.

CHAPTER XXXII
CARCINOMA OF INTESTINE

Statistics collected by Stengel from German sources include 26,340 cases
of carcinoma, 2255 intestinal, 8.56 per cent. The U. S. census (1914) shows
among 52,420 deaths from cancer, 6234 (n.8 per cent.) of the peritoneum,
intestine and rectum; 2690 in males, 3544 in females, 4 in infants under one
year, 19 under five years, and the highest incidence between 60 and 65 years.
The cecum and appendix follow the rectum as the chief location. The
increasing recognition of carcinoma of appendix will probably raise the pro-
portion above previous records. Of 3563 cases of malignant tumors of the
intestine Brill found only 89 (2.5 per cent.) in the small intestine.

Carcinoma of Ehiodenum. — From Geiser's statistics it appears that about
4 per cent, of intestinal carcinomas occur in the duodenum. The age of
incidence is much later than with other intestinal carcinomas, being placed
at 54 years by v. Heurlin, or 56 years by Geiser.

Three distinct forms of this disease may be recognized: (i) Carcinoma
following ulcer; (2) carcinoma at the papilla of Vater, and (3) carcinoma of
the third portion of the duodenum. This classification corresponds in general
to the topographical division given by A. Pic, viz., parapyloric, peri-ampul-
lary, and prejejunal. Of 40 cases collected by Rolleston 8 were in the first
portion, 24 in the second, and 3 in the third portion, while the distribution
of Geiser's 71 cases was in the same order n, 51, and 9.

(1) Carcinoma following duodenal ulcer has been recorded in 10 cases
by Letulle, Perry and Shaw, and Nattan-Larier. Its location, chiefly near
the pylorus, accords with the distribution of duodenal ulcer which, in Collin's
262 cases, occurred 242 times in the first portion of the duodenum, 14 times
in the second portion.

The gross anatomy and the symptoms are very similar to those of pyloric
ulcerocarcinoma. Stenosis and adhesions are usually present and metastases
are frequent and widespread. The stomach is usually much dilated.
Letulle's case showed colloid changes and gave secondary tumors. In
Eichorst's case the ulcer followed a burn. Ewald found a carcinomatous
area in the scar of a healed ulcer. In one case I found it difficult to determine
the exact significance of displaced and hyperplastic gland tissue in a scarred
duodenum. Butz reports carcinoma arising in an actinomycotic ulcer. I
have seen one carcinoma of pylorus extending over the first 2 cm. of the duo-
denal mucosa, ulcerating into gall-bladder, and causing intense jaundice.

(2) Carcinoma in the second portion of the duodenum usually arises in
or about the biliary papilla. Jaundice is therefore an early and very con-
stant symptom occurring in 23 of 25 cases quoted by Mathieu. The jaundice
is less severe and persistent than with carcinoma of the ampulla. Even in
advanced cases the occlusion of the duct may be incomplete, jaundice may
be absent and gastric symptoms prominent (Descos, Beriel). Dilatation
of biliary and pancreatic ducts commonly occurs and fat necrosis has been
observed by Krause, Gerster, and Geiser.

The early tumors are usually papillary growths surrounding the papilla
and in this stage they may prove fatal by biliary obstruction and severe

640

CARCINOMA OF INTESTINE 641

infection. In a case recently studied in this laboratory a small duodenal
papillary carcinoma surrounding the papilla proved fatal from a single
continuous hemorrhage. More extensive growths cause much dilatation
of biliary and pancreatic ducts, they form protuberant ulcers surrounding the
common duct, or extend laterally over a considerable area. Geiser describes
an ulcerating carcinoma which secondarily invaded the papilla. Many of
these tumors are difficult to distinguish from carcinoma of the ampulla.
Nothnagel points out that the former growths are sharply circumscribed
about the papilla, while the true duodenal cancer tends to encircle or extend
along the intestine.

The structure is commonly that of cylindrical cell adenocarcinoma derived
from the intestinal mucosa. An origin from Brunner's glands has been
suggested by Orth, and from aberrant pancreatic tissue by several writers.
Many of the cases are difficult to separate from primary cancer of the
pancreas.

(3) Carcinoma of the third portion of the duodenum, prejejunal, is rare.
Geiser has collected nine cases. Most of these took the form of a broad, flat
ulceration with stenosis. In Fenwick's case the ulceration extended over 8
inches of the mucosa, and the duodenum was 13 inches in circumference.
Above the stricture there is dilatation of duodenum and stomach, and gastric
symptoms with vomiting of considerable quantities of bile are prominent.
Icterus is absent. In Syme's case the ulceration was slight and the vomitus
was free from bile. In two of Geiser's cases there were more bulky tumors
with ulceration and perforation of the wall but without much stenosis. Local
extensions or local or general metastases were usually present. The structure
presented cylindrical cell adenocarcinoma or alveolar carcinoma.

Carcinoma of Ileum and Jejunum.— Carcinoma of the small intestine
is comparatively rare, forming about 3 per cent, of all intestinal cancers.
It occurs at a comparatively early age, average 46^ years, relatively often
before 40 years, and Duncan records a scirrhus cancer in a child of ^9 years.
Schleips in 1908 analyzed 43 cases, 28 in males. In location the tumors
increase in frequency as one approaches the stomach above and the colon
below.

The disease occurs in three somewhat distinct forms as (i) a part of a
local or general intestinal polyposis, (2) a late development of single or
multiple carcinoid tumors, and (3) as a localized adenocarcinoma with
carcinomatous variations in structure.

In all of these forms certain general features appear. The tumors
may produce polypoid outgrowths obstructing the lumen, or the lesions may
ulcerate early, or the main result may be stenosis from invasion of muscular
and subserous coats. Often there is dilatation of the bowel above the tumor,
and when the tumor lies in the upper jejunum the disease may simulate
pyloric stenosis (Riegel, Routier).

(i) Carcinoma following intestinal polyposis is rare in the small intestine,
the great majority of such cases affecting the colon.

Niemack reported papillary adenoma in the lower ileum in a child of 12
years in whose colon were many small polyps. Petrow found many polyps
in stomach, duodenum, and jejunum with adenocarcinomatous structure in
the jejunum. In Kukula's case there was a cylindrical dilatation extending
over 8 cm. of the jejunum, with polypoid outgrowths in the vicinity and
carcinomatous metastases in the mesentery. Thorel found a large adeno-
carcinoma of the lower ileum, 20 polyps in the ileum and one in the colon.
Kuttner considers that some multiple carcinomas of the ileum with stenosis
arise from intestinal polyposis, as in Hahn's case in which there were four

642

N EOF LAST 1C DISEASES

strictures in the lower ileum, but it seems more probable that the multiple
stenosing carcinomas arise from the carcinoid tumors of Lubarsch. Yet in
one of Kuttner's cases there were 18 strictures in the small and four in the
large intestine.

(2) Multiple benign embryonal carcinoid tumors of the intestine constitute
a peculiar group of tumors of the small intestine first described by Lubarsch.
They are found in ileum, jejunum and mesentery, and probably in the appen-
dix, in the form of single or multiple, firm, opaque nodules as large as a pea
or bean. They lie in the mucosa or submucosa and the muscularis mucosa
may be lost in the stroma of the tumor. In structure they form three groups,
resembling (a) pancreatic island tissue, (b) heterotopic intestinal mucosa, or

FIG. 282. — Small carcinoma of ileum causing marked stenosis, with dilatation above.

(c) Brunner's glands. Most of the tumors have been referred to heterotopic
intestinal glands, and Notthaft found a direct connection with thejiormal
follicles. The cells then form compact densely staining groups with traces of
alveolar arrangement or with mucous foci producing the appearance of cylin-
droma. The endothelium of the lymph spaces may be hyperplastic but does
not. participate in the tumor process (Lubarsch). The resemblance to basal
cell carcinoma has been noted by Bunting and Oberndorfer. Smooth muscle-
tissue may be found in the stroma and such growths have been described
by Trappe and others as adenomyoma. The prominence of muscle-tissue
and the more typical adenomatous structure serve to distinguish the
adenomyomas from the carcinoid tumors. A congenital misplacement of

CARCINOlfA OF INTESTINE

643

tissue must be assumed for the adenomyomas, while the carcinoid tumor
may be satisfactorily derived from acquired inflammatory heterotopia and
overgrowth.

In another group the structure resembles the parenchyma or islands
of Langerhans of the pancreas. In fact Saltykow considers that all the
tumors represent heterotopic pancreatic nodules. The cells are cylindrical,
cubical or rounded, and they surround pervious or closed capillaries, some-
times in rosette form, or exactly reproducing islands of Langerhans. Hetero-
topic Brunner's glands were identified in portions of a carcinoma described by
Schapper.

The significance of these small tumors has been much discussed. In
their simplest form they probably represent anomalies of development and

FIG. 283. — Gelatinous carcinoma of duodenojejunal flexure.

misplacement of gland tissue and are not true tumors (Toennissen, Saltykow).
Yet others show various grades of cellular overgrowth and invade the sub-
mucosa and muscularis and are true scirrhus neoplasms (Verse). In this
form they long remain localized, although sometimes reaching sufficient size
to obstruct the lumen. Others again form the source of malignant carcinomas
and produce metastases. Thus Ransom found extensive secondary tumors
in the liver. Verse found metastases in the lymph-nodes with a small
intestinal growth and malignant cases are described by Saltykow and
Schapper. It is probable that many small simple primary carcinomas of
the intestine and appendix with metastases originate in this way.

(3) The third group of intestinal carcinomas includes lesions which arise
under various conditions. Some develop from single intestinal polyps and
tend to maintain an adenocarcinomatous structure. The majority of in-
testinal carcinomas are of this type. When ulceration is delayed the tumors

644 N EOF LA STIC DISEASES

may reach a size sufficient to obstruct the lumen (Riedel). Ulceration and
stricture more commonly result and the structure becomes more atypical
and scirrhus. Metastases in mesentery, liver, lungs, peritoneum or elsewhere
were present in 1 6 of 42 cases collected by Schleips and adhesions were much
more frequent. That carcinoma may result from catarrhal, typhoidal
or other forms of intestinal ulcers seems possible but definite observations
are wanting. It is difficult to separate tumors of this group from those
arising from carcinoid growths, but the former are usually adenocarcinoma-
tous, bulky and more malignant; the latter atypical, scirrhus, and compara-
tively benign. Gelatinous adenocarcinoma is described by Marckwald and
by Kanzler.

Carcinoma of Appendix. — The occurrence of carcinoma of the appendix
has long been recognized, but its importance was first suitably emphasized
in 1903 by Elting and by Moschkowitz. It is interesting to note how the
recorded cases of this form of carcinoma have increased in proportion to the
attention devoted to it.

Of intestinal carcinomas the appendix furnished about 0.39 per cent, in
BatzdorfFs collection of 2336 cases, but this proportion is probably much too
low. Of 13,083 appendices removed at operation and included in the lists
of BatzdorfT, McCarthy, and the Bender Laboratory, there were 60 cases of
carcinoma, 0.46 per cent. BatzdorfT refers to 186 recorded cases. Over 50
per cent, are found with chronic appendicitis (Zaaijer), or 85 per cent., accord-
ing to Milner. The age of incidence has been from 5 to 80 years, and chiefly
in the third decade, while other intestinal carcinomas occur chiefly in the
sixth decade.

Gross Anatomy. — The tumors are located chiefly at the tip of the appendix
(59 per cent.), which is moderately swollen and stenosed or contains a small
tumor nodule which is readily overlooked and requires microscopic identifi-
cation. Over half the tumors were recognized only after laying open the
appendix (Me Williams). In more advanced stages there is a definite tumor
and the appendix is inflamed and bound by adhesions. In several cases the
whole organ was diffusely enlarged (Kudo) . Cystic forms of the disease occur
especially when there is mucous degeneration of the tumor and the mass may be
composed of a fibrous wall and gelatinous contents (Rokitansky) . Whether
the disease may produce the typical condition known as mucocele remains
uncertain but is not improbable. Many mucoceles however, are free from
any tumor element. An irregular cicatrix deforming the organ and obliter-
ating the lumen has been described in several instances. Rarely the lesion
takes the form of an ulcer (Baldauf). At the ileocecal valve the tumor may
project into or constrict the cecum and be difficult to distinguish from a tumor
of the cecum (Draper).

Extension of the tumor process beyond the appendix is relatively un-
common, occurring in about 6 per cent, of the cases (Batzdorf). Themesen-
teric and retroperitoneal nodes are first involved. Extensive peritoneal
carcinosis was observed by Elting, Konjetzny, Kelly, and Neugebauer. In
Whipham's case the patient died with secondary growths in nodes, liver, and
ovary. Ruyter's tumor was found in the stump of an amputated appendix.
As a rule the cases with metastases have been of the columnar cell or gela-
tinous type.

The clinical course is usually merged with that of chronic appendicitis
(McWilliams, Rolleston, Jones, Lit.).

Structure. — Two main varieties of the tumor appear, (i) columnar cell
or gelatinous adenocarcinoma, and (2) small polygonal, spheroidal cell,
alveolar carcinoma. The former type presents the same age incidence

CARCINOMA OF INTESTINE

645

(52 years) and general malignancy as other similar intestinal carcinomas,
while the former occur at any early age and are almost invariably benign
(Rolleston, Jones). Transitional forms of intermediate age incidence are
observed.

The columnar cell tumors show the usual structure of small or large
alveolar adenocarcinoma. In the gelatinous tumors mucous degeneration
may be extensive and destroy most of the tumor-cells. In the small alveolar
type the cells are composed chiefly of nuclei which are large and hyperchro-
matic. They are compactly grouped in small or large masses and foci of
mucous degeneration may give the structure of cylindroma. The appearance
often resembles that of basal-cell carcinoma. The stroma may be scanty or

FIG. 284. — Carcinoma of appendix.

so abundant as to give a scirrhus structure. Both of these tumors are
probably derived from the gland crypts. The small cell-tumors seem to be
homologous with the small multiple tumors of the ileum described by
Lubarsch, Bunting and others.

In some cases the epithelial cells possess little gro\vth capacity and become
more intimately incorporated with the increasing stroma so that the struc-
ture resembles that of endothelioma arising from the lymph spaces of
inflammatory connective tissue. These cases have apparently been inter-
preted as endothelioma by Glazebrook, A. O. J. Kelly and others. Sudsuki
and Milner regard this structure as indicating an inflammatory origin and
hold that the great majority of appendix carcinomas are spurious. Yet the
tendency of fibrosing basal-cell carcinoma to suggest an endothelial origin
is well known.

646 N EOF LAST 1C DISEASES

The occurrence of a specific type of carcinoma in an atrophying organ
which is often the seat of chronic inflammatory changes is of much theo-
retical interest, and its peculiar structure and benign course serve to empha-
size the principle that each organ has its own forms of carcinoma.

Carcinoma of Large Intestine. — Statistical. — At the Pathologic Institute
at Vienna between 1870 and 1893, 343 intestinal carcinomas came to autopsy,
of which 164 were in the colon and 162 in rectum, while only 7 were found in
the duodenum and n in the ileum (Nothnagel). Schleips collected 542
intestinal carcinomas of which 259 were in the colon, 257 in rectum, 20 in
duodenum, 16 in ileum. In Brill's statistics covering 3563 intestinal tumors
97.5 per cent, were in the colon, appendix, or rectum. The tumors increase
in frequency from the cecum toward the rectum. Of 123 intestinal carci-
nomas Kaufmann found 36 in the colon, 28 in sigmoid, and 51 in rectum. He
also 'states that over 60 per cent, of intestinal carcinomas and 5.25 per cent,
of all carcinomas occur in the rectum, which is therefore fifth in the list of
primary seats of cancer. Of 297 colon carcinomas reported by Korte,
Petermann, and Anschutz, 47 were in cecum, 22 in ascending colon, 19 at
hepatic flexure, 44 in transverse colon, 31 at splenic flexure, 10 in descending
colon, 124 in sigmoid.

Lonart collected 61 cases of carcinoma of large intestine between the
ages of 20 and 30 years. The disease is rather frequently observed at much
earlier periods, in the cecum at 12 years (Nothnagel), in the rectum at n to
17 years (Czerny, Stern, Schoning), in the sigmoid at 12 years (Garrard),
in the colon at 3 years (Clar).

General Etiology.- — A tissue predisposition appears definitely only in those
cases arising on multiple polyposis. The carcinomatous transformation
of single polyps is described by Hauser, Kraske, Verse, Allen and many
others. In the origin of these polyps a previous abnormality of structure
is to be assumed.

Although carcinoma often develops in subjects of hemorrhoids and
this relation has been emphasized by Volkmann, there is no satisfactory
evidence that cancer develops in tissues altered by hemorrhoids, fistulae
or cicatrices (Kraske). The slow development of rectal carcinoma extending
over two or three years suggests rather that the early symptoms commonly
referred to hemorrhoids are due to the beginning carcinoma. On the other
hand the sudden development of hemorrhoids is a common result and an early
symptom of rectal carcinoma. Zinner reports that 38 per cent, of his cases
of carcinoma of pars perinealis complained of hemorrhoids. It is somewhat
remarkable that carcinoma very rarely develops in chronic ulcerative proc-
titis or colitis.

The traumatic origin of rectal carcinoma has occasionally been asserted.
Illustrative cases have been reported by Goeckel, Korte and Anschutz. The
age of incidence is later than with other intestinal carcinomas. Cripps
in 380 rectal cases found between 20 and 30 years 3 cases; 30 and 40 years,
21 ; 40 and 50 years, 78; 50 and 60 years, 93; 60 and 70 years, 119; 70 and 80
years, 53 ; over 80 years, 4. The incidence of colon carcinoma is much earlier.

Some general and many special factors favor the development of carci-
noma in this region. Anatomical relations influence the development of
tumors at the ileocecal valve, at the junction of the appendix, at the rectal
folds, and at the anus, where there are more or less definite interruptions of
the structure of the intestinal wall. The considerable number of cases
occurring in children indicates that developmental anomalies at these
points serve as sources of carcinoma. While various gross abnormalities, as
megacolon or megasigmoideum, atresia recti, and diverticula sufficiently

CARCINOMA OF INTESTINE 647

indicate the frequency of disturbed development, none of these conditions
seems to be directly connected with tumors (Mya, Lowenstein, Keibel,
Stieda). Kraske could find no grounds for assuming that misplaced embryo-
nal tissue is concerned in the development of rectal carcinoma. He reported
two cases of adenocarcinoma, probably derived from embryonic rests, but
the tumors wrhich were of considerable size, lay behind the rectum, were
attached to the bones and secondarily involved the rectal mucosa. Similar
cases are reported by R. Meyer and Cohn. The chief factors leading to
carcinoma are irritations acting most effectively at relatively fixed points,
as cecum, the flexures, and the rectal valves. More than half the rectal
cancers arise between 2 and 4 inches above the anus (R. Williams). Kraske
however, finds most carcinomas in the upper rectum, so that excision requires
opening the peritoneum. Zinner explains the high proportion of rectal
carcinomas on the anterior wall (75 per cent.) as the result of pressure against
the prostate.

The gross and microscopical anatomy presents several distinct forms
which give a satisfactory basis for clinical and pathological classification.
These include: (i) Adenoma destruens; forming a broad superficial ulcerating
tumor with obstruction, (2) stenosing fibrocarcinoma; (3) gelatinous adeno-
carcinoma; (4) bulky polypoid or papillary carcinoma derived from polyps;
(5) multiple carcinoma following polyposis; (6) acanthoma; (7) melanoma.
The frequency is in the same order.

In nearly all cases secondary infection plays a prominent part in the
progress of the lesion, causing local or spreading suppuration, peritonitis,
fistulous tracts, and communications between adjoining coils of colon, or
with stomach, small intestine, and bladder. Above the tumor the intestine
is usually dilated, hypertrophied, chronically inflamed or thinned and even
subject to perforation. These secondary conditions are almost wholly
responsible for the cachexia which develops and which may be duplicated
by similar inflammatory processes without carcinoma. Hence few subjects
of this disease succumb because of the extent of the tumor.

It is a rule to which there are notable exceptions that carcinoma of the
colon and rectum is only moderately malignant. The course is compara-
tively slow, extensions beyond the intestinal wall occur late and metastases
are less frequent than with similar growths in other regions. Hauser points
out that gelatinous tumors tend to perforate the wall and produce metastases
in peritoneum and adjoining nodes, and rarely in the bone-marrow, medullary
carcinoma limits its metastases to lymph-nodes, while scirrhus tumors often
produce growths in the liver. Zinner supports these conclusions.

Lymphatics.— The lymphatics of the colon follow the blood-vessels of
the mesenteric system. In the rectum the lymph system is more complex.
Gerota describes four rectal groups: (i) The anal vessels form 4-5 branches
which traverse the skin of the perineum and thigh and reach inguinal nodes
in Scarpa's triangle. Other deeper branches join with those of the zona
intermedia and reach the anorectal nodes. (2) Branches from the zona
intermedia pass backward and follow the superior hemorrhoidal veins, to the
anorectal nodes, but occasional branches pass to a node at the foramen ischiad-
icum (Quenu's node). (3) Branches from the zona columnaris follow the
same course. (4) The pars pelvina is drained by vessels which pass below to
the anorectal nodes and above to the mesenteric nodes of the colon. Lymph-
nodes are missing in the wall of the anal portion, but in the fat tissue lying
between the muscular wall of pelvic and intermediate segments and the
rectal fascia, lymph-nodes (anorectal) are abundant. Metastases in adjacent
lymph-nodes, while common in autopsy material, are less frequent in opera-

648 NEOPLASTIC DISEASES

tive cases. In 59 post-mortems collected by Kraske and Iverson metastases
were present in 3 2 in nodes, liver, peritoneum, lungs, and brain. They usually
reproduce the original, structure. From these data and from the long dura-
tion of most cases it is clear that carcinoma of the intestine is a favorable
field for aggressive surgery.

According to Rotter the operative mortality in rectal carcinoma has been
reduced from 19.4 per cent. (Kronlein, 1899, 881 cases) to about 5 per cent.
(Petermann). Of 100 cases Rotter reports 36 living over three years (33
per cent.). Zinner reports that of 256 cases 64 had no recurrence before
three years. Mayo (1916) reports from 430 cases, 66 deaths from operation,
33 per cent, alive after 3 years, 28 per cent, after 5 years.

Histogenesis. — The histogenesis of carcinoma of the large intestine has
been fully traced by Hauser, Verse, and others. It has been shown that the
disease arises usually in a circumscribed area of mucosa in which the glands
become enlarged, the lining cells hypertrophied and multiplied, the production
of mucous cells increased, and the lumina elongated and bifurcated. The
neoplastic alveoli soon break through the muscularis mucosae and extend
along the submucosa, often reaching the surface at lateral points and thus
extending the lesion or penetrating the muscularis along lymph and blood
paths. In the early stages of most cases and in some throughout the disease
there is a gradual extension of the area of origin by the progressive trans-
formation of normal into neoplastic alveoli. This process is more pronounced
in the colon than in the stomach and is often indicated by a peripheral zone
of papillary outgrowths of mucosa about the ulcerated tumor, as well as by
microscopical evidence of such transition. Similar transitions have been
traced in originally benign polyps.

The extent to which the lateral growth proceeds by this method it is difficult
to determine. In some cases there is a very wide superficial tumor involving
10 to 15 cm. of the mucosa, a form strongly suggesting a gradual inclusion of
normal areas of mucosa. The structure is then typical malignant adenoma.

In more atypical and rapidly growing tumors the lateral extension is
slight and exclusively by invasion and replacement of normal glands by
tumor-cells.

In intestinal polyposis the transition of hypertrophic mucosa and papillae
into multiple carcinoma has been clearly traced (Bardenhauer, Wulf, Verse,
Doering). In certain cases of chronic colitis in young subjects preceding
definite polyposis the entire mucosa is lined by markedly hypertrophic
epithelium closely resembling adenoma destruens but lacking the hetero-
topia of a neoplasm.

Anatomical Varieties. — (i) Adenoma destruens produces at first circum-
scribed elevations in the mucosa which gradually extend deeply and laterally,
obstructing the bowel and soon ulcerating. At the ileocecal valve it pro-
duces a fungating tumor inclosing the orifice without marked stenosis
(Kaufmann). In the cecum the tumors are usually bulky and ulcerating,
with obstruction of the lumen, fistulae and anastomoses. Particularly wide
superficial extension is often observed in the colon proper, as in Hauser's
cases. I have seen 14 inches of the transverse colon involved in a cylindrical
tumor with few adhesions. In the sigmoid and rectum adenoma destruens
is the common tumor and here early ulceration, obstruction and local
extensions are relatively early.

The structure presents the most typical form of malignant adenoma, and
its usual variations. In some cases the structure is more atypical and car-
cinomatous and occasionally the growth is highly atypical, diffuse, and
resembles lymphosarcoma. '• \

CARCINOMA OF INTESTINE 649

(2) Stenosing fibrocarcinoma produces first a superficial ulcer with pro-
nounced induration due to fibrosis. The lesion may be circumscribed while
involving all the coats, but there is a tendency to encircle the lumen and
produce a tight annular structure, with its various complications. In
advanced stages of sclerosing and other carcinomas the length as well as the
lumen of the affected segment is reduced at times to a remarkable degree.
This result is due to cicatricial contraction and, as Schuchardt explains, to
loss of tissue by ulceration. Small annular strictures of the intestines may
occur at any point. Korte reports three of the transverse colon, six of the

FIG. 285. — An early circumscribed malignant adenoma of sigmoid.

splenic flexure, and several of sigmoid. These annular tumors may be
multiple (Brosch).

The structure of this tumor usually presents diffusely growing small
groups of atypical cells widely infiltrating the coats of the intestine and the
abundant new connective tissue. Transition stages from adenoma destruens
and adenocarcinoma are often found and suggest that the process begins
as adenoma destruens and that early ulceration in a relatively resistant
tissue leads to early fibrosis and cicatrization. Yet this tumor infiltrates
neighboring tissues and nodes rather early and offers an unfavorable surgical
prognosis, unless excision occurs before the intestine becomes fixed.

(3) Gelatinous adenocarcinoma of the large intestine is rather frequent
and occurs both in the colon and in the rectum. Kanthack and Furnival

650

N EOF LA STIC DISEASES

described such a tumor of the ascending colon in a boy of 17 years. Israel
reports a case in the splenic flexure in a boy of 13 years. Among 51 colon
tumors Korte had six of the gelatinous type, while of Zinner's 123 cases of
rectal tumors 41 per cent, were gelatinous. It is characterized by a tendency
to spread widely over a considerable length of intestine, by the production
of a bulky tumor-mass in which the original tissues are extensively replaced
by gelatinous material. The usual tendency to stenosis may be missing,
but the tumor ulcerates early and excavates the lumen in a thick rigid tube.
Extension to the peritoneum produces miliary nodules or bulky masses of
gelatinous tissue. I have found the pelvis completely filled by gelatinous
material ^containing little tumor- tissue derived from a localized ulcerating
tumor of the rectum. Lymphatic invasion is not prominent. Kaufmann

FIG. 286. — Structure of a bulky gelatinous carcinoma of colon.

describes a case of colloid rectal cancer with a single metastasis hY the liver
invading the hepatic duct with fatal icterus.

(4) Carcinoma Developing from Solitary Polyps. — The most common seat
of these polypoid adenomas is the posterior raphe of the lower third of the
rectum, where Rotter finds them often the source of carcinoma. They often
develop in childhood and become carcinomatous in later years.

Of the benign polyps there are several varieties:

0) The broad flat adenoma is usually found in the rectum just above
the squamous junction. It is of simple cylindrical cell adenomatous structure
and its position renders it specially liable to malignant change.

(6) The common pedunculated adenoma occurs throughout the intestinal
tract, chiefly in rectum and colon. It is single or multiple, small or as large
as the fist, and intussusception, obstruction, or prolapse may result. An
original structural anomaly or local tissue predisposition is probably present,

CARCINOMA OF INTESTINE

651

but mechanical and inflammatory factors have much influence on the pro-
gressive growth. The multiple polyps are probably related to intestinal
polyposis. The structure presents large and small alveoli lined by high
cylindrical epithelium and often filled or distended with mucus. All grades
of atypical cell growth are observed and some localized pedunculated tumors
have the typical structure of adenoma destruens with slight invasion of
submucosa. When the stroma predominates the tumor may be designated
"fibre-adenoma." The carcinomatous transformation of these polyps has
been observed by Hauser, Verse and many others. The change may begin
at the base or tip or throughout the tumor. Albu saw the recurrence as
carcinoma of a polyp showing some years before suspicious signs of adeno-

* .

FIG. 287. — A diffuse papillary adenoma of rectum.

carcinoma. Yeomans describes several conditions in which malignant trans-
formation seemed to occur.

(c) Villous papilloma is a well-defined variety characterized by a finely
papillary appearance, great vascularity, hemorrhages, and a pronounced
tendency toward recurrence and malignant changes (Esmarch) . It occurs at a
later age than other intestinal polyps, the youngest of Quenu's 14 patients
being 2 8 years old. The structure shows single or multiple layers of cylindrical
cells supported by delicate vascular adenoid tissue. They require thorough
extirpation of the base. I have observed a remarkable tumor of this type
which covered an area of 13 X 9 cm. in the sigmoid. It appeared to be
composed of a congeries of papillomas which had become fused. The
papillae J^ to i J^ cm. in height were closely packed, coherent, and flattened at
the tips. The muscularis was intact.

652 NEOPLASTIC DISEASES

(5) Intestinal Polyposis. Colitis Polyposa.- — The chief seat of intestinal
polyposis is the rectum and the great majority of carcinomas following this
condition develop in the rectum or colon. The ileum or jejunum is rarely
affected, but Hauser and Kaufmann saw the involvement of the entire
mucosa from pylorus or cardia to anus, and lesions in duodenum, jejunum,
and ileum are reported by Lubarsch, Niemack, Petrow, and others. Albu
found the lesion in isolated segments of sigmoid and rectum. Of 34 cases
collected by Thorbecke, 23 were in rectum, 5 in colon and rectum, and 6 in
colon alone.

The disease affects both old and young subjects and exhibits an heredi-
tary, individual, and local predisposition (Cripps, Smith, Bickerstedt,
Port). In the early stages I find a diffuse and pronounced hypertrophy of
the entire epithelial lining, a condition which supports Verse's view that the
sole element in the predisposition is the excessive reaction of the epithelium
to irritants. Peculiar catarrhal symptoms mark the onset of the disease,
and hemorrhage, anemia, emaciation, intussusception and prolapse, occur in
advanced cases. Some of the polyps may be discharged per anum.

Although many cases maintain their inflammatory character throughout,
there is a striking tendency toward the development of malignant adenoma
and carcinoma. According to Quenu and Landel about half the cases are
associated with carcinoma, while Hauser found this combination as the rule,
and Doering analyzed 50 cases in which of 37 fatalities 31 were from carci-
noma. Spontaneous regression has been observed after sidetracking the
affected region and after partial excision (Rotter). Some respond to the
#-ray.

The anatomical form of the carcinoma varies extremely. The polyps
may be very small, very numerous, widely distributed and the entire mucosa
hyperplastic, or they may be larger and less numerous. The carcinomatous
process usually begins in a single polyp, involving others later. Steinthal
found a larger single carcinomatous polyp in rectum and many small benign
polyps in the vicinity. Annular carcinoma with many benign polyps
scattered over a wide area are reported by Wechselmann and Brentano.
Diffuse polyposis of entire colon and adenocarcinoma of submucosa through-
out is described by Babler. As a rule one or more of the polyps are malig-
nant, the others benign. Thorbecke comments on the high mortality of the
disease, which is referable to metastases from the carcinomatous polyps, to
the progressive malignant changes in previously benign areas, and to the
functional disturbance of the organ. Oseki found metastases in many
retroperitoneal nodes, liver, lung, adrenal, and ovary.

In structure the tumors show various types of malignant adenoma,
adenocarcinoma, and alveolar carcinoma. In Babler's case there was diffuse
adenocarcinoma and alveolar carcinoma in the submucosa without metas-
tases. Wechselmann describes carcinomatous invasion of the base of a
polyp, the tip of which was also carcinomatous.

(6) Squamous-cell carcinoma arises from the anal epidermis or by meta-
plasia from the lower rectal mucosa. The frequency of this tumor is esti-
mated at 3 to 4 per cent. (Funke) or 20 per cent. (Quenu), of all rectal car-
cinomas. It presents the usual features of this tumor in its more malignant
form. Kraske describes four cases, three of which produced ulcerating
nodules destroying the sphincter, while one extended laterally over a very
wide ulcerating area. I have seen a very extensive and highly destructive
tumor following condyloma latum.

(7) Melanoma of the rectum is rare, but nearly all writers in this field
describe one or more cases (Kraske, Cripps, Ball, Heaton, Strasberger,

CARCINOMA OF INTESTINE 653

De Buck, Vanderlinden) . Paneth collected eight cases, and Wiener refers to
several others. Bulky, firm, relatively benign melanomas of the rectum are
frequent in horses (Eiselt).

The tumors are usually of considerable size, and form circumscribed or
pedunculated growths which obstruct the lumen and later suffer ulceration and
necrosis. In structure they have been described as carcinoma or sarcoma.
Kraske's carcinoma was a medullary growth composed of large polyhedral
cells with little stroma. The pigment was limited to the epithelium and
adjacent lymph-nodes. Two polypoid melanotic tumors were composed of
pigmented spindle-cells. The source and significance of the rectal tumors
present the same obscurities as surround other heterotopic melanomas.

CHAPTER XXXIII
EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER

Classification. — The difficulties in presenting an orderly arrangement of
primary epithelial tumors of the liver, so obvious in the older literature, are
still apparent in many recent studies.

There is first the occurrence of a wide variety of very rare tumors which
requires the admission of small groups of cases distinguished by their peculiar
etiology, gross anatomy, and histogenesis. Thus Simmonds finds that local
hyperplasia in the liver occurs as: (i) A solitary focus of congenital origin
in a normal liver; (2) multiple nodular hyperplasia; (3) multiple adenoma;
(4) solitary adenoma. All of these conditions occur with and without cir-
rhosis and many of the simple hyperplastic processes lead through benign
tumors into malignant neoplasms, thus complicating the task of separation
into groups. Secondly, the remarkable regenerative capacity of the liver-
cells leads to the frequent occurrence of partially neoplastic processes which
have been variously graded and named by different authors. Third, while
the typical structure of liver-cell tumors cannot readily be confused with
that of typical bile-duct adenomas and carcinomas, there remain many
structures of uncertain significance, resulting probably from a growth derived
from both these elements. Hence there will always be a fluctuating group
of mixed epithelial tumors of the liver. Moreover, not a few cases of homo-
geneous type and evidently single origin are so far removed from the usual
morphology that some doubt must remain regarding their true origin.
Finally there are highly atypical tumors of the liver which have been named
and classified on rather superficial resemblance to various forms of carcinoma
or sarcoma, which still require more careful analysis before their exact nature
can be established.

Two main classes of primary epithelial tumors of the liver are univer-
sally recognized as derived from (i) liver-cells, and (2) intrahepatic bile-
ducts. A third or subgroup includes (3) mixed tumors, in which both liver-
cells and bile-ducts contribute. The simplest terms designating these
tumors are liver-cell, biliary, and mixed hepatic carcinoma, or adenoma.
The term "hepatoma" has come into very general use and has the great
advantage of avoiding implications with adenoma and carcinoma, while it
sufficiently designates any tumor of liver-cells. Cholangioma is a parallel
but less satisfactory term designating tumors of bile- ducts. Rigid ter-
minology calls for such phrases as "hepatoma adenoides," etc., or "adenoma
hepatocellulare, vel cholangiocellulare." According to their gross anatomy
the tumors are solitary or massive, multiple or nodular, and rarely diffuse.

SCHEME OF FORMS OF EPITHELIAL HYPERPLASIA AND TUMORS OF THE LIVER

(1) Simple hypertrophy and hyperplasia

(a) Regeneration

(b) Congenital solitary hyperplasia

(d) Diffuse hyperplasia (Diabetes)

(2) Neoplastic hyperplasia
[(a) Hepatoma

(1) Adenoma

(2) Adenocarcinoma

(3) Carcinoma, solitary, multiple, atypical

654

EPITHELIAL IIYPERPLASIA AND TUMORS OF LIVER 655

(b) Cholangioma

(1) Adenoma, solid, cystic

(2) Adenocarcinoma

(3) Carcinoma

Hepatic Regeneration. — The regenerative capacity of the liver as exhib-
ited in destructive and inflammatory conditions furnishes necessary stand-
ards in estimating neoplastic processes in this organ.

Experimental excision of large portions of the liver in lower animals
reveals rather astonishing capacity for restitution (Ponfick, Podwyssoski,
Jr.). V. Meister extirpated up to four-fifths of the organ in rabbits, rats, and
dogs. The remaining lobes exhibited hyperemia, hypertrophy, mitoses and

FIG. 288. — Adenomatoid hyperplasia of liver following acute yellow atrophy. Specimen of

Dr. Elser's.

multiplication of peripheral cells of lobules, great increase in the size of the
lobules, and eventual restoration of much of the lost tissue. This type of
regeneration has been called morphallaxis (Morgan). Functional hyper-
trophy of the whole organ is observed in diabetes.

Extensive regeneration of necrotic areas is observed after focal lesions
produced by hemolytic agents (Jackson, Pearce), and especially in acute
yellow atrophy. Prolonged cases of this disease may show many islands
of new liver tissue springing from the surviving liver-cells on the peripheries
of lobules and producing irregular masses of deformed lobules which may
present a very bizarre and almost adenomatous appearance (Stroebe).
In one of Barbacci's cases a hyperplastic mass reached the size of an apple
and the structure approached that of adenoma. In these cases Meder traces

656

NEOPLASTIC DISEASES

rather clearly the origin of new liver-cells from proliferating bile-ducts,
but most observers have failed to determine this origin with certainty and
believe that the regeneration begins in islands of liver-cells. In Laennec's
cirrhosis the incarcerated lobules are often markedly hypertrophic, and in
Hanot's cirrhosis in younger subjects the hypertrophy is diffuse and asso-
ciated with hyperplasia.

Multiple nodular 'hyperplasia is a term applied to pronounced focal over-
growth of liver-cells in cirrhosis and other conditions. In cirrhotic livers
these nodules may be very numerous, firm, opaque, and yellowish, or soft-
ened, fatty, or hemorrhagic. In malarial cirrhosis, Kelsch and Kiener
described adenomatoid nodules arising in areas of compressed liver tissue,

;•

^ • «ii*v4 jwfA ^.Vi>* •>. »**

:^^% •<

*•* ~W?;.« ;

FIG. 289. — Adenomatoid hyperplasia of liver following acute yellow atrophy.

composed of regular cords of large liver-cells often undergoing fatty degenera-
tion, or caseation, with hemorrhage and liquefaction. In both of these
conditions loose masses of hypertrophic liver-cells may be found in the portal
and hepatic veins and should not be confused with the solid intravenous
growths of malignant tumors (Delepine).

In acute yellow atrophy the regenerating tissue may yield a pronounced
picture of multiple nodular hyperplasia without genuine neoplastic features
(Meder, Marchand). It is difficult to separate the reported cases of nodular
hyperplasia from those of the more advanced cancerous cirrhosis and adenoma.
Sabourin's observations refer to areas of simple hyperplasia which he
finds about proliferating branches of the portal-biliary connective tissue.

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 657

A very pure form of nodular hyperplasia without cirrhosis or previous
destructive lesion was observed by A. Jacobi and the writer, in a child suffer-
ing from hepatic stasis from enlarged retrohepatic lymph-nodes. Here the
otherwise normal liver was studded with myriads of miliary nodules resem-
bling tubercles, and composed of hypertrophic cords of liver-cells regularly
incorporated in the liver lobules. Very similar changes, but not in normal
livers, are described by Simmonds.

That all of these forms of hyperplasia may pass into single or multiple
progressive adenoma is fully attested by the difficulty of separating them
from destructive adenomas and cancerous cirrhosis. Nevertheless the
condition actually observed in many cases at autopsy is quite different from
that of true adenoma.

PRIMARY EPITHELIAL TUMORS OF LIVER

General Etiology. — Orth found primary carcinoma of the liver four times
among 258 cases of hepatic cancer and 713 cancers of all types (0.28 per cent.).
The statistics of Orth, Hansemann, and Rindfleisch give 0.5 percent, of all
cancers as primary in the liver. Yet Goldzieher and Bokay saw 18 cases,
1.3 per cent., among 6000 general autopsies, in five years.

The chief age of incidence is between 40 and 60 years, especially 50 to 60,
average 43 to 53. Biliary carcinoma occurs later than hepatoma, rarely
before 40 years, and more frequently in women. Aside from the congenital
local hyperplasia of Simmonds, congenital malignant adenoma has been
described by Ribbert, Prescott, Miller, Cleland, Karsner, and Milne, and
multiple hemorrhagic hepatoma by Mair. Pepere concludes that all
solitary adenomas are congenital. Of 29 reported cases in children Phillipp
accepts 12 as genuine. Rolleston adds several others. Reports of sarcoma
show much the same age incidence (Vecchi, Guerrini). Rolleston collected
32 cases under ten years of age.

Congenital maladjustment of groups of liver-cells predisposing them to
tumor growth seems to be a very rare factor in adults, while possibly of more
importance in infants and with solitary tumors. Among 20 cases of solitary
adenoma Caminiti found only four with cirrhosis. All liver-cells appear to
be capable of neoplastic overgrowth. A previous fatty and atrophic degen-
erative process is described by Oertel as a preliminary to further neoplastic
degeneration in islands of cells separated by connective tissue, but this
preliminary change is not constant.

Yamagiwa describes several cases of hepatoma in children, in two of
which he found islands of bone and mucoid tissue. The tumors lay deep,
were partly encapsulated, cells small, embryonal and rich in glycogen, and the
vessels dilated. These features he interprets as those of an autochthonous
teratoma, with metaplasia of superfluous mesenchymal material. Islands of
metaplastic cartilage and squamous epithelium occurred in cases of v. Hippel
and Philipp.

Relation to Cirrhosis. — Cirrhosis is the chief predisposing factor, occur-
ring in about 85 per cent, of hepatomas, and 50 per cent, of biliary tumors
(Eggel). The cirrhosis is usually portal and biliary in type and often of
alcoholic or syphilitic origin. Carcinoma was associated with hemochroma-
tosis in the cases of Lohlein and Rindfleisch. Echinococcus cysts were
observed in the cases of Dibbelt, Lohlein and Necker, and Yamagiwa reports
cases with distomiasis and schistosomiasis. There is little doubt that cir-
rhosis and the factors that lead to it cause degeneration followed by regenera-
tive overgrowth which may become excessive and neoplastic. This excessive

658 NEOPLASTIC DISEASES

hyperplasia signifies failing compensation and is favored by fatty degenera-
tion and thrombosis of veins (Rolleston). Hence the cirrhotic process
must be regarded as both contributing to and coincident with the tumor
growth. There seems little point in the effort to disconnect these interre-
lations. A secondary fibrosis may develop about old nodules of liver-cell
tumors, while biliary carcinoma is desmoplastic from the first.

Hepatic stasis frequently antedates the cirrhosis and the tumor process,
is very effective in stimulating overgrowth in the form of nodular hyper-
plasia, is often observed without cirrhosis, and is a prominent predisposing
factor in hepatic tumors. Local interference with the blood-supply appears
responsible for some solitary tumors.

Histogenesis. — The growth of hepatoma from the hypertrophic liver
cords was first clearly demonstrated by v. Heukelom, has been traced in
greater detail by Goldzieher and Bokay, and these observations have been
verified by many others. It has also been shown that there is a uniform
gradation between nodular hyperplasia, multiple adenoma, and multiple
carcinoma. These gradations may even be observed in the same liver, so
that, as Muir has stated, there is no essential distinction between the com-
paratively benign and the atypical malignant forms of the tumor. Ribbert
and Heussi contest the multiple origin of many hepatomas, finding very sharp
separation between hypertrophic and invading tumor-cells without great
disorder of the cords. Yet such a sudden transformation of hyperplastic
into neoplastic cells is characteristic of many tumor processes. During the
transition the cells may retain the granular character of liver-cells while
staining more intensely with basic dyes, or they may lose granules and pig-
ment and assume the transparent supposed embryonal character described
by Adler. Bile secretion diminishes with increasing anaplasia but may be
entirely missing in massive adenocarcinomas. Nuclear hypertrophy and
hyperchromatism is very constant, multinucleated and giant cells appear,
and mitosis and amitosis are frequent. Notable changes in the nuclei are
often seen in neighboring liver tissue, forming a feature of collateral hyper-
plasia. The first generations of tumor-cells are usually large, later they
become smaller and atypical. The preservation and newgrowth of capil-
laries is a remarkable feature, may accompany the intravascular growths
(Parcelier), and reaches its highest activity in the so-called angioplastic
pseudosarcomas. Renon, Geraudel, and Monier-Vinard particularly empha-
size the presence of a neoplastic process residing in the endothelium of the
capillaries and they conceive the hepatoma as a new formation of complete
embryonal liver tissue from the adult. It seems possible to overestimate
the importance of the endothelium in these cases. Yet Dominici and Merle
trace a sarcomatous process to the excessive growth of endothelium in an
atypical hepatoma.

Biliary carcinomas have also been traced satisfactorily to the proliferat-
ing bile-ducts in cirrhotic and other livers, and the usual series of graded cases
from adenoma to carcinoma is abundantly supplied in the literature (v.
Hippel, Fischer, Herxheimer.) Precancerous changes are supplied by Milne
and Yamagiwa in the form of angiocholitis proliferans. The multiple nodules
must be referred to the universally distributed small ducts, while the solitary
and cystic growths show some predilection for the hilus and subcapsular
areas. Yamagiwa finds that tumors of the larger bile-ducts yield tubular and
papillary adenocarcinomas while the small ducts produce chiefly carcinoma
simplex.

For the atypical and highly malignant growths from both sources there
are no observations to indicate their exact origin. They probably originate

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 659

in few or single foci, as Ribbert urges, and are rapidly disseminated through-
out the liver.

The histogenesis of the tumors of mixed type is not clear. Most of these
cases arise in extensively cirrhotic organs in which the formation of pseudo-
bile-ducts from incarcerated liver-cells and the elongation of tortuous bile-
ducts, render the picture very complex. The uniform mingling of two
tumor processes affecting liver-cells and bile-ducts must be accepted with
caution, and Muir and Rolleston emphasize the fact that typical hepatomas
may produce canals resembling bile-ducts.

Metastases. — Both single and multiple hepatomas very early invade the
capillaries, even when devoid of other malignant properties. Hence loose
intravascular thrombi may appear in relatively benign tumors which are
incapable of surviving a dislocation from the liver. They are, however,
capable of forming secondary nodules in the liver, and by this means of dis-
semination malignant tumors may be rapidly distributed over most of the
organ. Ribbert and Heussi, and many others, believe that this process,
rather than a multicentric origin, explains the distribution of tumor nodules
in many cases. Yet in not a few instances bulky tumor masses are found
in the portal and hepatic veins without very many secondary nodules.
Thrombosis of the hepatic or portal veins may occur without extensive
tumor invasion, by a passive discharge of softened tumor-tissue. Occasion-
ally the tumor thrombus extends into the vena cava and even up to the heart.
While no point of perforation of the large veins can usually be found, yet
Engelhardt describes the penetration of the wall of a large vein by infiltrating
tumor-cells.

The frequency of metastases is not great. Of 163 cases tabulated by
Eggel 46 were free from definite extensions, 50 showed growths limited to
the portal or hepatic branches, 30 gave metastases in thorax or lungs, 18 in
regional lymph-nodes only, and nine secondary tumors were distributed in
colon, pancreas, ovary, kidney, omentum, thyroid and cranium. GiachettTs
massive carcinoma gave very numerous metastases only in the brain.

Extrahepatic metastases are much earlier and more frequent in biliary
cancer than with hepatoma. In many instances the distant metastases
of hepatoma have shown secretion of bile (Schmidt, Hanot, Gilbert, Clan,
Pryn, Wegelin, Mair). Secondary hepatoma is often distinctly organoid in
structure, exhibiting liver- cords, Kupfer's cells (Mirolubow), capillaries, and
bile secretion.

Clinical Course.- — The history of carcinoma of the liver varies greatly
with the type of the disease. The presence of a malignant tumor is usually
indicated by anemia and emaciation, but Rolleston refers to cases which
gained 19 and 7 pounds in weight during rapid terminal growth of the tumor,
the liver weighing 16 pounds. After the appearance of a malignant tumor
life is seldom prolonged over four months (Hale White). Fever is observed
with rapidly growing tumors and from infections. Eggel found fever in
14 per cent, of his cases, jaundice in 61 per cent., ascites in 58.5 per cent. In
the urine no specific changes have been demonstrated. Several well-defined
clinical groups are observed:

(1) No symptoms are detected and the patient dies suddenly from
hemorrhage, or after an illness of a few days, as noted by Karsner.

(2) Latent carcinoma is found in patients succumbing to cirrhosis or
other diseases.

(3) The usual history of cirrhosis terminates rapidly with hepatic tumor,
jaundice, ascites, and cachexia.

660 NEOPLASTIC DISEASES

(4) The usual history of a malignant tumor pointing from the first to the
liver, develops in previously healthy subjects.

Recovery from the disease is very rare, but Keen and Yeomans report
successful excisions, some of which appear to have recovered permanently.
Yeomans states that a patient from whom he excised a portion of a large
tumor mass in the liver remains well after five years. A section of this
tumor I found to show typical trabecular and perithelial adenocarcinoma.

ANATOMICAL AND CLINICAL VARIETIES

(i) Hepatoma. — (a) Solitary Adenoma. Solitary Hepatoma.' — Solitary
liver-cell adenomas are rarely encountered but typical cases are described

FIG. 290. — Solitary adenoma of liver.

by Rokitansky, Salter, Engelhardt, Wegelin, Rolleston, and others. Two
or more massive tumors in one liver are properly included in this group.
Caminiti collected 20 cases, several of which occurred in cirrhotic livers.
Many appear in early life from 3 months and later (Milne) . Hence they are
often regarded as of congenital origin but it is probable that acquired lesions
may give rise to neoplastic overgrowth of isolated portions of the organ.
Christiani describes congenitally displaced lobules of liver tissue in Glisson's

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER

661

capsule, and Pepere found such lobules in liver and scattered over the perito-
neum. In Engelhardt's case the quadrate lobe was missing.

The solitary adenoma produces a gray, yellow, or bile stained, projecting
and encapsulated tumor, varying in size from a small nodule to a mass 8
inches in diameter.

The tumor is composed of cords, tubes, and alveoli closely resembling
the structure of the liver. In a case of the writer's all three struc-
tures were illustrated in different areas. The cells are granular and
acidophile, or very fatty. Bile stasis is usually absent, but many phases
of its secretion are often observed (Ciechanowski). The stroma is composed
chiefly of /capillaries.

The veins are not invaded in the typical solitary adenoma, but the benign
character is due chiefly to encapsulation and transitional forms to adeno-
carcinoma occur in which there is invasion of veins and multiplication of

FIG. 291. — Varying structure in adjoining lobules of malignant adenoma of liver cells.

tumors. B. Fischer describes a solitary adenocarcinoma with metastases in
lymph-nodes.

Adrenal rests in the liver have been described by Schmorl and others,
and yellow tumors possibly derived from these structures and closely resem-
bling adrenal tumors in other situations are described by Schmorl, Pepere,
de Vecchi, et al. Glynn, however, properly doubts the adrenal origin of these
tumors. Hirschler emphasizes the structure and very fatty character of his
tumor but the lipoids were chemically unlike those of the adrenal.

(b) Primary Massive Liver-cell Carcinoma. — This form of primary carci-
noma of the liver is highly characteristic. It occurs in young adults but more
often in elderly subjects and apart from the cirrhosis which frequently accom-
panies the tumor, it yields few symptoms until a brief terminal period is
reached. Eggel collected 14 cases at ages from 21 to 67 years, duration two
weeks to six months. I have reported a case in an old man who died suddenly
and unexpectedly from abdominal hemorrhage.

662

N EOF LAST 1C DISEASES

FIG. 292. — Adenocarcinomatous structure in a primary

tumor of liver cells.

^fe^^Sl^ft^

FIG. 293. — Variations in cell types in malignant hepatoma.

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER

663

The tumor appears as a large single yellowish friable mass, as large as a
child's head or occupying the whole right or left lobe. Small secondary tumors
in the liver may be present. The consistence is usually soft, and extensive
liquefaction necrosis and hemorrhage may produce a cystic appearance, or
rupture into the peritoneum. The large veins are usually invaded and
thrombosed and metastases while occasionally absent may be widespread
and bulky, especially in the lungs.

The structure presents wide variations but always reveals at some points
a definite resemblance to liver-cells. In the writer's case four separate
structures were presented in different portions: (i) Trabecular adenocar-
cinoma, composed of cords of very large granular acidophile cells resembling
large liver-cells, and separated by capillaries. Giant-cells of very large
dimensions were abundant in these areas. These cells have been described
by Hanot and Gilbert and by C. P.
White as a characteristic feature. (2)
Alveolar adenoma. These areas pre-
sented compact groups of smaller
granular epithelium sharply bounded
by very numerous wide capillaries.

(3) Peritheliomatous areas composed
of capillaries surrounded by one or
more rows of cubical granular cells
appeared in certain portions. This
structure has been noted by Goldzieher
and Bokay, Yamagiwa, and others.

(4) Diffuse carcinoma. In many
softened or necrosing areas all traces
of the orderly arrangement of cells
were lost, and the growth was com-
posed of diffuse round, polyhedral, or
spindle-cells with strongly hyperchro-
matic nuclei.

These structural types cover most
of those observed by other authors.
It is evident that this tumor repre-
sents a more rapidly growing atypical
and malignant form of the solitary
adenoma.

(c) Multiple Liver-cell Carcinoma or
Hepatoma. — In this group are included
the highly malignant rapidly growing
tumors occurring in livers in which
cirrhosis is either absent or so slight as to be of secondary importance. The
peculiar clinical course, gross appearance of the liver, and the microscopical
structure which is often atypical, justify the separate consideration of these
cases. There is however, no sharp division between this group and solitary
massive carcinoma on the one hand and multiple carcinoma following cirrho-
sis on the other.

While the highly characteristic cases are somewhat rare the group as a
whole is rather numerous. Eggel collected many examples, most of which
were associated with advanced cirrhosis. Hanot and Gilbert describe several
characteristic cases. There is reason to believe that many of the so-called
angiosarcomas of Arnold, v. Kahlden, Steinhaus, and Marx, are atypical

FIG. 294 . — Pseudo-epitheliomatous
structure in multiple hemorrhagic hepa-
toma. (L'Esperance.)

664

NEOPLASTIC DISEASES

forms of multiple hepatoma, and it is probable that other cases described as
alveolar or lymphosarcoma are of the same nature (Dominici, Merle).

The clinical course is chiefly notable for its rapidity, many cases lasting
only a few weeks, few continuing more than three or four months, and some
dying suddenly without very definite previous disturbance. Jaundice is
uncommon, but serous or bloody peritoneal effusions are often observed.
Rapid cachexia with enlargement of the liver and ascites are the usual clinical
signs. These tumors occur chiefly after middle life, but De Haan, Mair, and
others report cases in infants and children.

The liver is usually enlarged, at times to very considerable dimensions,
and is the seat of multiple nodules and tumor masses which are grayish or bile
stained or hemorrhagic and necrotic. A resemblance to multiple secondary
chorioma has been noted by Marx, Teacher, and L'Esperance. Although the
size of the tumor masses varies, it may be impossible to choose any one as a

FIG. 295. — Multiple hemorrhagic hepatoma. (After L'Esperance.)

single primary focus. Many small nodules are doubtless secondary. In
other cases, usually of slower development, there are one or more larger
masses with more numerous and probably secondary tumors in the liver.

Metastases are usually missing but local extensions to the portal nodes,
diaphragm, and gall-bladder, are observed, and in the more prolonged cases
they may be found in the lungs and other organs. Most tumors yielding
extensive metastases are associated with cirrhosis. The structure varies
greatly even in different portions of the same tumor and reproduces the more
malignant structures of solitary carcinoma. Thus one finds trabecular
carcinoma with giant-cells, small alveolar carcinoma with numerous capil-
laries, perithelioma, and diffuse carcinoma. A definite encapsulation of
tumor masses does not occur but Mirobolew points out that distended venules
may inclose tumor nodules.

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 665

L'Esperance has described an atypical form of primary multiple hemor-
rhagic hepatoma, which probably includes many cases of pseudosarcoma.
In portions of these tumors the original structure appears chiefly as a perithe-
lioma, with large or small cubical granular cells surrounding capillaries.
In hemorrhagic and necrotic areas this structure is lost and the tumor detritus
appears as a large spindle-cell or alveolar sarcoma. The occurrence of such
pseudosarcomatous areas in combination with typical hepatoma, as occurred
in one of my cases, reveals the true nature of the atypical forms of hepatoma.
The structure may somewhat resemble chorioma of the liver, as noted by
Cruikshank and Teacher, and Marx, but secondary chorioma from uterus or
testis regularly reveals its specific features and there is no reason to believe
that chorioma is ever primary in the liver.

(d) Carcinomatous Cirrhosis. Multiple Adenoma, Carcinoma or Hepa-
toma with Cirrhosis. — A more advanced stage of hyperplasia with atypical
morphology, local aggressive properties, invasion of veins and occasionally
with metastases, is described bv manv authors as carcinomatous cirrhosis

FIG. 296. — Gross appearance of universal cancerous cirrhosis of liver.

(Griesinger, Hanot and Gilbert, v. Heukelom, Thorel, Rolleston). Others
designate the condition as multiple adenoma or carcinoma (Marckwald,
Lit., Lancereaux).

No sharp division exists between multiple adenoma without cirrhosis,
multiple adenoma with cirrhosis, and carcinoma. Each of these conditions
exhibits'progressive, invasive and malignant tendencies (Muir).

The distinguishing feature of the present group of cases is the relation to
cirrhosis. The tumor process appears to be the direct sequel of, or essen-
tially connected with the cirrhosis. Hence the symptomatology is much
influenced by the history of cirrhosis, and both the clinical picture and patho-
logical anatomy are somewhat distinctive.

Cancerous cirrhosis develops in elderly subjects of 40 years or more, and
often in children, previously in good health, who develop symptoms of portal
stasis with ascites and slight jaundice. A history of cirrhosis regularly
precedes the development of the tumor, but is not always pronounced.
With the onset of the tumor process there are added increasing anemia,
cachexia, diarrhea and hemorrhages, and the disease progresses steadily

666 NEOPLASTIC DISEASES

to a fatal issue. After the appearance of ascites the duration is seldom more
than a few months and often only a few weeks.

The liver is usually contracted but in some cases is normal or greatly
increased in size. The surface presents multiple, projecting, yellowish
or bile-stained nodules which on section may be found to represent a large
part of the parenchyma. The nodules may be numerous, small, and almost
confluent, or larger, discrete, and encapsulated. One portion of the organ
may be quite free but frequently the lesion is nearly universal. A portal
cirrhosis is usually present and many of the nodules are surrounded by con-
nective tissue. In many cases the gross appearance of the organ resembles
that of Hanot's hypertrophic cirrhosis. The spleen is diffusely enlarged.
Borst found in one case much the same process in both liver and pancreas.
Many authors describe a diffuse form of hepatic carcinoma (Eggel,
Rolleston). Yet these cases commonly represent a very extensive develop-
ment of nodular carcinoma in a cirrhotic liver and not a diffuse growth of
tumor-cells. Regressive changes in the tumor and overgrowth of hyaline
connective tissue may also disturb the original structure and produce areas
of diffuse carcinoma.

The microscopical structure shows extensive replacement of paren-
chyma by adenomatous and carcinomatous nodules. The process begins
with the hypertrophy and hyperplasia of cell groups within the acinus and
apparently at any point in the lobule. These cell groups enlarge, forming
nodules which rapidly encroach upon the remaining parenchyma with atrophy.
The tumor-cells are of large size, forming thickened liver cords (trabecular
adenoma), or the nuclei multiply actively and numerous smaller cells result.
Peculiar forms of nuclear division, chiefly of the amitotic type, are observed.
Giant and syncytial masses often appear. Fatty degeneration may be promi-
nent and liquefaction may be added. The cells may contain globules of
bile and many hyaline cytoplasmic bodies. The structure may vary in
the same or different nodules. The cells may be arranged in small regular
alveoli with a fine lumen, or the lumen may be wide and the lining cells low
cuboidal. Many transitions from adenoma to adenocarcinoma and diffuse
carcinoma are observed, v. Heukelom was able to trace the origin from the
liver-cells and to follow the growth of early nodules into the central veins
and portal and hepatic radicles. By this route the tumor grows into the
larger veins which may be occluded by tumor masses although their walls
are intact and no point of penetration may be found. These tumor thrombi
may fill the hepatic or portal veins and enter the vena cava. Yet metastatic
growths are often wanting, but in about 20 per cent, secondary deposits
are found in lungs, or peritoneal nodes (Kelsch and Kiener, Brissaud,
Hanot and Gilbert, Frohmann, Goldzieher and Bokay).

The part played by the bile-ducts varies. In most cases they are con-
siderably increased in number in the cirrhotic areas but do not contribute
to the tumor process. In other cases the proliferation of bile-ducts is more
active and they appear to become transformed into tumor-cells (Birch-
Hirschfeld, Thorel, Marckwald). The structure is then apt to present many
small groups of tumor-cells lying chiefly in connective tissue, as well as the
typical hepatic adenoma. In such cases Marckwald, Theodorow, and
Parcelier and Fromaget conclude that two separate tumor processes exist,
one affecting the liver-cells, the other the bile-duct cells. Pure adenoma or
carcinoma of the bile-ducts presents a rather specific structure and will be
separately considered.

The relation of the tumor process to the associated cirrhosis is not always
identical. In many cases the rapid progress of the disease and the moderate

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 667

grade of cirrhosis indicate that the latter is secondary to the former process
(Lancereaux, Marckwald). Moreover extensive nodular hyperplasia, ade-
noma, and primary carcinoma occur without cirrhosis. Since focal hyper-
trophy is often observed in portal cirrhosis and the grade of cirrhosis is
often extreme, the liver being contracted and deformed, it is highly probable
that the condition in such cases represents a sequel of the cirrhotic process
(Simmonds, Orth, Schmieden, Travis, Peabody). In most cases the two
processes are probably coordinate (Watzoldt).

The many gradations presented by different cases between simple nodular
hyperplasia, multiple adenoma and adenocarcinoma, the multiple origin,
the peculiar localization of the disease to the liver, and the frequent absence
of local aggressive properties, have raised doubts regarding the genuine
carcinomatous nature of the disease. Borst, while admitting its morpholog-
ical identity with carcinoma, urges a distinction between secondary epithe-
lial proliferation after injury of liver tissue with hypertrophy, hyperplasia
of adenomatoid or carcinomatoid structure, and true primary autonomous
neoplasms of the liver. This point of view may be emphasized by the occur-
rence of congenital solitary hyperplastic areas, and solitary adenoma and car-
cinoma of this organ. Yet all the features of the malignant primary tumors
are observed in multiple adenoma or carcinomatous cirrhosis. Different
cases present every gradation from nodular hyperplasia to malignant carci-
noma, so that the distinction between multiple adenoma with cirrhosis
and true carcinoma without cirrhosis appears to be the condition of origin
and intensity of the process rather than in the essential nature.

Renon and Geraudel contrast the biological features of all the liver-cell
tumors (hepatoma) with (other) true cancers. They point out the multiple
origin, the lack of complete emancipation of the cells which do not survive
well outside the environment of the liver or frequently produce metastases,
the preservation of functional capacity in secreting bile, and hence they
discard the term carcinoma in favor of " hepatoma." I can only endorse
the employment of a specific term for such a peculiar process but must still
regard the process as essentially carcinomatous with certain features which
are duplicated by some carcinomas in other organs. Geraudel contends
that the hepatic parenchyma is of mesoblastic origin. Yet the liver-cells
are derived from exactly the same endodermal bud as the bile-ducts and the
only part of the parenchyma which is of mesodermal origin is the system of
blood-vessels.

CYSTS AND TUMORS OF BILE -DUCTS. CHOLANGIOMA

Cysts of the Bile-ducts.' — Biliary obstruction is the cause of a variety of
hepatic cysts.

(1) In cirrhosis obstructed bile-ducts may dilate, giving rise to very
numerous small or microscopic cysts containing fluid bile. Rolleston de-
scribes a case with many subserous cysts containing inspissated bile. In
cirrhosis with nodular hyperplasia or adenoma the hypertrophic nodules may
break down and yield small cysts in the parenchyma.

(2) Large single or multiple cysts from retention of bile are occasionally
observed. Bayer found a cyst containing 13^ pints of fluid, Aldous 12
pints, and North 5 pints, mostly clear or bloody fluid from which the bile
pigment had been absorbed. Doran's cyst contained 2% pints of colored
bile and was evidently more recent. In all these cases the wall is of fibrous
tissue in which are imbedded numerous bile-ducts. The lining may be of
cubical, cylindrical, or flat-cells, but the epithelium is much desquamated.

668 NEOPLASTIC DISEASES

Zahn collected 14 cases of cysts lined by ciliated epithelium. These suggest
an origin from congenitally misplaced aberrant bile-ducts (Moschkowitz).

(3) Congenital multiple cystic disease of the liver is a not infrequent
condition which is nearly always associated with similar changes in the kid-
neys (Bristowe, Still, Moschkowitz). Cystic kidneys however, are usually
found without cystic liver (73 per cent.,Lejars; 94 per cent., Luzatto). The
pancreas and spleen may also be involved.

The condition is rather common, although not always pronounced, in
malformed infants, especially females, and in various ways leads to early
death. Another group of cases is observed in adults who escape the initial
dangers or in whom the condition develops late. The chief symptoms are
uremic.

The liver may be of normal size, or greatly enlarged. MacDonald
records a cystic liver weighing 14 pounds. When the cysts are very small the
organ may appear fibrosed, otherwise a portion or the whole of the liver may
be the seat of a large number of cysts from one-tenth mm. to several centi-
meters in diameter. The parenchyma may be reduced to a trace and cir-
rhotic. The kidneys are usually more altered than the liver. The fluid
contents are clear, albuminous, mucoid, bloody or inspissated, and contain
urea, salts, and cholesterin, but no bile. The earliest stages of the process
show a multiplication of slightly dilated but otherwise normal bile-ducts
in widened portal canals. By progressive dilatation and fusion of smaller
cysts the larger develop. In adults the lining cells are cylindrical or
cubical, occasionally ciliated (Lejars) and often flattened or absent.

The structure does not favor the old theory of a fetal cholangitis, nor
the origin from hepatic degeneration with widening of new formed bile-
ducts. A neoplastic element was discerned by Rindfleisch and designated as
cystic fibrosarcoma. Any neoplastic element present is more probably
adenomatous, as appeared in unusual distinctness in cases of Siegmund,
v. Kahlden, and Workman, and especially in the kidneys in the cases of
Nauwerck and Hufschmidt. A congenital malformation is undoubtedly the
original factor. Shattuck suggests that the tubules represent remains of
mesonephros blended with the metanephros, and for the liver Still traces the
tubules to irregular diverticula from the duodenal invagination which develops
along with the normal bile-ducts. Moschkowitz finds aberrant atypical
ducts along with normal bile-ducts in the portal canals of cystic livers, but
Rolleston doubts this interpretation of these structures. I do not find them
in my cases, in which all the bile-ducts are alike. On the basis of this con-
genital anomaly progressive dilatation may occur or adenomatous processes
may be established. Some single and multiple cystic adenomas of the liver
probably develop in this way, and in the kidney 1 have seen highly cystic
Wilms' tumors which suggested a transition from the congenital cystic
kidney to congenital sarcoma.

Tumors of the Bile-ducts.- — The epithelium of the bile-ducts gives origin
to several varieties of true tumors. While the congenital cystic liver rarely
or never gives rise to a progressive neoplasm, single and multiple cystic
adenomas arise from the bile-ducts in cirrhosis; multiple solid adenomas of the
bile-ducts are rather frequently observed (Watzold); and a specific form of
multiple carcinoma develops from these structures.

Cystic Adenoma of Bile -ducts .—Definite tumors of this origin are rare
and the neoplastic nature of some of the recorded cases, of which Leppman
collected nine, is doubtful. Thus Shattuck removed a large cyst containing
a gallon of clear fluid, in the wall of which were many ducts and minute
cysts interpreted as adenomatous. A true multilocular cystadenoma was

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 669

successfully removed by Keen. It weighed 113 gm. and contained many
cavities lined by cylindrical cells and supported by fibromuscular tissue.
In Siegmund's case a large part of the liver formed an isolated cystic mass in
which were many areas suggesting active neoplastic growth of cubical cells.

A remarkable development of multiple cystic adenomas involving
the whole of a cirrhotic liver is described by Dinochowski and Janowski.
The organ weighed 10,850 gr., contained very numerous cysts, minute and
as large as a child's head, filled with clear fluid. There was extensive epithe-
lial proliferation filling some of the smaller cysts.

Multiple Adenoma of the Bile-ducts. — Is usually observed as a secondary
condition after death from other causes and of itself produces no symptoms
(Watzold, Hippel). The liver is usually the seat of stasis or cirrhosis.
In Brigidi's cases the liver weighed 6 pounds, the adenomas were small
and numerous, and an extensive cirrhosis was present. V. Hippel found very
little cirrhosis. The tumors lie beneath the capsule or deeper in the paren-
chyma and appear as grayish white nodules 0.5 to 2 or 3 cm. in diameter.
The gross appearance may resemble that of thyroid tissue when the alveoli
are filled with secretion (v. Hippel, Dreschfeld). Occasionally there is
bile stasis in the alveoli and the tumors are discolored. The nodules are
usually incased in connective tissue and are free from bile deposits.

The structure presents many small alveoli with definite lumina lined by
one or more layers of small, cubical or higher cylindrical cells in which the
nuclei are very prominent, and the cytoplasm clear. These alveoli resemble
the proliferating bile-ducts in cirrhotic livers. The adenomatous alveoli are
usually confined to the widened portal canals while the hepatic lobules are
pushed aside, but in some cases there is more active proliferation and the
alveoli grow between or within the lobules. The lumina of the alveoli are
usually empty or contain granular or hyaline detritus, but dilatation and
lateral outgrowths may occur, polypoid projections may develop and there
are many transitions to cystadenoma and adenocarcinoma. Thus Watzold
found 30-40 nodules under the capsule of the liver and showing many stages of
cystic dilatation. Kika describes these cases as proliferating cystadenoma.
They develop chiefly from the larger ducts.

Multiple Carcinoma of the Intrahepatic Bile-ducts.— Incidence, — Malig-
nant tumors of this origin occur under much the same conditions as multiple
liver-cell carcinoma but less frequently associated with cirrhosis. Regarding
their frequency opinions are widely at variance. Basing the diagnosis on a
structure presenting alveoli lined by cylindrical cells, Eggel found that 32
per cent, of primary carcinomas of the liver were of this origin. Pepere on
much the same data reduced the proportion to 14 per cent. B. Fischer on
the other hand encountered two typical cases and hastily undertook to
eliminate the entire group of liver-cell tumors, assuming that practically
all primary carcinomas of the liver arise from the bile-ducts. In the litera-
ture definite reports of bile-duct carcinoma are much less numerous than
cases of liver-cell carcinoma. Of the 53 cases collected by Herxheimer some
are of uncertain origin.

Bile-duct carcinoma appears chiefly in adult or later life, in subjects
of cirrhosis. A history of severe disturbance in the evacuation of bile, as in
Fischer's case, is relatively common.

Gross Anatomy.- — The liver is usually enlarged sometimes to very notable
dimensions, intensely jaundiced, and often the seat of advanced cirrhosis,
chiefly of the biliary type. The dilated larger bile-ducts may be visible
in the gross. The tumor process affects most or all of the organ, and produces
very numerous, usually small, firm nodules which may become confluent.

670 NEOPLASTIC DISEASES

Fischer found the most extensive tumor growth in the region of the hilus
where it probably arose from the larger bile-ducts. In most cases it is
impossible to locate any single primary focus and the origin is multicentric.
Massive forms of adenocarcinoma of bile-ducts with transitions to carcinoma
in multiple secondary nodules are described by Greenfield and Thorel.

The extensive hemorrhages, necrosis, the bulky soft tumor masses, and
prominent invasion of large veins which characterize hepatoma are missing.
A tendency toward cicatricial fibrosis of the tumors has often been noted in
the gross.

The structural features usually form a sharp contrast with those of liver-
cell carcinoma. The prevailing structure is that of adenocarcinoma or
alveolar carcinoma. The cells are cylindrical, high or low, or cubical, re-
sembling those of bile-ducts, and the cytoplasm is clear, lacking the granular
acidophile character of liver-cells. The nuceli are small and vesicular and
mitoses may be very numerous. Giant-cells are rare. Ciliated epithelium
is described by Sokalow and Cagnetto in otherwise typical cases. In more
atypical malignant tumors the resemblance to duct-cells may be lost (Wal-
deyer). Many observers describe the transformation of bile-duct cells
into liver-cells in tumors originating from the former (Fischer, Herxheimer).
Others reverse the order and trace bile-ducts forming from liver-cells (Rind-
fleisch, Muir, Rolleston). In many of these cases it is quite possible that the
tumor has a dual origin, as held by Wiegert, Witwicky, Ben eke, Marckwald,
and others, or that the tumor arises from cells which had previously assumed
the characters of pseudo-bile ducts.

The stroma is abundant and reveals the desmoplastic property of true
carcinoma, while in hepatoma the stroma is composed only of capillaries.
Elastic fibers derived from the thickened portal canals and formed anew are
demonstrable, and there is a strong tendency toward cicatricial contraction
of the tumor nodules. Most of the nodules are inclosed in capsules of con-
nective tissue and the gradation into hepatic parenchyma seen in hepatoma is
usually missing. Yet malignant tumors may widely infiltrate the paren-
chyma. With overgrowth of fibrous tissue a scirrhus structure may develop
which is not observed with hepatoma.

The outlying portal canals commonly exhibit marked proliferation of
bile-ducts as in biliary cirrhosis, and these ducts may be dilated, lined by
one or more layers of proliferating cells or filled with papillary projections
of epithelium. From such precancerous overgrowth every stage up to true
adenocarcinoma has been traced (Kika).

The arrangement of the cells in small alveoli is characteristic and at once
distinguishes most of the tumors from the coarse trabecular tumors of liver-
cells. In the slower growths the alveoli are regular and adenomatous, in
more malignant cases they become smaller, more numerous and irregular, and
in very active processes they break up into compact small groups of cells
which grow diffusely, as in mammary carcinoma. The lumina are empty, or
filled with hyaline material or inspissated bile. When bile is present in these
tumors it must be referred to retained secretion derived from neighboring
parenchyma (Lohlein).

When small cubical or indifferent cells form compact anastomosing
groups, Goldzieher and Bokay liken the structure to basal-cell carcinoma.
They recall the basal-cell carcinoma of the ductus choledochus described by
Burkhardt and suggest that these hepatic tumors may arise from the larger
bile-ducts. The liver tissue undergoes passive atrophy or degeneration, but
in rare cases hypertrophy of cords and cells is observed.

Although the small veins may often be invaded by carcinoma of the bile-

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 671

ducts, metastases are not commonly observed except with the very active
tumors. The portal and mediastinal lymph-nodes may be involved. In
Dreschf eld's and Lohlein's cases, probably derived from the bile-ducts, the
metastases were general. The structure of the secondary tumors may
reproduce the original or appear much more atypical. Bile formation is
absent. Bonnet describes the production of mucoid material in secondary
tumors, and Baschko saw a cystic growth with watery secretion reproduced
in metastatic tumors of lymph-nodes and rib.

SARCOMA OF LIVER

The possible sources of true sarcoma of the liver and the probability of
their, occurrence are suggested from the embryology of the organ. The
hepatic parenchyma, liver cords and bile-ducts, and gall-bladder develop
from a single endodermal bud, from which an early subdivision goes to form
the gall-bladder. The remainder branches out into a mesodermal matrix
which supplies blood-vessels to the growing parenchyma and connective
tissue in the portal canals. The primitive liver is a hemopoietic organ, with
marked activity of the endothelial cells, but later this function is replaced by
metabolic and secretory activities.

The presence of superfluous mesodermal material in the liver is- indicated
in the cases of hepatoma in which mucous tissue and cartilage of metaplastic
origin have been found. Great prolif erative capacity of hepatic endothelium
is exhibited in hepatoma, in which the growth of capillaries keeps pace with
that of the liver-cells, or in some cases of perivascular type seems almost to
outstrip the epithelial growth. Dominici has described a true sarcomatous
proliferation of the endothelial cells in a case of multiple hepatoma, and one
nodule seemed to be composed exclusively of endothelial overgrowth.

There is, therefore, somewhat scanty but direct evidence that both the
stroma-cells and the endothelium of the capillaries are susceptible of tumor
growth. In the early embryonal liver there are collections of blood-forming
cells which might be drawn into possible sources of round-cell sarcoma,
but in the normal liver at birth there is no structure which might reasonably
be expected to give rise to round-cell or lymphosarcoma. Arnold's lymph-
nodules are islands of normoblasts.

The supposed origin of sarcomas suggested by the observers who have
reported cases of this disease is extremely varied. Arnold thought of the
connective tissue about blood-vessels or acini. Delepine argued in favor
of the cellular elements of the vessels. Byrom suggested the perilymphatic
connective tissue. Demel derived the tumors from the normal connective
tissue. De Vecchi and Guerrini concluded that the new connective tissue in
cirrhosis was the source of the polymorphous and angiosarcomas. Marx
derived his angiosarcoma from a cavernoma. Rolleston and Trevor called
their case malignant hemangio-endothelioma. It is obvious that the source
of these tumors has never been actually traced.

Considering the structures accepted as indicating a mesoblastic origin
there is again direct conflict of opinion. Arnold included in his table of 26
cases of sarcoma several reported as carcinoma. De Vecchi and Guerrini
discard 20 and accept 21 reported cases. Marx questions the majority of
cases on various grounds as, incomplete autopsies, and the presence of other
and possibly primary tumors. Several reported cases were probably leuke-
mic. Rolleston warns against mistaking syphilitic lesions for sarcoma in
infants.

The clinical history of sarcoma fails to show any distinguishing features

672 N EOF LAST 1C DISEASES

from carcinoma (Rolleston). The disease occurs as a congenital or very
early tumor in infants, in children, and also in old age. Its course is usually
very rapid and the symptoms are those of malignant carcinoma. The gross
appearance of the organ recalls various forms chiefly of hepatoma, as massive,
multiple, hemorrhagic, and necrotic tumors, usually in much enlarged organs.
Rolleston and Trevor collected seven cases in cirrhotic livers.

According to histological structures the sarcomas may be grouped as
angiosarcoma, alveolar sarcoma, spindle- and round-cell sarcoma.

Angiosarcoma is much the most frequent variety (Arnold, v. Kahlden,
De Vecchi, Marx, Nazari). Yet in the descriptions of the cases one finds
the prominence of blood-vessels, the polymorphous granular cells, the giant-
cells, as well as the necrosis and hemorrhage so prominent in atypical car-
cinoma. The structure in Marx' case is exactly duplicated by areas of
L'Esperance's hepatoma. I do not believe, therefore, that the existence of
a true angiosarcoma arising from blood-vessels of the liver has been satis-
factorily demonstrated. The sole direct observation pointing to such an
origin is that of Dominici in a mixed spindle-cell sarcoma and embryonal
hepatoma.

The alveolar sarcomas also fail to commend themselves as true mesoblastic
tumors. Typical cases are those of Theodorow, Holm and de Haan. Rolles-
ton and Trevor mention an alveolar arrangement of polymorphic, round,
polygonal and giant cells, with perithelial structures resembling the angio-
epithelioma of Renon.

Some of the spindle-cell sarcomas seem more probably of mesoblastic
origin, but a pure spindle-cell tumor with uniform structure has yet to be
reported. Ford's tumor in a cirrhotic liver was largely necrotic, but a
metastatic tumor was composed exclusively of spindle-cells. Bramwell and-
Leith mention areas of spindle-cells with long oval nuclei, gelatinous foci,
and multinuclear giant-cells, in a large cystic hemorrhagic tumor replacing
the right lobe. Steinhaus describes eight large, hemorrhagic and necrotic
tumors in a much enlarged liver, the edges of which contained large spindle-
and giant-cells. The condition recalls atypical hepatoma. Some of the
polypoid and spongy spindle-cell tumors of Pepere's collection were probably
mesoblastic. Myxosarcomas in infants are reported by Meissenbach and
Bernhinz.

Primary melanoma of the liver is a very difficult diagnosis to establish.
Rolleston in referring to nine reported cases points out that no case can be
accepted unless the uveal tract has been examined after death. This pre-
caution has usually been omitted. In two cases very small uveal melanomas
were discovered only at autopsy. Marx refers to other reports and accepts
the occurrence of primary melanoma on somewhat uncertain grounds.

CARCINOMA OF GALL-BLADDERi

On account of its clinical interest carcinoma of the gall-bladder has been
very fully studied; by Frerichs (1861); Musser, in 100 cases, 1889; Courvois-
sier, 103 cases, 1890; and Futterer, 268 cases, 1901. A very full analysis
of the disease is given by Rolleston (Lit.).

It forms 5 to 6 per cent, of all carcinomas (Kaufmann), affects women in
the ratio of 4 or 5 to one man, and occurs almost always after 40 years, the
average in both sexes being 58 years. Maxon reported a villous carcinoma
in a child of four years, while Thomas and Noica observed the disease at
90 years. A remarkable etiological relation with cholelithiasis is one of the
most interesting features of this disease. Gall-stones were present in 69 per

EPITHELIAL HYPERPLAS1A AND TUMORS OF LIVER 673

cent, of Musser's cases, 70 per cent, with Futterer, 85 per cent. Zenker,
91 per cent. Courvoisier, 95 per cent. Siegert, and 100 per cent. Janowski.
In some cases gall-stones may have been passed earlier or they may have
been small and overlooked, or the catarrhal inflammation which commonly
leads to gall-stones excites a cellular overgrowth without the mechanical
irritation of the formed stone. The proportion of cases of cholelithiasis
which develop cancer is estimated from 4 to 18 per cent. (Rolleston, Slade).
Candler, finding only two cases of carcinoma in 315 cases of gall-stones among
the insane, argues that hospital statistics show an unduly high proportion.
Yet Slade found microscopical cancer in 10 of 17 (59 per cent.) gall-bladders
with calculi. Since secondary cancers rarely produce gall-stones these
calculi cannot be regarded as the result of the tumor (Siegert).

) Mechanical irritation of calculi, the relation to a peculiar form of lipoid
metabolism (cholesterin), and the irritative and digestive action of bile,
seem to combine in producing the remarkable susceptibility of this mucous
membrane to cancer.

Gross Anatomy. — The chronic inflammation associated with gall-stones
produces either a papillomatous outgrowth or an original downward growth

FIG. 297. — Adenocarcinoma with columnar cells diffused through the wall of the gall-
bladder.

with metaplasia. These initial tendencies or precancerous conditions deter-
mine the later course of the tumor, yielding three main forms: (i) Villous,
papillomatous or fungating, (2) gelatinous, and (3) diffuse, flat, infiltrating
carcinoma.

The disease first appears as a papilloma or as a flat induration, or as an
eroded ulcer. The location is usually at the fundus, or the neck, or at the
cystic duct.

(i) The papillary form grows out into the bladder as a coarse villous or
solid fungating mass which eventually distends and obliterates the bladder

674 N EOF LA STIC DISEASES

and forms a bulky, well-circumscribed tumor (Michaux). Early papillary
tumors are rarely seen but may appear as fragile, villous or warty growths
in a distended cavity. These may grow along the cystic duct into the bile-
ducts or the common duct (Devic, Gallavardin).

Secondary incrustations with bile-salts and tissue detritus may form.
Villous tumors gave rise to hemorrhage in seven of Musser's cases. Most
or all of the bulky tumors appear to originate as papillary adenocarcinomas
which reach considerable size before infiltrating the liver. The thickened
and distended wall of the bladder may become adherent to adjoining tissues.
The gall-stones may be found imbedded in the mass. In advanced stages
the infiltration and adhesions render it difficult to determine the origin and
early type of the tumor.

(2) The gelatinous carcinomas form bulky tumors which infiltrate
the wall and fill the cavity of the bladder and early extend to liver, lymph-
nodes, and peritoneum. After the stomach the gall-bladder is the most
frequent source of gelatinous carcinoma of the peritoneum (Kaufmann).
Yet reports of such cases distinctly traced to the gall-bladder are not numer-
ous. Musser found six.

(3) The infiltrating tumors begin as a submucous growth or as a local-
ized thickening or ulceration in a mucosa which has been the seat of chronic
inflammation. It early infiltrates the wall of the bladder which becomes
universally thickened and contracted. Extensions to the liver and adjoining
lymph-nodes are soon formed and the disease may run its course chiefly as a
secondary hepatic carcinoma. This event is particularly common when the
tumor originates on the hepatic aspect of the bladder-wall.

The majority of infiltrating tumors follow the scirrhus type, converting
the bladder into a hard contracted mass without increase in bulk, or constrict-
ing it in hour-glass form (Rolleston), and fusing the organ to adjacent viscera.

Extensions of the tumor to neighboring tissues are observed in all but
early cases, and metastases are frequent. The tumor is, usually adherent
to the liver, stomach, duodenum or colon, and bound down by adhesions
which inclose tumor-cells and along which further extensions are wont to
travel (Courvoisier). Extension along the walls of the bile-ducts into the
liver has several times been traced (Willigk). In my cases the sheaths of
nerve-trunks have formed a prominent channel of dissemination. Peritoneal
extensions may constrict the cystic or common ducts, the colon, duodenum,
or pylorus. Metastases are usually located in liver, abdominal nodes and
peritoneum. Musser in 100 cases found 55 with secondary tumors, besides
cases with direct extensions to colon, duodenum, and stomach. The liver
was involved in 54, abdominal nodes in 16, lungs or pleura 10, and pancreas
and adrenals occasionally. Mediastinal and supraclavicular nodes may be
extensively enlarged (Beadles, West). Tumors have also been found in ribs,
navel, rectum, uterus, ovary and kidney. Adrenal metastases may give
rise to cutaneous pigmentation suggesting Addison's disease (Warthin).
Fistulous tracts form in much the same manner as with migrating gall-
stones and are especially common when the carcinoma begins in the fundus.
The fistulous openings lead chiefly to the colon, duodenum and stomach,
rarely into the peritoneum or externally (Riedel, Moutier).

Suppuration, lateral sacculation, thrombosis of the portal veins, angio-
cholitis, and peritonitis are frequent complications.

Structure. — Precancerous changes are often pronounced in cases of
cholelithiasis. Janowski mentions the frequency of papillary outgrowths and
disorder of glands, without attributing to them any special significance.
Zenker describes elongation of glands, overgrowth of epithelium, fibrosis of

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 675

submucosa and round-cell infiltration, as preliminaries of cancer. Slade
found a high proportion of microscopical carcinomas in cases of cholelithiasis,
but the details of these lesions are not given. McCarthy in a considerable
series found only three cases of chronic catarrhal cystitis with carcinomatous
changes.

It is probable that the markedly scirrhus character of many cases of early
carcinoma of the gall-bladder results from the chronic productive inflammation
preceding the newgrowth. In some cases there are no precancerous changes
in the mucosa. In an early carcinoma at the neck I found a submucous
nodule as large as a pea lying beneath practically unaltered mucosa and
suggesting an origin from aberrant gland tissue. Other probable modes
of origin are suggested by the rare cases of cholesterin cysts of the mucosa
and of cystic adenomas which may project internally or externally and may
contain cholesterin concretions (Rolleston, Kaufmann).

In a case of cholelithiasis of long standing the enlarged and thickened
gall-bladder I found to present over its eroded mucosa very numerous, flat
or nodular opaque placques, 2 to 5 mm. in diameter. On section these proved
to be foci of cellular connective tissue surrounding groups of atypical glandu-
lar epithelium showing numerous mitoses. Here was evidently the begin-
ning of a carcinoma arising from multiple foci and destined to produce
a diffuse carcinoma of the organ.

The natural course of papilloma appears to be that of the benign growth
or of the rare villous carcinoma. Sand and Mayer, and Chappet, describe
advanced cases without loss of villous type. M. Dominici describes diffuse
papilloma of the entire mucosa without a trace of atypical growth. Pels-
Leusden, however, finds atypical downward as well as outward growth of
epithelium in early papillomas.

Luschka's glands consist of epithelial invaginations of the mucosa which
extend into the muscular layer and often to the serous surface of the gall-
bladder. Aschoff and others find very marked proliferation of these canals
in cholelithiasis, and Pels-Leusden believes that the irritation of cholesterin
granules and bacteria in these crypts is an important source of carcinoma
following gall-stones.

Aside from minor variations the established disease presents two main
structural types: (i) Adenocarcinoma, and (2) alveolar carcinoma.

Adenocarcinoma is the most frequent form and it produces papillary,
gelatinous, and scirrhus tumors. The growths present elongated vascular
papillae of connective tissue covered by cylindrical cells and infiltrated with
secondary alveoli lined by cuboidal cells. Mucous oversecretion and degenera-
tion is a very common feature of all the adenocarcinomas. It may appear
in isolated foci in the papillary and scirrhus growths and become universal
in certain cases which run the course of bulky and widespread gelatinous
carcinoma. They early tend to perforate the wall and extend to the
peritoneum.

In the scirrhus type extensive newgrowth of fibrous tissue surrounds
the isolated adenomatous alveoli in the bladder, but in the lymph-nodes and
liver the cells grow more rapidly and fibrosis is wanting. The extent of the
fibrosis is often remarkable, and only pyloric cancers show such desmoplastic
quality in ordinary adenomatous alveoli.

Alveolar carcinoma presents in the gall-bladder the usual features of this
neoplastic process. The most malignant growths are composed largely of
pseudo-alveoli of small, cuboidal or rounded-cells. Others show many traces
of adenocarcinomatous structure, and the frequent transition of one type

676 NEOPLAST1C DISEASES

into the other indicates that both arise from the same glandular structures
in the mucosa.

Squamous-cell carcinomas, pure or associated with cylindrical cell carci-
noma, are not infrequently observed (Rolleston, Lit.). Deetz reports
several cases in some of which the squamous characters with pearls and spine-
cells were highly developed. In Monckberg's case the two cell types were
intimately mingled in the original tumor but grew in greater isolation in
the lymph-nodes. These tumors probably arise in lesions which have
previously developed a squamous metaplasia. Thus Lubarsch found a
vesical papilloma the size of a bean resembling an acuminate condyloma. Or
they signify a progressive tendency, illustrated in Monckberg's case, toward
squamous metaplasia of the cylindrical cells of an adenocarcinoma.

A primary melanoma of the gall-bladder is described by Wieting and
Hamdi.

Clinical Features. — The symptoms of cancer of the gall-bladder may be
referred to (i) the preexisting cholelithiasis, (2) the local effects of the tumor,
and to (3) extensions and metastases (Rolleston).

Symptoms of gall-stones are absent in the majority of cases (Kehr),
but have preceded the tumor for 25 years (Jourdan). Initial symptoms may
be local pain, dyspepsia, or (50 per cent.) a local tumor. Jaundice suddenly
established and persistent occurs in most cases. Many cases simulate
hepatic carcinoma. Ascites is usually added from thrombosis of large veins
or peritoneal extensions, and the effusion may be chylous. The cachetic
stages are marked by fever from infections, cholemia, hemorrhages and
emaciation. The total duration is extremely variable but after the appear-
ance of jaundice few cases last more than six months.

SARCOMA OF GALL-BLADDER

Considerable uncertainty as well as theoretical interest surround the
interpretation of certain tumors recorded as primary sarcoma of the gall-
bladder (Bayer, Rolleston, Lit.). All of these cases appear to have occurred
in adults who long suffered from gall-stones and usually from suppurative
cholecystitis. The organ was much enlarged, once to the size of man's head
(Bayer), and the cystic central cavity contained fluid. One or many gall-
stones appeared in the cavity or wall. The course of the disease was pro-
longed. It is evident that a long period of chronic inflammation had pre-
ceded any neoplastic process which may have developed by the time the
tumor came under observation. Therefore in the interpretation of these
cases a wide range of productive inflammatory changes must be taken into
account. Iwasaki's very large tumor appears to have been composed largely
of inflammatory tissue, and in the case of Carson and Smith, a localized
large round-cell growth 8 cm. in diameter, the bladder-wall was the seat
of a pronounced productive and exudative inflammation.

It appears, however, that two forms of sarcoma arise on such an inflam-
matory basis, one derived from an overgrowth of smooth muscle-cells, the
other from the inflammatory new-growth of connective tissue and blood-
vessels.

Myosarcoma with the above general characters was described by Land-
steiner. The wall of the much enlarged bladder was 3 cm. in thickness.
There was beginning infiltration of the liver. The tissue was composed of
areas of spindle-cells arranged in parallel bands, and presenting the characters
of smooth muscle. Other areas presented larger rounded atypical cells
apparently derived from the spindle-cells. The liver nodules contained

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER

677

spindle-cells. Other spindle-cell sarcomas are recorded by Griffon and Segall
and Rolleston, and in the latter's case there were metastases in aortic and
inguinal glands. In connection with these cases Sutherland's adenomyoma
is of interest.

Sarcomas of fibroblastic type are of somewhat less definite nature.
Parlavecchio evacuated 2 liters of purulent fluid from a thickened gall-
bladder the wall of which contained sarcomatous tissue with polymorphous
cells.

FIG. 298. — Sarcoma of gall-bladder. (After Carson and Smith, A, S., 62.)

Bayer describes two very large gall-bladders containing many stones,
one 8 cm. in diameter, with fluid detritus. The wall was composed of
sarcomatous tissue containing vascular connective tissue and areas of spindle,
rounded, and giant-cells and epithelial remnants. One of the tumors had
invaded the liver and gave peritoneal nodules. In the other, areas of cartilage
and bone were found. An angiosarcomatous structure was described by
Klingel, the neoplastic nature of which is doubted by Landsteiner. Seibert

%.'*?&&?&. tex/spa

•:• ^r->&3 • fo *?A rt$ . •'-* .l: •' ,<3? *

s^^i^^Ma*

V;^ ^V^/^ ^|g , .- ,\^^. J&$& v

mBBISfeli^^KiB

FIG. 299. — Structure of. tumor in Fig. 298. Sarcoma of gall-bladder.

described a very large cystic and necrotic tumor as a degenerating lympho-
sarcoma. Becker's endothelioma seems of uncertain nature.

CARCINOMA OF THE LARGER BILE-DUCTS

Epithelial tumors of the large bile-ducts present much the same etiolog-
ical, gross anatomical, and microscopical features as carcinoma of the gall-

678 N EOF LA STIC DISEASES

bladder, but their location favors early mechanical obstruction of important
channels, which promptly declares itself in the form of severe jaundice and a
rapidly fatal course of the disease. The fatal effects of such comparatively
miniature and relatively benign tumors render these growths of much
surgical interest.

The chief locations of these tumors are: (i) Ductus choledochus, (2)
ductus cysticus, (3) ductus hepaticus. A common seat of carcinoma is the
point of junction of the three ducts, of which Donati collected 33 cases.
Rolleston finds the following distribution in 90 cases: Common bile-duct,
44, junction of three ducts 27, hepatic duct, 22, cystic duct, 7. Lapointe and
Raymond collected 32 cases in the hepatic duct and 37 at the junction.
Miodowski analyzed 41 cases.

Etiology. — The relative infrequency of gall-stones (22 per cent, in 264
cases) and the predominance of the disease in males (50-35), contrast car-
cinoma of the larger bile-passages with that of the gall-bladder. Possibly the
trauma of migrating calculi may be a factor.

Gross Anatomy. — Chiefly because of the early appearance of mechanical
obstruction carcinoma of the bile-ducts is encountered when the tumor is
small. These early tumors are villous, nodular, or diffuse.

(1) Villous growths may be single, or multiple, and may fill and distend
the duct. Extensions may form while the original tumor remains small
(Lamble, Schmidt).

(2) Nodular masses appear in the submucosa and muscular wall and the
very small size of some of these tumors is notable. They tend early to encircle
and constrict the passage, and may appear merely as a cicatricial stenosis,
the cancerous nature of which can be determined only by the microscope
(Devic, Gallavardin, Lit.).

(3) A more diffuse growth may extend along the duct converting it into a
smooth rigid tube from the inner surface of which project minute carcinoma-
tous vegetations (Jenner, Chapper). Bulky tumors rarely develop from the
bile-ducts.

The extensions are usually limited to the walls of the ducts, but in later
stages adjoining viscera are involved by various channels. In 12 cases of
carcinoma of the hepatic ducts Lecene and Pagniez found the tumor limited
to the ducts. Beginning at one point the growth infiltrates the wall until it
involves a large portion of several ducts or the gall-bladder. Extensions of
papillary tumors through the hepatic ducts may invade .the liver. More
' frequently the liver is invaded through the lymphatics of the duct. In
either case the condition may simulate hepatic carcinoma. Extending to
the pancreas the head of this organ may be infiltrated, simulating pancreatic
carcinoma. Carcinoma of the cystic duct is rarely demonstrated but in
not a few cases the tumor involves both cystic duct and bladder so that its
original source cannot be determined. The gastrohepatic and other nodes
are frequently involved.

The condition of the gall-bladder varies with the location of the tumor.
Carcinoma of the hepatic ducts leads to contraction of the bladder or per-
mits its moderate distension by mucus or calculi. The intrahepatic ducts
may then become the seat of catarrhal, suppurative or gangrenous cholan-
gitis, and the liver parenchyma may undergo focal icteric necrosis (Futterer).
Similar results follow when the tumor is lower down in the common duct.
Tumors involving the junction usually lead to distension of the bladder,
but when the cystic duct is occluded the bladder remains small (Lapointe,
Raymond). Tumors of the common jiuct regularly permit filling and dis-
tention of the gall-bladder.

EPITHELIAL HYPERPLASIA AND TUMORS OF LIVER 679

Courvoisier stated the principle that the gall-bladder is usually distended
with cancer and contracted with calculi of the ductus choledochus. Very
moderate compression is capable of bringing about bile-stasis, so that the
stenosed duct may readily admit a probe or become pervious on manual
compression of the bladder.

The structure of carcinoma of the bile-ducts presents the same types as
in the gall-bladder, differing chiefly in the greater tendency to fibrosis. In
some cases it is remarkable to find such extensive areas of fibrous tissue about
the hilus of the liver or head of the pancreas with so little epithelial tissue,
so that small carcinomas in these regions frequently require microscopical
detection.

The usual structure is that of adenocarcinoma with cylindrical cells and
mucus production. Occasionally the alveoli are small, the lining cells
cuboidal or spherical. Leith describes a colloid carcinoma. Squamous
metaplasia is occasionally observed.

According to their chief clinical features Devic and Gallavardin divide
the cases as follows: (i) Enlargement of the liver with distended gall-
bladder. This form is regularly associated with tumors of the lower segments
(supraduodenal), rarely with tumors of the upper subhepatic segments of
the ducts. (2) The liver varies in size and the gall-bladder is not enlarged,
with most tumors limited to the hepatic ducts. (3) Hypertrophic biliary
cirrhosis may be simulated by tumors in vaiious locations. Persistent
jaundice and local pain are nearly constant. The duration has varied from
3 to 19 months.

Carcinoma of the Ampulla of Vater. — The duct formed by the junction
of the common bile-duct and the pancreatic duct (Wirsung) and opening
into the duodenum at the papilla, is called the ampulla of Vater. Carcinoma
arises in the corrugated mucosa of this structure and at the duodenal papilla.
Cases have been collected by Busson (i) Georges (20), and Rolleston (19),
(Lit.). Except in very early cases it is difficult to determine the exact origin
of these tumors. Some arise at the termination of the common bile-duct,
others in the mucosa of the pancreatic duct, still others in the ampulla proper
or at the papilla. The etiological factors are similar to those of carcinoma of
the bile-ducts.

Gross Anatomy. — The tumors are small villous or papillary growths or
diffuse infiltrations of the wall. McCarthy found the papilla excavated by a
cancerous ulcer. They early cause stenosis of the duct with cholemia.
Aynoud found that 20 per cent, of the cases progress far enough to produce
secondary extensions and metastases, chiefly in the adjacent lymph-nodes.
The structurally benign growths are almost equally effective with the malig-
nant in producing obstruction and the anatomical relations are so intimate
that the mechanical effects are very similar in all the various locations.
The gall-bladder and the bile-ducts from the point of the tumor to the intra-
hepatic radicles are usually dilated. Jaundice, at first intermittent later per-
sistent, is a nearly constant symptom, but is often absent with tumors of the
papilla. Suppurative cholangitis with fever may result especially with
tumors of the papilla. The pancreatic duct becomes widely dilated, usually
without secondary changes in the pancreas (Dieulafoy).

Structure. — Columnar-cell adenocarcinoma is the type almost always
observed. The architecture is villous, fungoid, or infiltrating, without much
variation in structure. Alveoli lined by smaller cubical or rounded-cells
appear in tumors of Wirsung's duct (Letulle), and have been described in a
growth traced to the duodenal mucosa or B runner's glands by Klotz. In a
small villous growth at the termination of Wirsung's duct Carnot and Harvier

680 N EOF LA STIC DISEASES

found all transitions from finely villous papilloma with cylindrical cells to
infiltrating alveolar carcinoma. Tumors of the duodenal papilla arise chiefly
from the duct mucosa and contain columnar cells (Schuller). A highly
pigmented but otherwise typical villous adenocarcinoma of the ampulla
was described by Duval, an observation which speaks strongly in favor of
the local origin of certain melanotic tumors.

The results of surgical treatment of carcinoma of the gall-bladder and
ducts is highly unsatisfactory. In 93 cholecystectomies collected by Quenu
the operative mortality, chiefly from hemorrhage, was 18 per cent, and only
14 of 52 cases were known to be living after one year. Quenu mentions 9
excisions of tumors of the bile-ducts, and Mayo two. The final results were
unfavorable. For carcinoma of the ampulla, Quenu in nine cases found
6 deaths, and Oehler the same proportion. Borelius reports several fatal
operations from Sweden. The early stage of growth at which these tumors
declare themselves encourages surgical interference. L'Esperance, in his
laboratory, has observed just within the papilla a papillary carcinoma, 5 mm.
in diameter, which has caused a single fatal hemorrhage.

CHAPTER XXXIV

TUMORS OF PANCREAS

Adenoma of Pancreas. — Adenomas are very rarely observed in the pan-
creas. Borst states that he has seen nodular hyperplasia of the pancreas
associated with a similar condition in
the liver.

Cystadenomas may be separated
from retention cysts by the abundant
growth of epithelial papillae. Lazarus
describes many stages in the develop-
ment of cystadenomas from dilated
ducts. Edling collected 13 cases from
the literature, which illustrate single
and multiple cystadenomas, lined by
single layers of cubical or cylindrical
cells, or partly or completely filled by
epithelial papillae. Atypical overgrowth
and signs of malignancy appear in some
cases. Kaufmann saw malignant
changes in a portion of a large cysta-
denoma of the cauda, and Sotti's tumor
gave papillary metastases.

Solitary adenomas appear as small
solid tumors well circumscribed from
the parenchyma. Neve's scirrhus ade-
noma measured 2^2 X 2 inches and
constricted the duodenum. Thierfelder
shelled out of the pancreas a small tumor
composed of alveoli of cylindrical cells.
Other cases are reported by Biondi and
Chauffard. All of them appeared to
arise from the ducts. Cesaris-Demel
describes an adenoma which suggested
an origin from the glandular acini.

Adenoma of island tissue has been
described by Nicholls, Helmholtz, and
Cecil. They were single small yellowish
nodules as large as a pea and presented
a structure strongly resembling that of
island tissue. Cecil, in describing such
a structure, traces the transition from
the hypertrophic islands of various con-
ditions and concludes that the small
tumors are more properly to be re-
garded as markedly hypertrophic islands
rather than neoplasms.

Carcinoma of Pancreas. — Cancer of the pancreas has long been a subject
of much clinical interest. It was extensively discussed by Classen in 1842

681

FIG.

300. — Cystadenoma of pancreas.
(After Roman.)

682 N EOF LAST 1C DISEASES

(older Lit.), by Ancelet who analyzed 200 cases in 1860, and by Miraillie
in 1893.

Bard and Pic (1888) emphasized certain features of the disease as con-
stituting a specific syndrome, viz.: distension of the gall-bladder, absence of
hepatic enlargement, jaundice, and rapid cachexia.

General Etiology. — Cancer of the pancreas formed 1.76 per cent, of Kauf-
mann's autopsies on malignant tumors. Of 2943 autopsies on cancer referred
to by Korte there were 59 pancreatic cases, 2 per cent. Bashford collected
1000 cases of primary malignant tumors of the pancreas among 84,000
cancers. Owing to the difficulty of accurate diagnosis the value of miscella-
neous statistics may be doubted. Ollivier has pointed out the necessity of
very careful histological study in order to avoid confusion with cancer of the
duodenum and bile-ducts. The disease occurs between 30 and 50 years
but often in younger subjects. A. Kuhn describes a cylindrical-cell carcinoma
in a cirrhotic pancreas with pulmonary metastases in a child of 2 years and
refers to other cases at an early age. I have observed one case associated
with a large pancreatic cyst.

Many cases occur in cirrhotic organs and a parallel may here be drawn
between the liver and the pancreas since it appears that carcinoma of the
ducts follows periductal fibrosis, carcinoma of the parenchyma appearing
after interstitial fibrosis (Hulst). Only rarely are there preliminary symp-
toms, as in Leriche's case of transient jaundice, pointing to a cholelithiasis
or pancreatic calculus. Lazarus mentions five cases of adenocystoma with
pancreatic calculi. The gall-bladder is usually free of calculi and contains
thick bile and mucus. Reasoning from analogy with the liver, carcinoma of
the pancreatic parenchyma may be regarded as beginning in a functional
hyperplasia following cirrhosis, and carcinoma of the ducts from chronic
irritation and stasis in these canals.

The occurrence of aberrant pancreatic tissue in the duodenal mucosa
and about the head of the pancreas suggests that certain tumors, especially
those involving both duodenal wall and pancreas, may arise from such aber-
rant tissue (Heinrich, Lit.). In some of these accessory glands there is
extensive multiplication of ducts from which a cylindrical-cell tumor might
arise.

Gross Anatomy. — The location of the tumor is usually in the head or
extending diffusely over most of the organ. Tumors limited to the body are
much less common and the tail is rarely affected. Of 386 cases collected from
the literature 158 were diffuse, 156 limited to the head, 28 in body, 12 in tail.
The organ is regularly enlarged, but in scirrhus tumors the gland may be
small but very hard.

While small tumors may be limited to the pancreas (12 of 127 cases,
Segre), more advanced growths early infiltrate the surrounding tissues
and cause compression. The common duct is occluded with bile-stasis, dila-
tation of the bladder, and varicosities of the bile-ducts up to and into the
liver. The pancreatic duct may be distended and tortuous and filled with
mucinous fluid. Lachmann reported rupture of the gall-bladder. Muller
observed displacement of the stomach with hour-glass contraction. The duo-
denum was stenosed in eight scirrhus: cases collected by Hagenbach. Stenosis
of the aorta is reported by Boldt. Portal thrombosis has been recorded in
five cases (Korte). The soft tumors may necrose and perforate the stomach
or the large veins with fatal hemorrhage.

Metastases are very commonly observed and appear first in adjacent
lymph-nodes and liver. Bard and Pic emphasize the occurrence of very
numerous minute nodules in the liver without enlargement of the organ,

TUMORS OF PANCREAS

683

whereas secondary gastric carcinoma causes bulky growths in the liver. Very
numerous nodules may appear over the peritoneum and in the peripancreatic
fat tissue. Extensive invasion of the pancreas and adjoining tissues may be
.complicated by hemorrhages and fat necrosis. General metastases are not
common, probably because the disease is rapidly fatal.

Structure. — Two main types of pancreatic carcinoma are observed,
(i) Cylindrical-cell adenocarcinoma, arising from the ducts, and (2) carci-
noma simplex arising from the parenchyma. The former may rarely show
extensive gelatinous changes, and most cases of the latter are scirrhus (Kauf-
mann, Miraillie).

(i) Carcinoma of the ducts may be associated with proliferation of lining
cells in the outlying regions, which Hulst observed in a case of periductal
fibrosis and interpreted as precancerous. Ollivier also traced his case of

IP
V'

£$

FIG. 301. — Structure of an infiltrating and fibrosing adenocarcinoma of the head of the

pancreas.

cylindrical-cell tumor from such preliminary changes. Muckenbeck, how-
ever, found reason to believe that cylindrical-cell tumors might develop from
the parenchyma.

The tumors are regularly located in the head or corpus and form some-
what massive growths which are imperfectly separated from the parenchyma.
They are firm from fibrosis or contain many small cysts,. or the central mass
is broken down, suggesting an origin from cystadenomas.

The structure is composed of papillary outgrowths and alveoli lined by
cylindrical or cuboidal cells. In atypical areas the cells may lose their
cylindrical form and grow more diffusely. Yet Kulst found the cylindrical
type preserved in secondary tumors of lymph-nodes and liver, and Satti
reports a cystadenoma papilliferum with typical metastases in lymph-nodes,
lungs and peritoneum.

The local extensions of the tumor have been traced by Ollivier through

684

NEOPLASTIC DISEASES

ducts, lymphatics and nerve-trunks. Kaufmann found the large and small
veins invaded but without metastases.

(2) Carcinoma of the parenchyma produces a more diffuse, rapidly
growing tumor which is firm or soft according to the proportion of fibrous
tissue. The cells are small or large, granular, hydropic, or fatty, resem-
bling those of the pancreatic alveoli. The cell borders are often indistinct,
and the vesicular nuclei occupy much of the cell. Nucleoli are poorly
developed. The relatively large size of the nuclei is often a notable feature.
The cells are arranged in small or large alveoli separated by a fine stroma
and in some cases the appearance suggests a simple cirrhosis in an otherwise
unaltered pancreas (Bard, Pic). In the larger alveoli the outer cells may
be cubical. In some cases there is a definite lumen in the cell groups, filled
with coagulum. These spaces may then be lined by high cuboidal or low

FIG. 302. — Structure of a carcinoma of pancreas.

cylindrical cells. Large mononuclear giant-cells may appear in numbers
and persist in metastases.

In more atypical and malignant tumors the cells are smaller and embry-
onal in type and the arrangement may be irregular and diffuse. Such cases
may resemble lymphosarcoma with a faint alveolar tendency. In one of
my cases the original tumor recalled lymphosarcoma while the pulmonary
metastases contained small cuboidal or spindle-cells.

The origin of this tumor has been traced by Ollivier, in an early case, to
the pancreatic alveoli and the transformation of gland-cells into tumor-cells
he has sketched in detail. Usually all early stages of such origin are lost.

The desmoplastic properties of pancreatic carcinoma are somewhat un-
usual and probably account for the large proportion of scirrhus cases. A
preexisting cirrhosis is also a factor. Extensions throughout the pancreas
occur early and travel by ducts, lymphatics, blood-vessels, nerve-trunks,
and alveolar spaces. In one of my cases the organ was diffusely infiltrated and
the seat of very numerous small cysts, dilated ducts containing minute calculi.

TUMORS OF PAXCREAS 685

The parenchyma shows interesting changes. There may be a collateral
or preexisting hyperplasia of the gland tissue which is difficult to distin-
guish from invading carcinoma. The islands of Langerhans are usually hyper-
trophied and may be much increased in number, showing many transitions
from secreting to island tissue. The islands may also exhibit a peculiar
hypertrophy approaching the structure of the tumor. It was apparently
this appearance which led Fabozzi to conclude that all parenchymatous
cancers arise from the islands. This interpretation has been discussed by
Reitmann and Helmholtz. Another feature which might suggest such an
origin consists in focal adenocarcinomatous areas which somewhat resemble
hypertrophic islands. In an invaded lymph-node I found such structures
exclusively represented. These various peculiarities seem to justify the
claim of Bard and Pic that the histology to pancreatic cancer is specific.

The symptoms frequently present the characteristic syndrome of Bard
and Pic, but only when the tumor is located in the head. Progressive jaun-
dice without remissions, great distension of the gall-bladder, absence of
hepatic enlargement, subnormal temperature, and rapid emaciation and
cachexia, form a rather specific group of clinical features observed in the
majority of cases. A palpable tumor is often missing, but was detected in
about one-fourth of MiralhVs 113 cases. The liver may be considerably
enlarged (Mirallie, Eloesser), and the metastases may be bulky (Oser).
When the growth involves only body and cauda, the ampulla of Vater may
remain pervious, the gall-bladder is not distended and jaundice is absent.
Such clinically atypical cases .are described by Pic and Tolot. An unusual
predisposition to hemorrhage is emphasized by Eloesser. Pain is very
constant. The loss of pancreatic fluid and bile leads to acholic and fatty
stools. This condition however, is by no means constant, and occurred
in only 20 cases collected by Mirallie, Oser, and Fitz. Imperfectly digested
bulky stools are described by Oser. Glycosuria is rare. In 30 cases of
carcinoma of pancreas (13 primary). Pearce found intermittent glycosuria
in one, diabetes in another. Persistent glycosuria occurred in 21 cases
collected by Mirallie and Oser.

Sarcoma of Pancreas,— Very few satisfactory reports of pancreatic sar-
coma are available. Schilling collected 24 cases and Kakels 21, most of which
are of uncertain nature, but from these data it appears probable that spin-
dle-cell sarcoma and lymphosarcoma arise in the pancreas.

K. Ehrlich described two large cystic tumors the walls of which were com-
posed, one of spindle-cells, the other of alveoli of rounded, spindle, and giant-
cells which he regarded as of endothelial origin. Each tumor gave local or
visceral metastases. The author concluded that they arose in the walls of
primary cysts. Weil also found spindle and giant-cells in the wall of a
pancreatic cyst. Kakels found a large solid tumor of the tail, composed of
spindle, round, and giant-cells. Some very vascular tumors are reported as
angiosarcomas (Kronlein). Michaelson's case of carcinosarcoma may signify
a participation of the stroma of the gland or metaplastic changes in a carcinoma.

Of lymphosarcomas, L'Huillier found a small tumor in the head of the
pancreas of a newborn infant. It was composed of lymphocytes and giant-
cells. Litten's case occurred in a child of four years and gave intestinal
metastases. Schirokogoroff describes a diffuse tumor-growth in the pancreas
of a man of 54 years, with extensive visceral metastases. The cells wer.e
embryonal in type and of quite uncertain origin. Some of the difficulties in
the diagnosis of pancreatic sarcoma are illustrated in Piccoli's cases, which
differ from most of the reports in being so fully described that several critics
have recognized them as carcinomas (Borrmann, v. Kahlden).

CHAPTER XXXV

MAXILLARY TUMORS OF DENTAL ORIGIN

The dental origin of cer-
tain cystic and dentigerous
tumors of the maxillae has
been recognized for at least
a century, and the struc-
tural details and probable
histogenesis were rather
clearly conceived by several
writers since about 1850
(Barnes, Guzack, Delpech,
Dupuytren, Forget, Nela-
ton). At this time it was
generally supposed that all
the cystic tumors arose
from dilated dental follicles,
and in 1872 Magitot classi-
fied the series upon this
basis, excluding certain
cysts which he thought to
develop between the perios-
teum and the tooth. In
several solid tumors also
some authors detected epi-
thelial structures which
they interpreted as deriva-
tives of the enamel organ
(Robin, Wedl). The odon-
tomas were systematically
classified by Broca in 1868.
The entire subject was
greatly simplified in 1885
by the classic study of Ma-
lassez, who referred most of
the tumors1, to embryonal
remnants of the enamel
organ.

Debris epitheliaux par-
adentaires. — Under this
term Malassez (1885) de-
scribed numerous cell
groups which he found in
the fetus scattered along
the borders of the teeth
from apex to crown. They
are divisible into three
groups: (i) Superficial cells
lying just beneath the gin-

686

MAXILLARY TUMORS OF DENTAL ORIGIN

687

gival epithelium; (2) intermediate, lying along the sides of the tooth; and (3)
deep, connected with the enamel organ. The structure of the cells varies
considerably. Some are round and of indifferent character and are found
in all three situations. The superficial groups also include round-cells en-
circled by cylindrical, and canals lined by one layer of cylindrical cells.
About the enamel organ lie groups of cells, which show transitions between
cylindrical enameloblasts, round-cells, and stellate cells. Many of these
groups he was able to show, persist in the adult. Malassez interpreted the
cell groups, not as accidental offshoots or misplacements of the enamel organ,
but as analogues of the very rich dental apparatus of some lower vertebrates
and as giving rise to the supernumerary teeth of the so-called third denti-
tions. They are derived from the invaginations of gingival epithelium
which go to form the enamel organs.

W:^M

:,««*

l^i IS? i *W

& **

FIG. 304. — Section of inferior maxilla of fetus of five months, showing epithelial cell groups
beneath gum. (After Malassez.)

These observations of Malassez have formed the basis of our knowl-
edge of many inflammatory and neoplastic processes connected with the
teeth. About inflamed and carious teeth the cells multiply, hypertrophy,
wander out into the tissues, become infiltrated with leukocytes and partici-
pate in the expulsion of the teeth in pyorrhea alveolaris. They are concerned
with various fibrous or myxomatoid outgrowths attached to the borders of
the teeth (fungosites radiculo-dentaires). Dilatation of the lumina of these
vestigial alveoli gives rise to various simple cysts found in contact with or in
the neighborhood of the roots. In many epulides atrophic or proliferating
groups of epithelial cells are found which are derived from the original
paradental structures. The numerous cysts of the maxillae with single or
multiple chambers and containing walls or cavities and imperfect or well-
formed teeth, appear to be derived from these paradental structures and from
the specialized mesodermal elements over which the enamel organ exerts a
formative control. In the various forms of odontoma enameloblasts and
enamel are usually more or less prominent, and these elements Malassez

688

N EOF LA STIC DISEASES

derives from the paradental structures. Finally in the entire group of cystic

and solid, malignant, epithelial growths
arising in the maxillae, the sole source is to
be found in the paradental epithelium.

The views of Malassez regarding the
importance of the paradental structures
have received general acceptance. Galippe
has recently reviewed the entire subject,
tracing in greater detail the natural history
of the paradental structures and illustrat-
ing by selected cases their pathological
relations.

It still remains uncertain to what ex-
tent the dental follicle itself is concerned
in the formation of dentiferous and denti-
gerous cysts. Many believe that the com-
plex odontomas and dentiferous cysts arise
from original or supernumerary dental
follicles and Malassez and Galippe admit
such an origin for certain cases. It is
reasonable to suppose that there are all
transitions between simple groups of para-
dental epithelium and true supernumerary
enamel organs and that the structure and
contents of maxillary cysts will vary ac-
cordingly. In the very complex processes
located in the maxillae in connection with
the formation of two sets of teeth abundant
opportunity is presented for abnormal
overgrowths of several structures in various
stages of evolution. It is, therefore, un-
likely that any single embryonal event
such as gives rise to the ordinary para-
dental debris is responsible for all the very
numerous clinical forms which these abnor-
malities present.

Adamantinoma. — Tumors of this group
arise from the paradental epithelial debris.
They are solid or cystic growths located
within the alveolar borders, excavating a
cavity within the maxilla, distending the
tissues until they become surrounded by a
thin parchment-like bony capsule which
crepitates on pressure. Eventually the
capsule may rupture and the disease ex-
tends further by continuity into antrum,
orbit, or other tissues and cavities. The
cystic tumors may reach a large size,
Bryck's tumor weighing 1.5 kg. I found

FlG 305.— Groups of superfluous at autopsy a solid tumor of the^upper jaw

as large as a child's head, projecting ex-
ternally, into the nasopharynx with dys-
phagia, and into the orbit with extreme
exophthalmos.

\
K\

epithelial cells found in five successive
sections of the alveolar dental ligament
of an adult man. (After Malassez.)

MAXILLARY TUMORS OF DEXTAL ORIGIN

689

FIG. 306. — Adamantinoma of inferior maxilla.

FIG. 307. — Relations of a cystic adamantinoma of inferior maxilla. (After Fritsch.)

690

NEOPLASTIC DISEASES

The cystic tumors are unilocular or multilocular and the small cystic
ramifications may penetrate extensively into the cancellous tissue (Beneke).
The cysts contain serous fluid or mucous or inspissated fatty and scaly
material. Calcine particles, probably remnants of imperfect enamel, maybe
mingled with the fluid. The cavity may be smooth-walled or lined by pap-
illary projections of epithelium. In the cyst wall one finds cellular or fibrous
connective tissue, calcified areas, or masses of bone or cementum. Cellular
overgrowth may give the structure of spindle-cell or myxosarcoma (Albar-
ran), and it is probable that by exaggeration of this process apparently pure
sarcomas may arise. Bilateral cystic tumors were observed by Flaubert.

The tumors composed of small cysts are often traversed by fibrous tra-
becula which constitute the bulk of the tumor. In such a case Chibret found

FIG. 308. — Glandular adamantinoma.

A! any small cysts lined by columnar enamelo-
blasts.

areas of well-formed enamel lying on shallow beds of dentine. Smaller
deposits of enamel were observed by Bernays and by others.

The solid tumors present every gradation from the small cystic variety.
As a rule they are more cellular and malignant. On section they usually pre-
sent a papillary appearance and many fine cysts may be detected. Or by over-
growth of the stroma they may appear firm, solid, and sarcomatous. Some
of the solid tumors from their early stages project from the alveolar border as
a form of epulis, and when the vessels are overabundant their gross appearance
may closely resemble that of a vascular epulis of sarcomatous type. The
ordinary epulis, however, fails to distend the ramus of the jaw.

That all these tumors are essentially of one nature is indicated by the

MAXILLARY TUMORS OF DEXTAL ORIGIN 691

numerous intermediate forms described in the literature and by the occasional
transformation of unilocular into multilocular, cystic or solid tumors, in
recurring cases (Guibout, d' Amiens, Malassez).

Structure. — The epithelial cells of adamantinoma exhibit all variations in
form between stratified squamous epithelium and specialized adult enamelo-
blasts, thus recalling the changes traversed in the normal development of
the enamel organ.

Superficial adamantinomas of the alveolar border present many of the
characters of acanthoma, but the central cells in the epithelial columns usu-
ally exhibit the peculiar reticulated structure of the central portion of the
enamel organ. In some cases there is a direct connection between the gin-
gival epithelium and the deeper groups of characteristic reticulated enamelo-
blasts, so that Buchteman and Eve assumed that such tumors arise fromHhe
gingivallming. Malassez is probably correct in referring these appearances to

FIG. 309. — Structure of adamantinoma resembling epidermoid carcinoma.

secondary union by upward growth of the tumor, or to supernumerary invag-
inations of epithelium, but it is sometimes difficult to distinguish between
primary acanthoma of the gum and squamous-cell adamantinoma. Galippe
holds that the adult gingival epithelium has lost all capacity to differentiate
toward enameloblasts and that the squamous-cells of superficial tumors arise
from the superficial debris paradentaire, which may be regarded as the
atrophic duct of the enamel gland.

The epulis of adamantinoma presents a fibrous or mucoid or giant-cell,
sarcomatous stroma, supporting cords and groups of epithelium of the enamel
type. The cells vary as usual from squamous-cell to columnar and vesicular
forms and the origin of the squamous-cells presents the same problems as in
the case of other superficial tumors of the gums. In various cases described
by Malassez, Heath, and Eve, the features of adamantinoma were prominent.
Haasler finds that the common epulis is usually connected with a granuloma
of the dental root.

The solid intramaxillary or projecting tumors present a variable structure,
the cells exhibiting many gradations from enameloblasts to squamous epithe-

692

NEOPLASTIC DISEASES

Hum. Three main types of structure may be recognized: (i) Acanthoma; (2)
plexiform epithelioma; (3) glandular adamantinoma (L'Esperance). Malas-
sez's classification included squamous, cylindrical, and carcinomatous cell
types. All the growths are locally aggressive and fall in the general class of
carcinoma. The glandular tumors are adenocarcinomas. Some tumors pre-
sent chiefly one structure, others show sharp and extreme variations in the cell
type, and the arrangement of the cells is very diverse. Acanthoma presents
anastomosing cords of squamous epithelium in which are spine cells and many
pearls, but the characters of the enamel organ appear in isolated foci of large
vesicular cells.

Plexiform epithelioma presents broad convoluted columns of epithelium
without marked squamous character, lying in dense or cellular connective
tissue. Many small cystic tumors present this structure.

FIG. 310. — Adamantinoma. Large cell groups composed of very small epithelial cells
surrounded by compact columnar enameloblasts.

Glandular adamantinoma (adenocarcinoma) covers a variety of structures
in which the columnar enameloblasts predominate. The tumors may be
composed exclusively of such cells arranged in long columns or alveoli. Or
the columnar cells may inclose islands of reticulated cells. Or numerous
pearls may be surrounded by reticulated cells with a border of columnar
enameloblasts. Considerable areas of spindle cells may simulate sarcoma.
Such spindle cells may be extremely small, suggesting round-cell sarcoma,
but a limiting border of columnar cells usually indicates the embryonal epi-
thelial character of such areas. Extensive metaplasia and extreme anaplasia
may be observed in recurring tumors. During a period of four years in
five recurrences of an original plexiform and squamous epithelioma I observed
a continuous loss of specific characters, the tumor eventually spreading widely
as a large round-cell perivascular growth without a trace of its epithelial
origin.

MAXILLARY TUMORS OF DEXTAL ORIGIN 693

Secretory products appear in the form of mucous droplets in the cells or as
small cysts with mucous, fatty, or calcine elements. Deposits of well-formed
enamel lying on beds of dentine have been observed.

The stroma may be very dense and hyaline as in the gubernaculum
dentis, or cellular, myxomatous or sarcomatous. In the stroma of some ada-
mantinomas one may find an exact reproduction of the structure of the giant-
cell epulis. Portions of cementum or bone may appear in the capsule. The
blood-vessels may be overdeveloped. In one large tumor projecting from the
alveolar border the vessels became thrombosed and the stroma was every-
where infiltrated with blood.

FIG. 311. — Glandular adamantinoma. Sheets of spindle-shaped epithelial cells surrounded

by columnar enameloblasts.

Clinical Features. — The tumors occur chiefly in adults but have been
observed as early as the sixth year (Coate), and many occur from 60 to 70
years (Bornig). The duration of the process is usually prolonged, 18
years in Kruse's case, 23 years in one of Malassez's, 26 years in Bryk's, and 38
years in Albarran's. A history of extraction of a carious tooth usually
precedes by some years the appearance of the tumor. Hence the age of onset
is earlier than would appear in many reports and probably begins shortly
after the full development of the teeth. Women are more often affected than
men. The lower jaw is the chief seat of cystic tumors (Pincus), while the
upper yields most of the solid and more malignant growths.

The course of adamantinoma varies extremely with the type and location
of the tumor. All the cysts and tumors are of slow development and their
natural history is prolonged. The superficial growths and small cysts may be

694

NEOPLASTIC DISEASES

readily extirpated, but the deep-lying multilocular cysts recur persistently and
often require the sacrifice of the maxilla. Tumors of the upper jaw are much
the more serious, and the solid adamantinomas of all types recur locally and
invade antrum, orbit, and nasopharynx. In spite of their relatively benign
structure the prognosis in this group is unfavorable. Yet the lymph-nodes
are almost never involved, except by malignant recurrences. In one very
extensive nbro-epithelial tumor I found metastases in one cervical node and a
small nodule in the lung. In another very malignant case the fourth recur-
rence was in the cervical nodes and loose tissues of the neck and probably in
the lungs.

Adamantinoma of Tibia. — B. Fischer describes a tumor involving the outer
portions of the shaft of the tibia, with mucoid stroma and many cell groups

FIG. 312. — Atypical structure of adamantinoma in late recurrence.

presenting the typical structures of adamantinoma. In the origin of this
tumor he assumes a downward growth of embryonal ectoderm reaching the
bone and differentiating as enamel organ, just as the gingival epithelium
penetrates the maxilla.

Radiculodental Cysts. — The roots of carious or normal teeth frequently
exhibit small excrescences composed of cellular connective tissue in which lie
strands and groups of epithelial cells. Malassez showed that these struc-
tures are derived from the deeper debris paradentaire, portions of which he
finds closely applied to the apex of the root and even extending into the pulp
canal.

Small radiculodental cysts frequently develop by proliferation of these
epithelial structures and dilatation of the lumina which they surround. Sup-
puration may destroy or alter the epithelial lining of such cysts and the lesion
appears as a small abscess. Larger radiculodental cysts of this same origin

MAXILLARY TUMORS OF DENTAL ORIGIX

695

have been described by several authors (Sirantoine). They inclose a portion
or the whole of the root and may reach the size of a robin's egg, or hen's egg,
with considerable absorption of bone. Galippe shows how similar cysts may
develop without directly exposing the root. The lining of these cysts is of
squamous epithelium, so that they have sometimes been regarded as of der-
moid nature. Yet occasionally the lining is partly or wholly of columnar cells
which indicates their paradental origin. Witzel holds that these cysts arise
from dilatation of v. Brunn's sheath, which is the continuation of the enamel
epithelium over the root of the tooth. Malassez includes this atrophic
sheath with the " debris paradentaire." The walls of the cysts may be very
cellular or sarcoma tous and the contents are serous, mucous, fatty, or caseous
and inspissated (Galippe, Mickulicz).

FIG. 313. — Topography of a radiculodental cyst. (After Malassez.} i. 2, Connec-
tive tissue of wall. 3, 4, 5, Cellular connective tissue of inner layer of cyst, infiltrated with
lymphocytes. 6, 7, Epithelial lining of cyst. 8, Cyst cavity.

Multiple cysts of this character were found by Wilks, five separate cavi-
ties surrounding the roots of as many teeth in a child of 1 2 years. Or a single
cyst may surround several roots (Gosselin). The cyst may lie at some
distance from the root (Vitalis), or project through the absorbed ramus of the
jaw externally (Ancelot, Sourier), or into the maxillary sinuses (Berger).
The radiculodental cysts are much more frequent in the upper than in the
lower jaw (76 to 29, Witzel).

Coronodental Cysts. Dentigerous Cysts.— All the dental anomalies thus
far considered relate to already erupted teeth. The remaining cysts and
tumors affect the tooth before its eruption and usually prevent its full
development.

696 N EOF LA STIC DISEASES

Coronodental cysts present small intra-alveolar cavities into which project
one or more imperfectly formed teeth. The wall is fibrous and the lining is
composed of squamous or cylindrical epithelium or both types. The tooth is
usually misplaced, lying horizontally, a position which prevents its eruption.
The root is imperfectly formed owing to fibrosis of the pulp, the cementum
may be hypertrophied, and the dentine may be eroded (Albarran). Heath
observed a cyst in each maxillary sinus, one containing a canine, the other a
molar, while in another case the tooth lay loose in the cyst cavity. Legouest
found two teeth in the same cyst, and Broca saw three. Bayer identified a
milk canine and a permanent canine, indicating the fusion of two original
cysts. Nelaton found one well-formed tooth projecting into the cavity and
numerous rudimentary teeth in the wall. Grosse saw 8 well-formed teeth
in the same cyst in the middle of the upper jaw. These two cases indicate
that the hypertrophic dilated enamel organ is still capable of inciting the for-
mation of nearly complete teeth. In several cases the tooth was completely
inclosed in the cyst wall, or in a secondary cyst in the wall (Nelaton, Remy-
Duret). Haasler describes cases in which separate cysts seem to have formed
about crown and root. Finally Allgayer found a small solid fibrous tumor
involving four teeth and containing groups of epithelium. This tumor prob-
ably originated in the gubernaculum of one or more teeth but without the
usual formation of cysts.

The origin of these coronodental cysts is referred by Galippe to the
stimulus exerted upon the debris paradentaires of the gubernaculum by an
imperfectly formed tooth which becomes arrested in the course of its eruption.
Fibrosis of the gubernaculum, opposing the eruption of the tooth, with dilata-
tion of the paradental alveoli extending to the original enamel organ, would
also account for most of the relations observed. Others regard them as true
follicular cysts arising by hypertrophy and dilatation of the enamel organ
(M. B. Schmidt).

Dentigerous Cysts and Odontoma.- — In this group of anomalies are
included cysts and solid tumors caused by an increase in number of more or
less well-formed teeth. The most striking illustration of dental overgrowth
is seen in the rare case of third dentition described by F. J. Hunter.

The extensive hypertrophy of a single tooth is described by Virchow,
Wedl, and Billroth.

A unique case of remarkable multiplication of teeth is described by
Hildebrandt. In a boy of nine years whose erupted teeth were normal in num-
ber but misplaced, both upper and lower jaws were swollen and contained 150
to 200 teeth lying singly or variously fused, most of them being well-formed.
After two thorough extirpations the condition recurred and again about the
same number of new teeth were removed, leaving a thin shell of bone. In
this case it is clear that there had been an enormous over-production of dental
follicles and that the dentigerous cells remaining after the first two operations
were capable of reproducing well-formed teeth. In the curetted tissues
Hildebrand found many rudimentary teeth, enamel organs, and tubules
resembling the debris paradentaires. Somewhat similar cases are recorded
by Coleman, Bland Sutton, and Matthias.

Dentigerous cysts appear in several forms. Supernumerary teeth are
sometimes inclosed in a cyst formed probably from the dilated gubernaculum
or follicle, containing one or more well-formed teeth, and serous or mucinous
fluid. They lie in the alveolar ramus or at considerable distances, especially
below the orbit.

In many cases the tooth is very imperfectly formed or appears in rudi-
ments only, but these rudiments are multiple. Thus Annandale found a

MAXILLARY TUMORS OF DENTAL ORIGIN 697

large cyst with bony and fibrous wall in which were areas of enamel. Broca
described a cyst containing three irregular masses chiefly composed of
dentine, and fused in a mass of tissue containing islands of dentine, imperfect
enamel, and pulp tissues. Broca cites a very similar case in which a large
central mass of dentine, with several roots and crowns, was covered with
enamel.

Odontoma. — The typical odontoma is composed of a congeries of more or
less perfectly formed teeth usually surrounded by an epithelial membrane
and fibrous capsule. Since there are many grades of development of the
teeth and these may incompletely fill the inclosing cysts, there is no sharp
dividing line between dentigerous cysts and odontomas. The coronodenta
cysts are also closely related to odontoma, since they present one or more
imperfect tooth crowns in a roomy cavity. In Chibret's case the dentigerous
cyst contained irregular masses of dentine and enamel. When the enamel
and dentine exhibit an orderly arrangement and pulp tissue and canals
appear, the tumor becomes a true odontoma.

Localized hypertrophies of portions of the teeth are also conditions
related to odontoma. Enamel pearls are small nodules of enamel which
form along the borders of the teeth as a result of overactivity of a group of

FIG. 314. — Composite odontoma. (After Gilmer, J. A. M. A., 56.)

enameloblasts. The verrucous crowns of Satler consist of overgrowth of
enamel which may at times reach considerable dimensions. These over-
growths may consist of both dentine and enamel and may even contain a
diverticulum of the pulp canal, producing a form radicular odontoma.

The typical odontoma occurs chiefly in young subjects and almost
invariably in the lower jaw. Lloyd's mixed odontoma occurred in the upper
jaw. It forms a solid tumor in the maxilla and is sharply separated from
the adjacent bone by an inclosing cyst-wall. There is usually an absence
of one or more teeth, usually wisdom teeth, whose eruption is obstructed
or whose structure is included in the tumor. Incision may evacuate serous
fluid or pus from the cavity in which the tumor lies. Looking into "this
cavity may often be found the crown of an obstructed tooth which, after
removal of the tumor, may assume its normal position in the alveolar border
(Krogius). On gross section the tumor is composed of fused teeth in which
enamel, dentine, and pulp tissue reproduce the form of the teeth which lie
in disorderly arrangement. The surface is nodular from the projecting
ends of the teeth. Well-formed teeth may not be discernible and the tumor

698 NEOPLASTIC DISEASES

may be composed of irregular masses of dentine, enamel, and pulp canals, all
covered by a layer of enamel (Forget). Enamel may be missing and the
tumor be composed of masses of dentine and bone (Uskoff). Or enamel is
reduced to traces and the tumor composed of dentine and cementum
(Krogius). Such tumors may be designated as amorphous odontomas.

A complex cystic odontoma is described by Robin. It contained three
well-formed molars in adjoining cysts, two rudimentary teeth rooted in bone,
and projecting into small cysts, and three small pedunculated fibromas.

Tapie describes a cyst in the angle of lower jaw, of five years' standing.
A thick fetid sebaceous discharge drained from two sinuses. The wisdom
tooth on that side was missing. A molar crown projected into the cyst, its
root embedded in the wall which presented also a large number of small
conical teeth and calcareous points. Free in the cyst lay a composite
odontoma with several teeth fused by cementum. The cyst was lined by
stratified epithelium. Tapie interpreted the case as an invagination of
dentigerous gingival mucosa. Galippe thinks the cyst arose from paradental
debris and that the odontoma arising outside penetrated the wall.

Soft Odontomas. — In some cases the odontoma is composed chiefly
of connective tissue in which lie many rudimentary teeth (Perthes, Partich).
In Schlossmann's case, in a boy of ten years, the last molar and wisdom teeth
were missing from the lower jaw which presented a tumor 3.5—3.2 cm.,
composed of firm connective tissue in which lay many small hard structures
as large as a pea or bean. The structure presented numerous well-formed
enamel organs about which were layers of dentine in various stages of develop-
ment. Enamel was found only where dentine came in contact with the
enamel organs. There were no traces of dental papillae. Regressive changes
affected the older teeth in the center of the tumor, where vessels were invading
the enamel organ at the expense of the active cells. The authors concluded
that the tumor arose from the follicles of both missing teeth, which became
displaced and disturbed in growth by neighboring teeth in the confined
region of the angle of the jaw.

General Etiology. — Odontoma almost always appears before the age of
25 years, or before the full development of the teeth has been reached. In
this period also most dentigerous cysts are observed, while adamantinoma
as a rule appears in later life. Odontoma affects almost exclusively the
lower jaw, adamantinoma frequently the upper. This contrast suggests
a somewhat different mode of origin for the two groups. The second or the
first molar is frequently missing with odontoma, indicating that the tumor
arises from the structures which normally give origin to the tooth. The
factors which initiate the abnormal growth are at present undetermined.
Trauma has been only a rare antecedent. Schlossmann traces the origin to
misplacement of a dental follicle during the early period of growth, which
is especially favored in the confined quarters of the angle of the lower jaw.
The extensive variations in the composition and relations of odontoma,
as illustrated in the preceding cases, renders quite difficult the task of tracing
its origin.

Broca recognized four periods in the development of the tooth: (a)
embryoplastic, before the appearance of definite dental structures, (b)
odontoplastic, (c) coronal, and (d) radicular, and he divided odontomas
accordingly. He assumed that all the tumors arose from dental follicles,
the formative process residing chiefly in the pulp tissue. By multiplication
of pulps several teeth might form as in the composite odontoma. But the
structure of our tumors does not always correspond to this direct plan,

MAXILLARY TUMORS OF DENTAL ORIGIN 699

which is not fully in accord with the development of the teeth (Wedl). A
purely anatomical classification was used by Sutton, who recognized
cementomas, dentomas, osteodentomas, and mixed dentomas. Yet cemen-
tum is probably only a secondary product added to stationary odontomas
(Schlossman). Malassez and Galippe refer the majority of odontomas to
proliferation of the " debris paradentaries," but it is difficult to adjust all the
types of these tumors as well as of adamantinoma, to this single source.

Several modes of origin seem to be involved in the different forms of
odontoma and of the closely related dentigerous cysts. The absence of a
normal tooth indicates that the odontoma arises in the follicle of this missing
organ and the growth of several well-formed teeth in its place indicates
that all the structures, especially the pulp, are concerned in the tumor process.
Many of these tumors lie in a cyst or are surrounded by a wall in which
are proliferating islands of enameloblasts, showing that this structure also
participates in the process. The varying proportions of enamel, dentine
and pulp tissue point directly to overgrowth of particular elements but not
to distinctly different modes of origin.

Where all the normal teeth are present a supernumerary follicle first pre-
sents itself as the most probable source of the tumor.

A congeries of imperfectly developed teeth, as in Schlossmann's case, sug-
gests an extensive multiplication of enamel organs and dental pulps, which are
as readily derived from a single original follicle as from multiple foci of para-
dental debris. Hildebrand's case shows that practically all the follicles of
both jaws may be incited to this form of organ multiplication. It is difficult
to conceive of such orderly but active growth from embryonal paradental
debris.

Cystic dilatation of the original enamel organ in the follicle adequately
explains the dentigerous cyst with a single tooth, and multiplication of pulps
may be assumed where multiple teeth are observed. Since the enamel organ
almost completely surrounds the developing tooth (v. Brunn), the inclosure
of many odontomas in an epithelial cyst is readily understood.

Cementum is added to many odontomas after the limit of growth has
been reached. The extensive overgrowth of bone, sometimes observed, must
be referred to the periosteum, and it seems probable that some nearly pure
maxillary osteomas may arise under these conditions.

This conception would therefore limit the domain of the debris paraden-
taires to the adamantinomas and the cystic tumors lined by epithelium and
containing only irregular rudiments of dental structures, while the cysts with
multiple well-formed teeth and the various odontomas may be referred to the
enamel organ and the pulp tissue.

Tumors of Maxillary and Nasal Sinuses (Antrum of Highmore). — The
nasal passages and their accessory sinuses are the seat of a series of tumors,
benign and malignant, which form one of the most important departments of
rhinology. The complex embryology of this region gives abundant opportu-
nity for the origin of tumors from developmental anomalies, while the peculiar
anatomy of the part gives unusual chances for the growth of tumors as a result
of inflammatory processes. The frequency of these tumors is considerable.
At the Memorial Hospital during the years 1916-17, out of 1892 cases of cancer
of all types admitted, 48 (2.53 per cent.) were in this region, and of these 35
involved the maxillary sinus.

From the diagnostic standpoint it will be serviceable to review the tumors
occurring in this region:

700 N EOF LA STIC DISEASES

Nares. Polyps. Mucous, myxomatous, fibromatous, angiomatous. I

Choanal angioma, angiomyxoma. Myxosarcoma.
Mucosa. Schneiderian adenoma, carcinoma.

Lymphosarcoma. Melanoma.
Antrum. Mucosa. Cysts. (Empyema) Mucoid. Cystic myxoma. Fibroma.

Epithelial papilloma. Carcinoma.

Bones. Osteoma. Fibro-osteoma. Osteosarcoma. Chondroma.

Teeth. Dental cysts. Odontoma. Adamantinoma.

Ethmoidal sinuses. Fibroma. Osteoma. Carcinoma.

Sphenoidal sinus. Polypoid myxoma.

Frontal sinuses. Osteoma. Carcinoma.

Pharyngeal vault. Angiosarcoma. Chondroma. Chondrosarcoma.

Hypophyseal duct. Epidermoid carcinoma. Adamantinoma. Dermoids.

Epignathi. Teratoma.

Any one of this formidable array of neoplasms may present itself as a
mass obstructing the nares, with or without purulent or bloody discharge, and
requiring for its successful treatment an accurate identification. Of the
above list the benign tumors have been briefly discussed elsewhere, but the
epithelial tumors of the nasal mucosa and maxillary sinus present many spe-
cial features which may be considered at this point.

Cysts of Antrum. — Chronic empyema of the antrum may become confined
by closure of the orifices, the inner wall may yield to pressure giving a pro-
truding tumor of the nasal passage, while the contents may become inspis-
sated and cheesy. The bony wall may undergo absorption or necrosis while
the lining may be transformed into squamous epithelium. Chronic inflam-
mation and edema of the mucosa may lead to filling of the cavity with myxo-
ma-like tissue which has often lead to difficulty in diagnosis from the material
excavated from the antrum. In many cases but by no means in all a chronic
empyema has preceded carcinoma or papilloma of the antrum. Certain
osteomas of the antrum have been described as containing one or more cysts.
They were probably of dental origin. Polypoid fibroma or myxoma fre-
quently develops from the orifice or the fundus of the antrum. Those arising
from the fundus fill and may considerably distend the antrum, but many pro-
trude through the orifice by elongated pedicles and appear as ordinary nasal
polyps. They are usually firmly attached to the periosteum and may require
opening the antrum for complete eradication. In fact some rhinologists
recommend opening the antrum for all antral polyps (Moore).

Epithelial papilloma occasionally arises in the antrum. It has consider-
able growth capacity, recurring after operation and until the base is removed.
I have observed a case in which the papilloma recurred after many operations
over a period of ten years and eventually became carcinomatous.

Carcinoma of Antrum. — There are two separate sources of malignant epi-
thelial tumors of the antrum: (i) from the mucosa, and (2) from epithelial
dental structures, tumors of which may first appear in the antral cavity.
In each of these classes there is a considerable variety of structure and many
peculiarities in course.

From the mucosa arise:

(1) Papillary carcinomas, some of which represent malignant transforma-
tions of papillomas, as above described. These are originally of slow growth
but eventually become fully malignant.

(2) Carcinomas of the basal-cell type arise within the antrum and also
from the nasal mucosa. They are composed of anastomosing cords of small
cells consisting chiefly of nuclei. The stroma is scanty and undergoes hyaline
or mucoid degeneration so that the structure resembles thyroid gland, or the
mucous masses are more abundant and the tumor is reported as adenoid cystic
epithelioma, or cylindroma. Endothelioma is also a favorite designation of

MAXILLARY TUMORS OF DENTAL ORIGIN 701

these tumors. They are of relatively slow growth, but recur presistently
after incomplete removal, and they may invade the bone and eventually the
lymph-nodes.

(3) Squamous-cell carcinoma is rarely seen in the antrum except as a
secondary invasion, but either from metaplasia or through origin from pre-
viously altered lining epithelium this type of growth may arise. It pur-
sues the usual course of acanthoma.

(4) Cylindrical-cell carcinoma is a common form of antrum cancer. It
forms a bulky rapidly growing tumor which distends the cavity, protrudes

FIG. 315. — Carcinoma of antrum, probably arising from the mucosa, and showing many

globules of mucus.

into the nares, erodes bone, ulcerates and bleeds, and usually extends widely
with recurrence after operation. The structure is adenocarcinomatous, or
the cells grow in large sheets and in polyhedral form. This same structure is
seen in tumors arising from the maxillary sinus, the ethmoid cells, the frontal
sinuses, and the Schneiderian membrane. Wisotski has collected three cases
of frontal sinus carcinoma, and one acanthoma.

(5) Round-cell carcinomas of atypical structure composed chiefly of
rounded or polyhedral cells consisting chiefly of nuclei, arise in the nasal
passages and accessory sinuses. They probably form the majority of the
socalled sarcomas of this region. On account of the absence of alveolar
structure and definite epithelial characters, the true origin is easily over-
looked, while many reporters of cases have assumed that the highly malignant
course indicates a sarcomatous nature. The diffuse growth of undifferenti-

702 N EOF LA STIC DISEASES

ated cells is facilitated by the recurrence after incomplete operation to which
most of these tumors are subjected, but if the primary structure of the original
tumor is secured or the tissue in recurrences is carefully prepared and exam-
ined, the epithelial character is sufficiently revealed. The conditions of origin
and the course of these tumors are those of carcinoma, and the existence of a
mesoblastic tumor of this type has not been demonstrated. Lymphosar-
coma occurs in the nares as a part of a more general disease, but I have seen
one case of lymphosarcoma in which the main lesions requiring attention
were nasal and laryngeal.

Melanoma of the nares is a very rare tumor, of which I have studied one
example, reported by Coley, in which the pigmentation was prominent and
the structure carcinomatous.

(6) Dental tumors not infrequently develop in the antrum. They
include radiculodental cysts, dentigerous cysts, and squamous and glandular
types of adamantinoma (#.&.). They can usually be recognized on their
peculiar structure and also by the occurrence of disorder in the adjacent
teeth early in the course of the disease. Yet the antral growth may be well
advanced before the teeth are disturbed, so that this group of dental tumors
is of relatively unfavorable prognosis.

(7) True sarcomas of the riares and antrum are chiefly angiosarcomas
and myxosarcomas arising from the mucosa. Many authors describe
fibrosarcomas without reference to their exact nature (Richou). Osteogenic
sarcomas of this region are comparatively rare and are easily recognized
by their structure. From the choana and vault of pharynx arises the
chondromyxosarcoma of infants and children.

Clinical Course of Malignant Tumors of Antrum.- — Since the prognosis
of established malignant tumors of this region is extremely unfavorable
almost the only real service the physician can render in these cases is the
early recognition of the disease. At the Memorial Hospital it is found that
most of these patients have passed the period of hopeful therapeutics, un-
noticed, or with nasal douches, or extraction of teeth.

Richou separates the initial symptoms into two groups, in one of which
the disease is preceded or accompanied by purulent or bloody discharge
from the nares, while in the other no such signs are observed but the tumor
is discovered only after it has reached such a size as to produce pressure
symptoms. It is important to note that many cases are long regarded as
pyorrhea, toothache, neuralgia, or simple sinusitis, only to reveal them-
selves later as malignant tumors. Occasionally the histological report on
a benign process removed from the outskirts of a malignant tumor has
obscured the true condition (Richou). Thus the thorough exploration of
every suspicious case seems to be indicated as soon as possible. The condi-
tion of the antrum should be determined by an #-ray photograph.

Among the conditions simulating the early stages of malignant tumors
Jacques and Gaudier mention disorders in the development of the teeth,
misplaced molars and wisdom teeth with cysts arising therefrom, simple
osteitis and periostitis, mucocele of the antrum, empyema of antrum, and
forms of syphilis and tuberculosis.

Three stages in the course of malignant tumors are emphasized by
Jacques and Gaudier. In the stage of latency, the presence of a tumor
may be suspected from aching or neuralgic pain in the jaw, purulent dis-
charge, epistaxis, polypoid growths about the orifice of the sinus, and in
the case of dental tumors loosening of the teeth. In the stage of deformation
of the maxilla, there is a swelling of the walls of the sinus, projecting exter-
nally, or into the nares, or into the orbit, together with more definite symptoms

MAXILLARY TUMORS OF DENTAL ORIGIN 703

of the earlier stage. In the stage of invasion there is destruction of the
walls and adjacent structures, hemorrhage, ulceration, and extension to
skin, pharynx, orbit, skull, or lymph-nodes. The general duration of the
disease is from four months to two years, and is closely related to the degree of
histological differentiation of the tumor-cells. Recovery from the squamous-
cell or true carcinomas is very rare.

The lymph-nodes were invaded in 19 of 64 cases reported by Windmuller,
and in 19 of 51 cases of Winiwarter. On the whole this invasion occurs
rather late and infrequently, considering the activity of the process. The
nodes chiefly affected are those behind the angle of the jaw and above the
expansion of the aponeurosis of the sternomastoid (Sebileau). The lym-
phatics of the superior maxillary region tend to pass posteriorly, join with
those from the nasal mucosa and vault of pharynx and descend along the
deep cervical chain. I have observed bulky pulmonary and hepatic metas-
tases in two cases of antral and Schneiderian carcinoma in which no invasion
of lymph-nodes could be discovered.

The best results in the treatment of carcinoma in this region are secured
by early operation combined with or preceded by radium. The English
rhinologists especially seem to have developed considerable reliance on this
latter agent.

CHAPTER XXXVI
EPITHELIAL TUMORS OF THE SALIVARY GLANDS

Three groups of epithelial tumors are observed in the salivary glands:

(1) Benign Adenoma,

(2) Malignant Adenocarcinoma or Carcinoma, and

(3) Autochthonous Mixed Tumors.

The parotid is by far the most frequently involved, but all the above
growths occur in the submaxillary, the sublingual is occasionally affected,
while mixed tumors of the salivary gland type are also found in the lip,
cheek, palate, nares, and pharynx. The lachrymal gland may also be
included with the salivary organs in the study of its tumors.

Adenoma. — Adenoma of the salivary glands is rare. In the parotid,
Nasse describes four cases and others are reported by Lecene, Lexer, Ribbert,
and Wood. In the submaxillary, Chevassu analyzed five reported adenomas,
concluding that two were cases of chronic inflammation (Duplay, Poncet),
one a cystic dilatation of the ducts (Bougie), one a carcinoma (Wolfler),
and one a papillary cystic adenoma (Talazac).

Sublingual adenomas are described by Duplay, Zeisel, Ferreri, and
Kuttner. Of 132 tumors of the lachrymal glands Warthin found 13 de-
scribed as adenomas. In these cases the tumors have exhibited very slow
growth, the duration in Nasse's cases being from 8 to 12 years. They are
encapsulated, cystic or solid, and well-incorporated in the gland or attached
to it. In the gross the tumors are lobulated by traversing septa, or composed
of solid gland tissue, or of many minute cysts or of one large cyst. The
structure is alveolar, reproducing the acini of the glands, or cystic and
papillary. The stroma is of moderate development and all traces of mucoid
or cartilaginous deposits are missing. In the cysts there may be much
mucous or serous, secretion. Transitions to malignant adenocarcinoma are
observed (Chevassu), and Nasse describes in upper lip and nose combinations
of adenoma with basal-cell carcinoma. Several authors have described
transitions to myxochondrocarcinoma.

Carcinoma. — Pure malignant epithelial tumors of the salivary glands are
by no means rare. Most of the parotid carcinomas are reported in studies
of the mixed tumors, and appear in the series of Paris theses (Paller, Lit.),
and in the collections of Volkmann, Ehrich, Chevassu, and others. Pure
carcinomas without any trace of the features of mixed tumors are described
in the parotid by Pailler, Ehrich, and Nasse, in the submaxillary by
Prengrueber, Waldeyer, Volkmann, Kuttner, Lowenbach, Nasse and
Chevassu. Warthin collected six carcinomas of the lachrymal gland. Most
of the malignant tumors of this organ are of the basal-cell type. I have
studied three pure carcinomas of the parotid. It is evident that many of
the pure endothelial tumors described by Volkmann and others are of
glandular epithelial origin, but being chiefly of the basal-cell type they are
included with the mixed tumors.

Whatever may be their relation to the mixed tumors, pure carcinomas of
the salivary glands are highly characteristic both clinically and histologically.

The carcinomas usually develop rapidly and while at first they may

704

EPITHELIAL TUMORS OF THE SALIVARY GLAXDS

705

be encapsulated they soon invade the whole gland, the capsule, and regional
nodes. The more adenomatous tumors may contain cysts, while the more
malignant growths are solid, firm and opaque and in many cases lobulated.
After extirpation prompt recurrence is usually observed, even when the
structure suggests an adenomatous nature (Chevassu). In advanced cases
there are local and general metastases, and in Nassers case many bones
were involved. The clinical malignancy of these tumors is therefore pro-
nounced. In Prengrueber's case the growth was accompanied by continuous
salivation. In some cases there is a history of a quiescent growth of long
standing which eventually became active, indicating a change from a benign
to a malignant structure. I have observed carcinoma developing on a
granuloma of three years' duration in the submaxillary gland.

Structurally there are two main varieties, adenocarcinoma and alveolar
carcinoma. To these must probably be added a third group of diffusely

FIG. 316. — Structure of an adenocarcinoma of submaxillary gland.

growing tumors of spindle or rounded cells which are atypical carcinomas
(Chevassu).

The adenocarcinomas are alveolar or papillary. The former develop
from the acini and the latter from the ducts. The alveolar growths reproduce
more or less exactly the acini of the gland. The lumina and the cells may
contain hyaline, mucous, or serous secreuon. Chevassu describes a dendritic
adenocarcinoma arising in the ducts, in which very numerous papillae were
lined by multiple layers of cubical or cylindrical cells. This tumor promptly
recurred after operation and grew rapidly.

Under the term cylindroma has been described a rather frequent form of
adenocarcinoma of the salivary glands (Lowenbach, Lit.). These tumors
are composed of anastomosing cords or broad masses of epithelial cells,
inclosing many spaces filled with mucus. There are coarse trabeculae of
connective tissue which may undergo hyaline or mucoid degeneration. The
structure suggests a relation to basal-cell carcinoma of the type of adenoid
cystic epithelioma, but Lowenbach was able to trace the origin in one case
to the ducts and in another to the acini of the gland.

706 NEOPLASTIC DISEASES

The fully developed carcinomas of the salivary glands usually exhibit
traces of the acinar structure of the adenocarcinomas, but the most anaplastic
tumors grow in broad, cellular masses or diffusely, while some highly atypical
growths take the form of so-called round-cell sarcoma. Three structural
peculiarities suggesting an origin from the salivary glands are often present,
in three structural varieties of these tumors.

(a) Marked squamous metaplasia, affecting very many small groups of
cells, appears in carcinomas composed of anastomosing columns of opaque
granular, cubical, or cylindrical epithelium. These features suggest an origin
from the ducts in which squamous epithelium may result from inflammatory
changes.

(b) Peculiar large mucoid globules may distend many cells in small alveo-
lar carcinomas, yielding a structure which is quite specific.

Round-cell Carcinoma. — Malignant round-cell tumors of the salivary
glands have been described as round-cell sarcomas by Kuster, Nasse, Koch,
Degen, and Schridde (Lit.). Kuttner collected six cases of round-cell sar-
coma of the submaxillary. Some of the tumors presented a distinctly alveo-
lar structure, while most others exhibited nests of polyhedral cells strongly
resembling epithelium. Schafer found well-marked epithelial characters in
portions of a tumor chiefly "sarcomatous." Schridde describes among the
round-cells remnants of gland tissue in markedly hypertrophic condition,
which he interprets as collateral hyperplasia. As the tumors were large
and rapidly growing, none of the authors was able to trace the origin of the
growth. In some cases there was pronounced perithelial arrangement such
as is often seen in the mixed tumors (Dubreuil, Volkmann). All of these
features are much more satisfactorily explained as belonging to atypical
rapidly growing carcinomas. Chevassu argues strongly in favor of this
view. Lymphosarcoma originating in the reticulum cells of the lymph-
follicles is not infrequently seen in the salivary glands, as in Mikulicz's
disease, and may be difficult to distinguish from round-cell carcinoma,
but apart from these lymphoid tumors sarcoma of the salivary glands has
not been satisfactorily demonstrated.

Mixed Tumors of Salivary Glands, etc.— In the salivary glands, buccal
mucosa, palate, lips, neck, orbit, and lachrymal gland and face, occurs a group
of tumors about the origin of which has long been maintained an active con-
troversy. These tumors are of complex structure, usually presenting epithe-
lial elements in the form of cell strands, alveoli, or diffuse masses, and meso-
blastic tissues chiefly cartilage, mucous tissue, and cellular connective. Any
one of these elements may predominate, giving nearly pure chondromas, sar-
comas, or carcinomas, but usually all the cell types are represented.

These tumors were originally regarded as carcinomas, and while Virchow derived the
cartilage from the connective tissue by metaplasia, Cohnheim regarded it as a derivative of
remnants of the branchial arches. The epithelial nature of the tumors was undisputed
until C. Kaufmann, on the strength of peritheliomatous and sarcomatous features, placed
them among the sarcomas.

In 1879 Wartmann maintained that the polyhedral cells were derived from the lymphatic
endothelium, and from this time the endothelial theory gained general acceptance in Ger-
many, especially through the study of Volkmann. Although the main conclusion of this
author has been proven untenable, his study was of much value in revealing the extent to
which embryonal epithelial cells may simulate endothelium, and his view that the meso-
blastic structures in the tumors are derived by metaplasia from embryonal connective
tissue still remains a matter of discussion.

In France the endothelial theory failed to receive much attention, and Collet in 1896,
Pitance (1900), and many later writers adhered consistently to the epithelial interpretation.

EPITHELIAL TUMORS OF THE SALIVARY GLAXDS 707

The first definite attack on Yolkmann's theory was made by Hinsberg (1899) with
Ribbert's support. He strongly maintained the cancerous nature of the tumors, demon-
strating that the pearls observed in many cases by himself and previously by Nasse, Volk-
mann, Mauclaire, Cavazzani and others, exhibited spines, and disposing of many histo-
logical arguments which had been used in favor of the endothelial theory. By embryo-
logical studies he endeavored to show that the tumors are derived from very early invagina-
tions of buccal epithelium and inclusion of mesoblastic tissue connected with the mandible
arches. He found islands of salivary gland tissue included within the periosteum of the
maxilla, and concluded that the mixed tumors arise from the isolation of a mass of tissue
including both salivary gland and periosteal tissue. His conclusions have been accepted
with certain reservations by Wilms and Landsteiner, and represent one of the prevailing
opinions at the present day. In America they have been endorsed especially by Wood and
Verhoef. Yet Borst and Kaufmann will not abandon the possibility that some of the
tumors are of endothelial origin, although they do not specify their distinctive features.
Recently Steinhaus and Martini espouse the endothelial theory but with arguments which
appear to the writer inadequate.

The arguments favoring the endothelial theory relate chiefly to the morphology of the
cells and their relation to surrounding structures. The cells are small, often polyhedral,
and under pressure readily assume a flat or spindle form. They are often very intimately
adherent to the supporting connective tissue and may give the appearance of merging with
that tissue in a manner rarely observed in carcinoma. It has repeatedly been pointed out
that the cells may be continuous with those lining lymph-spaces and capillaries. In certain
cases diffuse masses of these cells reproduce a structure closely resembling spindle-cell
sarcoma, and in the various forms of cylindroma and perithelioma structures appear which
have commonly been recognized as sarcomatous.

Especially the relation of the tumor-cells to the growing masses of hyaline, mucinous,
or cartilaginous material suggests their mesoblastic nature. The early tumors may be
sharply separated from the gland structures, and many observers have been unable to find
any signs of derivation of the tumor-cells from gland-cells. Finally, in no other situation
do any tumors of known epithelial origin exhibit such peculiar relations to mesoblastic
tumor elements, whereas in known forms of endothelioma, sprouting of capillary endothe-
lium, persistence of lumina, pearl formation, phagocytosis of blood-pigment, intimate
relation or fusion with the stroma, and ultimate transformation into hyaline connective
tissue, are observed.

While the above arguments appeared at one time as conclusive, they must to-day be
regarded as inadequate or even superficial. The cells show no minute characters which
permit their identification as endothelium. Instead of a clear cytoplasm, condensed cell
border, and small nuclei writh indistinct nucleoli, their cytoplasm is granular, the borders
ill-defined and the nucleoli often prominent. The long strands of cells resembling sprout-
ing vessels are reproduced in carcinoma, as is also the intimate contact of cells with sup-
porting stroma. In the pearls many have found spines and fibrils connecting the cells, thus
furnishing the strongest evidence of their squamous epithelial nature. The structures
identified as lymph-spaces may equally well represent lumina of gland alveoli. In fact
this latter origin has been clearly demonstrated in some cases, whereas the existence cf
many dilated lymph-spaces in these tumors has not been satisfactorily proven. The
alveoli often contain secretion similar to that found in the atrophic salivary gland alveolus.
Many of the tumors are encapsulated and do not involve the normal lobules of the gland so
that the opportunity to trace the fate of gland-cells when included in the tumor is rarely
given. Yet this encapsulation is often incomplete. Krompecher, Pailler, Ehrich, and
others have clearly traced the derivation of the flat-cells lining narrow spaces from the
glandular epithelium. I have studied cases in which normal gland alveoli were being in-
closed in hyaline material on the edge of the advancing process. Here the epithelial cells
became transformed into flat-cells exactly resembling those lining supposed lymph-vessels,
and giving the appearance of sprouting capillaries. The structure of cylindroma or peri-
thelioma does not indicate an endothelial tumor, since this structure is often produced by
carcinoma. The mixed epidermal and mesodermal origin is rendered acceptable by
embryological studies, and it is in accordance with this view that nearly pure chondromas
or carcinomas may occur when one element becomes predominant. It is only in the
intermediate group of cases where both elements are commingled that the question of
endothelioma arises.

Hence it seems necessary to abandon the theory of the endothelial origin
of the common tumors of the salivary glands. If, as Borst, Kaufmann and
others assume, true endotheliomas occur in these organs their specific char-
acters remain to be pointed out.

With the demonstration of the epithelial nature of the tumors the subject
of their histogenesis is by no means completed.

708 X EOF LA STIC DISEASES

In a series of studies Krompecher reaches the conclusion that the mixed
tumors of the salivary glands and many other regions belong in the class
of basal-cell carcinoma, and especially in the subgroup of adenoid cystic
epithelioma. In the soft pliable stroma of these growths he finds that the
epithelial cells readily split off, fibrillate, and assume the spindle or star-shape
of mucoid or embryonal connective tissue-cells. Under these conditions he
finds that true connective tissues, and by further metaplasia cartilage, may
be derived from basal epithelium. Hence, Krompecher interprets the sali-
vary growths as of purely epithelial origin, with peculiar mucoid and car-
tilaginous metaplasia. Concerning the exact source of the originating epithe-
lium he does not specifically state whether the cells are embryonal and mis-
placed, or located in the salivary ducts. For many of the tumors of salivary

\
ft

7*'.' €f*> --K ^ '?>•'' V'

v/; ^s |\-4p « - .-.- v " I -..»*

FIG. 317. — Mixed tumor of parotid gland. Showing transformation of epithelium into

spindle-cells.

glands and mucous membranes Krompecher's interpretation must, I think,
be accepted. Especially the encapsulated growths consisting of anastomos-
ing cords of small cubical or spindle-cells with hyaline stroma and cartilag-
inous areas, this mode of development appears to be followed. Both the
structure and the clinical course of these tumors are identical with those of
adenoid cystic epithelioma of the skin. Misplaced portions of buccal or
branchial epithelium or superfluous duct-cells may well serve as origins of
such tumors.

Not all of the tumors, however, may be disposed of in this manner. A
large portion of them, covering a wide variety of structures, are probably
derived from the ducts and acini of the salivary and mucous glands. The evi-
dence in favor of this view is well presented by Ehrich, and is duplicated in

EPITHELIAL TUMORS OF THE SALIVARY GLAXDS

709

much of my own material. He finds that many tumors are not encapsu-
lated but uniformly fuse with the gland and reproduce hypertrophic lobules
of the gland bounded by regular septa. In several cases the tumors have
been multiple, indicating that the process originated in several lobules of the
gland (Ehrich, Nasse, Krieg).

In these tumor lobules neoplastic ducts and acini multiply and break up,
and the cells become disseminated in the soft mucoid stroma. Cartilage
appears chiefly in the centers of such lobules where the metaplastic process is
oldest and most advanced. The cartilage cells are derivatives of the epithe-
lium. The part played by the original stroma is subordinate, although in
fibrous areas elastic fibers mav be derived from the stroma and blood-vessels.

8982%

FIG. 318. — Structure of a portion of a mixed tumor of parotid gland, showing transition

of cell types.

Yet genuine collagen and elastic fibrils develop in the mucoid material under
the influence of the modified epithelium. The mucoid material is a secretion
from the epithelial cells and its diffusion prepares the way for the dissemina-
tion of modified glandular and pavement epithelium. Squamous metaplasia
occurs readily in the proliferating cells of both ducts and acini, as in pure
carcinomas.

According to this view many of the salivary tumors are pure adenocarci-
nomas with peculiar and exceptional metaplasia, and not requiring any peri-
osteal or other mesoblastic derivative in their cells of origin. However
violently this interpretation may conflict with long-established views regard-
ing tissue growth, it appears to be necessary to accept the facts so well attested
by the close study of these tumors. To a considerable extent Krompecher's
studies have rendered the exclusive epithelial origin more acceptable. It is not
necessary to assume that similar violations of the ordinary laws of histogene-
sis occur in other tumors, since the salivary gland tumors, under the influence
of mucus production and ptyalin secretion, appear to form an exceptional
class. Yet a very similar inclusion of epithelial cells in cartilage may some-

710

NEOPLASTIC DISEASES

times be traced in chondrocarcinoma of the dog's breast. That the duct-
cells possess a notable capacity for multiplication and squamous metaplasia
is shown in the results of ligation of the ducts or partial extirpation reported
by Ribbert, Broussis, and Carraro. Lowenstein describes notable hyperplasia
of acini occurring in areas infiltrated by lymphocytes in chronic inflammation
of the salivary glands and he finds in this altered groundwork the cause of the
proliferation which leads to tumor growth.

While the above theory satisfactorily explains the mode of growth
of the established tumor it is less convincing in regard to the exact cells of
origin of the beginning growth. Some very small encapsulated tumors do not

'* i!.

FIG. 319. — Dissemination of epithelial cells in mucinous stroma of a mixed tumor of

parotid.

exhibit any relations to the ducts or acini of the gland. The basal cell type
of growth is also less clearly connected with the normal gland structures than
is the adenomatous. The theory of branchial origin seems to cover this
deficiency and deserves careful consideration. The grounds of this theory
have been stated by Hinsberg, Cuneo and Veau, Chevassu, and others, and
attacked by Forgue, Vialleton and Massabuau. Chevassu has shown that
branchial cysts may contain pharyngeal epithelium and salivary glands, which
furnish a satisfactory origin for some of the salivary tumors. An inclusion of
fragments of the aural cartilages is strongly suggested for certain tumors
which early involve the ear. Weisshaupt thinks that the tumors which are
sharply separated from the gland tissue probably arise from an embryonal
diverticulum of the parotid duct, which regularly exists in man.

EPITHELIAL TUMORS OF THE SALIVARY GLAXDS

711

The position of some tumors, attached to rather than lying within the
gland, is readily explained by the branchial theory. The occurrence of much
striated muscle tissue in a mixed parotid tumor, described by Prudden, shows
that an extensive local malformation was
concerned in its origin. The epithelial
structures in this tumor were, however,
quite peculiar. Of similar significance is
a congenital tumor of the usual type as-
sociated with an accessory tragus and
auricular fistula, described by Wood. On
the other hand the wide distribution of the
tumors in lips, cheek and palate, is not
easily adjusted to an exclusive branchial
origin, but suggests rather that the con-
ditions of their origin are fully provided
in salivary and mucous glands.

The view expressed by Forgue and
Massabuau that the tumors are true em-
bryomas is without adequate foundation.
Teratomas of the neck are reported by
Weyl, Poult, (Lit.), McGregor and Work-
man, Ficheaux, and others, but these
tumors were quite different from the
common mixed growths.

The present status of our knowledge of
the origin of mixed tumors of the salivary
glands may be summarized as follows:

(1) The endothelial origin has been
disproven.

(2) No single source of the mixed tumors meets all the requirements.
Some are distinctly adenomatous and probably arise from the acini and ducts

FIG. 320. — Early encapsulated mixed
tumor of parotid.

FIG. 321. — Parotid tumor with congenital malformations of ear and face (accessory tragus
and auricular fissure.) (After Wood.)

of the gland in which they are well incorporated. Others are encapsulated
or extraglandular and take the form of basal-cell or adenoid cystic epithe-
lioma. These probably arise from misplaced and occasionally embryonal

712 NEOPLASTIC DISEASES

portions of gland tissue. Branchial remnants may possibly be connected
with this group.

(3) The derivation of mucous tissue and cartilage from gland epithelium
has been satisfactorily proven and there is no necessity of including in the
originating tissue any cartilaginous structures.

General Etiology. — Epithelial mixed tumors of the salivary glands are
comparatively common, and when all the subvarieties occurring about
the pharynx and face are included they become quite numerous. The litera-
ture contains many reports each covering from 30 to 60 cases.

They occur at all ages, Pailler observing one case in a girl at n months,
and another at 73 years. Wood reports a rapidly growing mixed parotid
tumor at 7 months and Wagner a mixed sublingual growth in an infant
of 12 weeks. While thus frequently observed in younger subjects, the major-
ity occur between 20 and 40 years. Of 50 submaxillary tumors Chevassu
found 14 occurring between 10 and 19 years and 14 between 20 and 29 years.
In several cases a quiescent or slowly growing tumor had existed from birth.
Both sides and both sexes are about equally affected. According to Bohme
and Kuttner the parotid furnishes about 90 per cent, of the tumors, the sub-
maxillary 10 per cent., and the sublingual i per cent., but this proportion of
parotid growths is probably too high. Most tumors in the floor of the mouth
are probably derived from aberrant portions of the' submaxillary (Ehrich).
In the lachrymal gland War thin collected 13 cases reported as adenoma and
five as carcinoma. Verhoef records five mixed tumors of the lachrymal gland.
If one includes all the deep orbital tumors of basal-cell and mixed types, this
group at once becomes numerous.

In the cheek and lips characteristic basal-cell or mixed tumors are de-
scribed by Wood, Semponoff, Krompecher, Lenormant, and Collet, in the
buccal mucosa and vault of palate, byLaraberie and Bergem: in the antrum
of Highmore by Marchand and Gutekunst: in the nares by Dembrowski:
in the tonsil and alveolar border by Krompecher. Few of these miscellaneous
tumors duplicate the complex structure of the salivary growths. Most of
them are more simple and fall in the group of adenoid cystic epithelioma or
cylindroma.

Clinical Course. — In the great majority of cases a quiescent tumor has long
preceded the development of an active growth. Very often the quiescent
nodule was observed for eight to ten years, Pailler reporting an inactive period
of 37 years and Wood 53 years. Trauma rarely appears as a possible factor.
Once established active growth proceeds slowly but varies with the histolog-
ical type. The average duration of operative cases is about eight years. A
limitless growth is by no means a necessary attribute. Thus in Martland's
case, after two years' active growth, the tumor remained stationary for 13
years, the patient dying from phthisis. This fact has a bearing on the
therapeutic results of radium, which is of much value in this group of tumors,
as well as on the wisdom of surgical removal which is often followed by recur-
rences of increasing malignancy. On the other hand, some old tumors be-
coming active soon infiltrate the capsule and gland and even invade the
lymph-nodes in a few months (Wood, Case IV). There are some indica-
tions that the addition of malignant properties may come from some sec-
ondary neoplastic process established in the adjoining gland, or by perforation
of the tumor capsule. There are thus very wide variations in the clinical be-
havior of the tumors. Occasionally the growth is steadily progressive from
the first. After surgical interference encapsulated growths do not as a rule
recur, but others are very prone to return at once or after an average in-
terval of two and one-half years (Ehrich) or as late as nine years. In

EPITHELIAL TUMORS OF THE SALIVARY GLAXDS 713

Wood's 37 cases there is a record of 17 recurrences, 45 per cent.; while 12
cases were checked by a secondary operation, and 20 (55 per cent.) were per-
manently cured. Successive recurrences with many operations have extended
over a period of 20 years (Wood) and 23 years (Billroth). In the recurrent
tumors the structure may remain constant, but more often it becomes in-
creasingly cellular, atypical, and malignant.

Undisturbed tumors rarely invade the lymph-nodes, but after unsuccess-
ful operation, while the recurrences are usually local, the cervical nodes may
be progressively involved. In the case of Barozzi and Lesne both cervical
and tracheal nodes were invaded by an epithelioma with mucous stroma. I
have observed soft cartilage in the supraclavicular nodes. In the case of
Griffini and Trombetta a chondrocarcinoma invaded cervical and bronchial
nodes, lung and pleura, with carcinoma in the nodes and cartilage in lung

FIG. 322. — Mixed tumor of parotid apparently involving the entire gland.

and pleura. Very cellular growths tending toward the carcinomatous or
so-called sarcomatous types may generalize. Wide local extensions and
displacement of surrounding structures marked the natural history of a pro-
longed case of adenomyxoma of parotid, which I studied at autopsy. The
growth occluded the pharynx, eroded the superior maxilla and orbit, caused
extreme exophthalmos, and displaced the inferior maxilla, after ten years'
duration in a girl of 20 years.

Gross Anatomy. — Beginning as a small firm nodule in or upon the
salivary gland, the tumor usually grows within a capsule until it reaches
considerable size. Fusion with the septa of the gland is commonly observed
and in lobulated tumors the dividing trabeculae seem to be continuous
with the interlobular septa. While small tumors may be completely separ-
able, larger growths show increasing fusion and some are fully incorporated
with the gland from the first. It is usually impossible to excise the tumor

714 N EOF LAST 1C DISEASES

without including fragments of the gland. Nasse, Ehrich, and Krieg found
multiple early tumors in the same gland. The location of the tumors is not
always in obvious connection with any gland. They may first appear in the
retropharyngeal region or in any part of the lateral wall of the pharynx or
floor of the mouth. Some develop along Steno's duct, others appear below
or behind the ear and seem to involve the aural cartilages, while a few
are found well below the submaxillary. The consistence is usually very
firm or hard, but cellular and mucoid growths may be soft and elastic.
Small cysts are frequently seen and rarely the tumor consists of one large
cyst. Cross-section reveals opaque cellular areas which may be vascular,
softened gelatinous masses exuding mucus or serum, hard fibrous or hyaline
zones, or areas of cartilage and rarely of bone. Few of the tumors are free
from the evidences of mucus secretion. Predominance of one element may
give nearly pure myxoma, chondroma, fibroma, carcinoma or sarcoma.

Structure.- — While the majority of the tumors are of rather uniform type,
the variety of structures to be included in this group is very great. Although
the entire series is connected by transitional cases a serviceable classification
may be given as follows:

(1) Myxochondrocarcinoma.

(2) Basal-cell carcinoma with hyaline stroma.

(3) Adenoid cystic epithelioma.

(i) Myxochondrocarcinoma. — The majority of the tumors present broad
areas or narrow zones of epithelial cells which surround and fade into masses
of mucoid, connective or cartilaginous tissue. The epithelium shows all
gradations from adenomatous alveoli derived from the glandular acini
and duct, to solid masses or narrow strands of small flattened compact
epithelium of basal type. The transformation of gland structures into
tumor-tissue can at times be fully traced and has been described in great
detail by Pailler, Ehrich, and others. As previously stated these appearances
represent the mode of extension rather than the necessary mode of origin
of the tumor. Small alveoli lined by cubical cells and filled with dense
acidophile secretion are frequently seen, and these tubules often become
flattened so as to resemble lymph-spaces lined by endothelium. It is con-
ceivable that such flattened tubules may actually fuse with capillary
endothelium, as claimed by Hansemann. The mucoid tissue is in variable
quantity and usually most abundant in the central portions of lobules walled
by epithelium. Its source is chiefly from the dissemination of epithelium
into the swollen interacinar and interlobular stroma which has been infiltrated
by mucous secretion of the epithelium. Into the composition of this tissue
all preexisting fibroblasts and endothelium are entitled to enter, but ap-
pearances indicate that the epithelium plays the predominant part. The
fully formed cartilage cells must be regarded as derivatives of the epithelium.
In the fibrous or mucinous matrix many collagen and elastic fibers may
form, but it is difficult to trace their origin. Many foci of lymphocytes or
areas of diffuse lymphoid tissue may be found in the stroma. Collections
of fat-cells are rather frequently included in the tumor, but fail to show
neoplastic growth.

Squamous-cells appear in many tumors, and exhibit fibrillation, inter-
cellular bridges, pearl formation, and keratohyalin granules. They were
found in 14 of Ehrich's 26 cases. Glandular acini may predominate and
several authors have found chondro-adenoma in one portion, with pure
adenoma in other parts of the same tumor. In slowly growing tumors the
epithelium may almost entirely disappear leaving nearly pure myxoma or
chondroma. Peritheliomatous structures may be found in the original

EPITHELIAL TUMORS OF THE SALIVARY GLANDS 715

tumor or develop in recurrences, and it is probable that many angiosarcomas
of the salivary glands develop in this way, since some myxocarcinomas are
vascular.

Yet v. Haberer has described a large hemangioma simplex of the parotid, and more
cellular or slightly sarcomatous growths of this type are reported by Hartmann, Herxheimer
and others. In true angiosarcomas of the salivary glands there is an obvious circulation of
blood through the tumor units. Lymphangiomas of the parotid or submaxillary, usually
congenital and once symmetrical, have been described by Lannelongue and Achard, Robin-
son, Fuhr, and Hagenbach, but they suggest no relation to the atypical mixed tumors.

In recurrences the original structure may be retained, but the secondary
growth is often more cellular and malignant. Thus spindle-cell, round-cell
and perithelial sarcomas have been observed after extirpation of chondro-

FIG. 323. — Adenocarcinoma of parotid infiltrating sternomastoid muscle.

carcinoma, and it seems probable that most of the so-called sarcomas of the
salivary glands are atypical epithelial growths (Menetrier, Chevassu, Wood).
Rarely these large cell sarcomas are pigmented, but they lack the malignancy
of true melanoma. The more cellular structures of the original tumor may
exclusively appear in the recurrence. Forster reports a tumor contain-
ing mucoid tissue and cartilage in one area, and sarcomatous tissue in an-
other, the latter alone appearing in the recurrence. In several cases only car-
cinomatous portions of the original tumor appeared in the recurrence (Land-
steiner, Volkmann, Case XVII). In some cases the recurrence probably
represents the development of a new tumor in the remaining portions of
the gland.

(2) Basal-cell carcinoma with hyaline stroma is the type observed in
many small early tumors, it forms the bulk of a minority of the larger growths,

716 3EOPLASTIC DISEASES

and it appears frequently in tumors outside the salivary glands. This
structure may be uniform throughout, or associated with chondrocarcinoma
or adenoid cystic structures, but squamous changes are rarely added.

The cells are small, cubical or spindle, darkly staining, with hyper-
chromatic nuclei, and arranged in narrow anastomosing cords, or thin
flattened strands. They are often intimately fused with the hyaline stroma
and appear to inclose spaces like the endothelium of lymph-spaces
(Krompecher, /. c., Figs. 12, 13, 16). The hyaline stroma appears in narrow
strands or large cords or rings inclosing the cells, and is quite variable in
bulk.

(3) Adenoid cystic epithelioma observes the same distribution as the
other basal-cell types. It usually presents a specific structure which has
long been passed as cylindroma. Throughout broad coherent masses of
darkly staining cubical or polygonal cells appear small droplets or globules or
larger rounded masses of mucus which are sharply outlined against the
surrounding epithelium. This material may contain much or little mucin.
Its sources are two, first, a secretion of the epithelial cells, when it appears
in broad rounded cellular areas inclosed in dense connective; and, second,
from mucous degeneration of fine strands of stroma originally supporting
the epithelial cords. When these tumors are entirely free from myxomatous
and chondromatous areas they are properly classed with the pure
adenocarcinomas (q.v.).

In the submaxillary gland simple benign epithelial tumors are extremely
rare.

Malignant dendritic adenocarcinoma arises from the ducts and produces
a firm circumscribed tumor which, in the case of Prengrueber, involved only
a portion of the gland. In Chevassu's case the tumor, although encapsu-
lated, recurred promptly after two operations.

Infiltrating carcinomas of tubular or alveolar structure arising from
the acini, and proving quite malignant, are described by Waldeyer, Volkmann,
and Chevassu.

CHAPTER XXXVIT

TUMORS OF KIDNEY
EPITHELIAL TUMORS OF KIDNEY

While indications of the structure of epithelial tumors of the kidney
appear in the early descriptions of J. Konig, Raver, and Cruveilhier, the
first definite success in tracing the epithelial origin of these tumors was
accomplished by Robin in 1855, who showed that the tubular epithelium
proliferated, destroyed the membrana propria, and produced cancerous
nodules. Waldeyer in 1867 also traced the beginnings of renal cancer to
proliferating cells of the renal tubules. The validity of these observations,
which to-day may be questioned, was accepted by Klebs, Recklinghausen,
Lancereaux and by writers generally, who classified the tumors as circum-
scribed benign adenoma and malignant infiltrating carcinoma. Ebstein
as late as 1877 evidently identified the sarcomas of infants with the
carcinomas of adults. More specific details of the origin of renal tumors
were obtained by Sturm, 1875, who distinguished between solitary adenoma
of normal kidneys and multiple adenoma of sclerotic organs, and recognized
the slow transformation of adenoma into carcinoma. Sabourin described
two forms of multiple adenoma, with lining of cubical or cylindrical cells,
and compared these small tumors with multiple adenomas of the liver.
In 1883 Weichselbaum and Greenish designated the two forms of adenomas
as papillary and alveolar.

Up to this time the epithelial origin of the small tumors was regarded
as proven and their transformation into the common malignant tumors
appears to have been accepted, while the existence of a separate group of
yellowish tumors of the cortex, of fatty nature, was recognized. In 1883
Grawitz contested the lipomatous nature of the small yellowish tumors,
showed that their structure was often identical with that of the cortical
hyperplasia of the adrenal (Virchow's "struma suprarenalis"), proposed for
the renal tumors the term "strumae suprarenales aberratae renalis, " estab-
lished the occurrence of adrenal rests in the capsule and cortex of the kidney,
and traced the origin of an important group of malignant renal tumors to
these rests. Grawitz' interpretation was supported and elaborated by many
later authorities.

Beneke traced the origin of certain sarcomas of the kidney to adrenal
cells. In 1892 Birch-Hirschfeld introduced the term, "hypernephroma," for
the adrenal tumor of the kidney. By some the scope of this group has been
regarded as including the majority of renal tumors and structures of various
types, and even the papillary growths (Horn). Sudeck in 1893, contested
the adrenal theory, holding that the papillary and alveolar tumors
are essentially the same and that the majority of the hypernephromas are
renal adenomas. Stoerk has adduced considerable evidence to show that the
identification of adrenal rests from fatty renal epithelium may be difficult
and has been too hastily undertaken; that renal epithelium may undergo
marked fatty changes, especially in the adenomas of sclerotic kidneys; that
papillary structures and lumina so common in hypernephroma are rare in
tumors of the adrenal itself; and that many of the features regarded as
typical of hypernephroma are reproduced in renal adenocarcinomas.

718 NEOPLASTIC DISEASES

The discussion of the adrenal theory has also been carried through phases
of chemistry, comparative pathology, and embryology, without reaching a
final solution, but tending on the whole to restrict the Grawitz tumors to a
relatively small group in which the structure is exactly duplicated by tumors
of the adrenal gland itself.

Epithelial tumors in which the cells are grouped about blood-vessels
have been erroneously interpreted by Paoli as angiosarcoma and by Driessen,
Hildebrandt, Hansemann and others as endothelioma. Manasse, in a com-
prehensive study, recognized many varieties of renal growths, including
renal adenomas and carcinomas, adrenal tumors of various types, endothe-
liomas from both blood- and lymph-vessels and various sarcomas of meso-
blastic origin. Birch-Hirschfeld's group of adeno-angiosarcoma, derived
from Wolffian remnants and the lipomyosarcomas remain, however, the
only well-defined varieties of renal sarcoma which have been fully divorced
from a probable epithelial origin.

Classification.- — Four groups of epithelial tumors of the kidney require
recognition:

1. Adenoma, single and multiple, essentially benign, and arising from
renal tubules.

2. Adenocarcinoma and carcinoma, arising from renal tubules, and often
from adenomas.

3. Papilloma and papillary carcinoma of the pelvis.

4. Adrenal tumors. Hypernephroma.

ADENOMA

Renal adenomas appear first as single or multiple tumors as large as a
pea or bean, in the cortex or capsule of the kidney where they are easily
detected as gray, white, or yellowish nodules. The multiple tumors are
usually seen in sclerotic kidneys in which they may be very numerous, while
in normal kidneys the nodules are usually single. The great majority never
pass beyond a small size, but tumors as large as an egg and of cystic character
are occasionally observed, and some becoming malignant progressively in-
crease in size. Nobiling refers to a case in which one kidney was the seat
of miliary cystadenomas, while the other presented a Grawitz tumor. The
frequency of these tumors is variously estimated. Zehbe collected 250
small tumors of which 40.5 per cent, were solid, 59.5 per cent, papillary or
alveolar. They are more frequent in elderly subjects and Weichselbaum and
Greenish found them in 10 per cent, of all persons over 70 years of age.

The structure of small adenomas presents several distinct varieties,
some of which appear to be very similar to adrenal rests.

A papillary structure, occurring in a small cyst and exhibiting papillary
characters from the first, has been generally accepted as indicating a renal
origin. The papillae are composed of thick branching strands of connective
tissue lined by one layer of cubical or cylindrical epithelium. Or the connec-
tive-tissue strands are thin and vascular and the epithelium more abundant.
Sabourin pictures papillary adenomas consisting chiefly of convoluted layers
of granular epithelium with very little stroma.

This group of tumors represents the renal form of cystadenoma arising
in organs which are the seat of chronic inflammation with the production of
cysts. Along with the tumors cysts without papillary ingrowths are often
seen. The small growths usually present a single cavity, while the larger
ones may be multilocular, as in Edmund's case. The tumors may reach the
size of a child's head while retaining a benign papillary structure (Scudder).

TUMORS OF KIDXEY 719

There is every reason to believe that the cells of origin are the adult epithe-
lium of the affected tubules. While the lining cells are often granular and
opaque, it is important to note that very early papillary tumors may contain
large clear cells containing fat and doubly refractive lipoid material (Stoerk,
Zehbe). Progressive growth and malignant transformation of these papillary
cystadenomas has repeatedly been observed, and it is probable that some
papillary adenocarcinomas of the kidney arise from such benign lesions
(Sturm, Beneke).

An alveolar structure in early renal adenomas has been described by
Klebs, Sabourin, Weichselbaum and Greenish, Sturm, Stoerk, Zehbe, and
others and there is little doubt that true renal adenomas may follow this
type. The cells are cubical or cylindrical and of large size. They are often
very fatty and fail to stain with eosin. Yet in a group of solid nodules,
described by Zehbe, the cells are granular and free from fat. When the cells
contain much fat it becomes very difficult to distinguish such small tumors
from adrenal rests, so that there has been much conflict of opinion regarding
the nature of this tumor. Stoerk traces the development of the alveoli
from convoluted tubules with coincident transformation of opaque granular
epithelium into swollen fatty cells. Since the typical adrenal rest fails to
show lumina surrounded by cells, the uniform presence of such spaces in the
cell groups of small renal tumors must stand strongly in favor of their renal
origin.

The fate of the alveolar adenomas has not been satisfactorily determined.
Many long remain of small size. The development of a progressive and
malignant process would produce a tumor of adenocarcinomatous and alveo-
lar or papillary type with clear cells, resembling certain hypernephromas.
This relation is claimed by many, but still remains to be definitely proven.

Some of the large congenital adenomas of children described by Weigert,
Targett, Kelynack, and others, presented a purely alveolar arrangement,
suggesting a relation to the small alveolar adenomas of the adult.

Tubular adenoma is a form of renal tumor described by Ricker, and
composed of elongated and irregular canals lined by small cells free from fat
and consisting chiefly of nuclei. Similar structures appear in some of Sa-
bourin's cases. The stroma is abundant and vascular. The peripheral
alveoli may pass gradually into the surrounding renal tubules, while in the
central portions the tubules are wider and may become cystic.

In the histogenesis of renal adenoma two conditions appear to be chiefly
concerned. In the group of cystadenomas in sclerotic kidneys the tumors
arise in cysts resulting from the sclerotic process. The character of the cell
lining may be assumed to vary with the location of the cysts, which affect
tubules of all types, including especially the convoluted and collecting tubules.
Single tumors in otherwise normal organs may be attributed to localized
cicatrices.

Congenital anomalies in the structure of the organ are probably connected
with the origin of certain adenomas, especially those of embryonal type with
small cells, some cystic tumors, and the tubular adenomas. The occurrence
of a variety of structural defects in the kidney is fully attested but few of
them have actually been traced into tumor development. Displacement
and imperfect development of renal tubules has been described by Albarran
in the renal cortex and capsule. Luzzato and Antona have traced the de-
velopment of adenoma and adenocarcinoma from such pararenal rests. In
Antona's case the tumor lay outside the kidney. Beneke and Ulrich identi-
fied renal tubules in the adrenal, and Ricker found such islands of renal
tubules in adrenal connected with the kidney by strands of connective

720

NEOPLASTIC DISEASES

FIG. 324. — Group of isolated embryonal tubules in cortex of a normal kidney. A probable

source of renal carcinoma.

tissue.

Since the renal tubule is formed of two originally separate por-
tions, secreting and discharging, which
later fuse, there is abundant opportunity
for the miscarriage of this process, re-
sulting not only in the congenital cystic
kidney but in isolated cysts which give
rise to cystadenomas. Nauwerck and
Huf schmidt and v. Kahlden have pointed
out the probable relation between the
cystic kidney and some cystadenomas.
The case of Keyes in which the entire
kidney was the seat of very numerous
solid adenomatous nodules as large as
ij^ cm-> recalls the distribution of mul-
tiple congenital cysts. Microscopic
islands of renal tubules lined by small
densely staining cells are not infre-
quently encountered in normal kidneys.
Under the term "spotted kidneys,"
Guillebeau and Vaerst have described
in the cow, and Schmey in the horse,
characteristic wedge-shaped areas in the
renal cortex which they attribute to im-
perfect development of the cortex.
They resemble adenomas, but are
properly interpreted as hamartomas, in
the sense of Albrecht. They are not
associated with nephritis. E. Meyer

FIG. 325. — Congenital malformation
of kidney of newborn infant. The organ
is enlarged and the cortex everywhere
the seat of superfluous undifferentiated
tubules.

TUMORS OF KIDNEY 721

describes a spotted kidney in a child, the areas involving both cor-
tical and medullary tissue; with defect in the convoluted tubules. R. L.
Thompson found in a two-year child a hyperplastic pyramid adjacent
to a normal cortical area. In the intermediate zone the structures were
greatly disarranged. In a well developed but stillborn infant with large
cyst of umbilical cord, I found both kidneys much enlarged. The renculi
were of unequal size and irregularly placed. The cortical tubules were
deficient and many glomeruli immature. Many tubules, probably the
collecting, were of embryonal type lined by very large cells with hyperchro-
matic nuclei, and appeared in numerous foci throughout the organ, resembling
miliary fetal adenomas (Fig. 325).

CARCINOMA

Malignant tumors of renal epithelium appear in two main forms: (i)
Papillary adenocarcinoma and (2) Alveolar carcinoma.

The structural subvarieties of these main groups are rather numerous and
constitute a field still awaiting investigation from the histogenetic and clin-
ical standpoint.

In general it may be stated that the two forms of carcinoma accord with
the two chief groups of adenoma from which many of them arise. The
cystadenomas form a continuous series from the simple benign growths up
to highly cellular and malignant tumors. This group includes many vascu-
lar growths with clear cells, which are often confused with hypernephroma.
The relation of the true alveolar carcinoma to alveolar adenoma is less
distinct. These tumors are less frequent than the papillary type and many
of them are of embryonal origin.

Papillary Adenocarcinoma. — These tumors are much the most frequent
of renal growths. They occur chiefly in adults but occasionally in children.
Most of them are recorded in the literature as hypernephroma, so that sta-
tistical data regarding them are scanty and unreliable. For general clinical
information the reader may refer to the elaborate monograph of Albarran
and Imbert. The group includes two well-defined varieties and one small
subgroup of minor importance, (a) Papillary adenoma and carcinoma
with clear or glassy cells; (b) Papillary adenocarcinoma or carcinoma with
granular cells; (c) Malignant tumors arising from simple cystadenoma.

Of these tumors the first (a) produces large single, less often multiple,
yellowish circumscribed vascular or hemorrhagic tumors, composed of villous
or thin papillary strands of connective tissue, lined by one layer of cubical or
cylindrical clear fatty epithelium. These tumors are often confused with
hypernephroma, but their pronounced papillary structure and the occasional
presence of areas containing characteristic renal epithelium free from fat,
usually permit their recognition. Characteristic cases are described by
Kelynack under the term malignant cystadenoma. The necessity of dis-
tinguishing this renal tumor from others and of separating it especially from
hypernephroma is recognized by most recent writers (Albarran, Stoerk,
Ipsen, Willson and Willis).

The second form (b) appears as multiple, solid whitish and cellular growths,
less distinctly encapsulated, commonly free from hemorrhage, and composed
of numerously branching strands of connective tissue, lined by one or several
layers of opaque, granular epithelium, free from fat.

The third group (c) includes cystadenomas which have become malig-
nant.

It must be admitted that the character of the cytoplasm of the tumor-
cells is an uncertain basis for classification. Stoerk has shown that fatty

722 N EOF LAST 1C DISEASES

changes occur readily in foci of small renal adenomas in which the cells
are mainly granular. Zehbe finds that several types of renal adenomas
present, indifferently, clear or granular cells. In a tumor composed chiefly of
small alveoli lined by low opaque cells I have found sharp transitions to
papillary adenoma with clear cells. It is probably impossible to establish a
markedly different histogenesis for the two types. Nevertheless the above
cases are exceptions to the rule that tumors with clear cells and those with
opaque granular cells arise under different conditions and yield peculiar
gross as weL as microscopical appearances.

FIG. 326.- — Circumscribed papillary and cystic adenocarcinoma of kidney.

(a) Papillary Carcinoma with Clear Cells. — -The gross appearance of the
papillary carcinoma with clear cells is usually characteristic. The tumor
begins as a small circumscribed cortical or medullary solid nodule of light
yellow color and considerable vascularity. The growth commonly reaches
considerable dimensions and when encountered in surgical material it is as
large as a hen's egg or the fist and lies within the' renal capsule which is
distended. On section portions of unaltered or thinned renal tissue appear
at one or several segments of the mass. Of 194 renal tumors chiefly of this
type, Kuster located 80 in the middle segment, 60 in the lower pole, and 54
in the upper pole. Ipsen who recognized the renal origin of his tumors, found
13 in the upper, 10 in the middle and 12 in the lower lobe. The gross struc-

TUMORS OF KIDNEY

723

ture is divided into many small cysts containing clear or brownish or bloody
or gelatinous material. Areas of necrosis and hemorrhage may be frequent
and these may fuse, yielding large cystic cavities. There may be considerable
calcine deposits. As a rule, these tumors are not encapsulated.

From the presence of numerous small cysts with gelatinous contents,
gross evidences of a papillary architecture, and a greater tendency to invade
surrounding renal tissue, these tumors can usually be distinguished by the
naked eye from tumors of adrenal rests.

In advanced and fatal cases the tumors become very large, destroying
most of the kidney and undergoing further necrosis, hemorrhage, and cystic
softening. They extend by continuity to the kidney, renal pelvis with
hydronephrosis, adrenal, lymph-nodes, and abdominal wall, and they invade
the renal and other veins often very early. In the renal vein they produce
tumor-masses reaching through vena cava to the right heart (Coyne, Troisier,
Wyler, Gardner and Coats). Yet invasion of the veins is not always followed

FIG. 327. — Adenocarcinoma of kidney metastatic in brain.

at once by metastases, and Albrecht records recovery after extirpation of such
a tumor. Stoerk noted that the histology is not always a safe guide to the
viability of^the cells, some apparently simple structures proving exquisitely
malignant.

Israel, in 18 cases of "hypernephroma," observed characteristic fever
curves, remittent and intermittent, initial, intercurrent, and terminal. He
states that fever occurs in all malignant tumors of the kidney without relation
to histological structure, size, rapidity of growth, or invasion of vicinity.
Cabot records high leukocytosis in several cases.

Metastases are very frequent. Albrecht found the lungs involved in all
his advanced cases. Albarran, in 249 collected cases of renal carcinoma, found
the lungs involved in 75, liver 71, lymph-nodes 60, renal vein and cava 23,
pleura 14.

The frequency of bone metastases has long been recognized. In most
reports it has been assumed that the tumors arose from adrenal rests, but it
is probable that most of these cases were renal carcinoma with clear cells.
P. Albrecht found bone metastases in 8 of 14 fully studied cases of hyper-

724 NEOPLASTIC DISEASES

nephroma. They occur chiefly in ribs, spine, skull, scapula and long bones.
They are sometimes mistaken for primary tumors or other diseases of the
bones, the renal tumor being discovered only late in the disease or at autopsy.
In a well-known group of cases a solitary bone-tumor arises from a compara-
tively small renal growth. Such tumors have been successfully extirpated,
the patient succumbing later to the renal disease.

Late bone metastases, occurring 5, 8, 9, and even 10 years after removal
of the primary tumor, are also recorded (Clairmont, Albrecht). The slow
development of the tumor-cells may be referred to the early invasion of veins
with accompanying phlebitis which for a time blocks their further transport.
The structure of the bone-tumors often reproduces exactly that of perivascu-
lar or papillary adenocarcinoma, but giant-cells have been found in very
large numbers on the advancing edge of the tumor, while occasionally the

FIG. 328. — Papillary carcinoma of kidney with clear cells.

secondary growth is much more atypical and malignant than the primary.
Osteoplastic tendencies were noted by Albrecht.

The structure of the primary tumor is usually papillary. In some cases
there are cross-sections of very numerous small blood-vessels surrounded by
one layer of larger glassy epithelial cells. In other cases the trabeculae are
long and thin, covered by one layer of high cubical or cylindrical epithelium
resembling those of the collecting tubules. Adjoining trabeculae may seem
to inclose long sections of tubules. Rarely an alveolar appearance is pro-
duced. In a third group the lining cells appear in several layers, the cells
are extremely large and elongated and the layers of adjoining trabeculae
fuse. Yet a diffuse carcinoma of this type probably does not occur. Even
in metastases the papillary character and the glassy appearance of the cells
are retained. Albarran has described this tumor under the term adenoma
dheolare a cellules claires. Sabourin groups it with the papillary growths.

TUMORS OF KIDNEY 725

Sudeck reported several cases but failed to distinguish them clearly from ad-
renal growths. Ipsen describes papillary, alveolar, and solid structures
and concludes that all the tumors are essentially papillary. The structure
often resembles some cases of hypernephroma of perithelial type, but careful
study of different sections reveals a predominant papillary and alveolar type.
In hypernephroma the cells form thick anastomosing sheets or columns
between which lie many dilated blood-vessels. The presence of alveoli filled
with mucous secretion, or with basic staining concentrically striated globules,
also belongs to renal adenoma.

In very cellular growths nutrition is poor, the cells may become widely
distended with fat and watery fluids, and giant-cells may form. Appro-
priate stains reveal the presence of much glycogen, fat, and lipoid material
but in very variable amounts.

The study of the chemistry of these tumors has been pursued elaborately
by Lubarsch, Sisson, Stoerk, Ipsen, and others, but it does not appear that a
differential diagnosis can be established on the character of the lipoids.
The glassy cells may be almost entirely free from fat, or very large deposits
of material reacting to osmic acid or Sudan III may be present. Glycogen
is usually abundant, but sometimes missing.

Ipsen found that the renal tumors yield about 10.7 per cent, of fat and
0.2 per cent, of P, while the horse's adrenal contains 30.8 per cent, of fat, and
i per cent, of P. The lipoids are cholesterin esters.

Histogenesis. — Papillary carcinoma with clear cells has been subject to
several different interpretations. The older authors uniformly regarded
it as of renal origin and this view is maintained perhaps by the majority of
recent authors. With the advent of Grawitz' theory these tumors were
frequently classed as hypernephroma, because of the clear cytoplasm of the
cells. The pronounced papillary character appears to the writer as incom-
patible with an adrenal origin, although contrary to Stoerk, it must be
admitted that adrenal tumors occasionally present a certain papillary tend-
ency. Strong evidence of the renal origin of the growths is the occasional
presence of tubules reproducing the exact features of hypertrophic renal
tubules, which are not observed in tumors of proven adrenal origin. The
adrenal tumors which simulate papillary carcinoma most closely present
a pseudopapillary structure and are composed of thin but usually solid
anastomosing columns of clear cells supported by thin vascular septa.

Papillary carcinoma with clear cells has also figured as endothelioma
and as angiosarcoma, in the reports of Driessen, Hildebrandt, Manasse and
Hansemann. Yet it is now recognized that the close approximation of large
clear cells about the walls of capillaries, or the presence of extravasated blood
in the lumina of vascular adenocarcinomas, does not indicate an angio-
blastic tumor. Many so-called peritheliomas are true adrenal tumors. It is
possible also that the intravascular proliferation of endothelium may give
rise to new tumors of the kidney, as described by Hansemann under the term
adenoma endotheliale, but there is no satisfactory evidence that these growths
may reach the size or follow the course of renal adenocarcinoma.

(b) Papillary adenocarcinoma with granular cells, resembling those of the
renal tubules, occurs under several conditions.

(i) Multiple adenocarcinoma in sclerotic kidneys is one of the best defined
varieties of renal carcinoma. It was early recognized and fully described
by Sabourin, Klebs, Weichselbaum and Greenish, and Sturm, who encoun-
tered chiefly simple adenomas. One or both kidneys may be involved by
very numerous small circumscribed light colored tumor nodules which may be-
come so abundant as to leave little intact renal tissue. The organ retains

726

N EOF LA STIC DISEASES

its form and may be only slightly or not at all enlarged. In the early
stages the tumors may be small and miliary, later they become as large as
peas or beans, but bulky tumors are rarely if ever produced.

The structure follows a papillary adenomatous type with thin strands of
vascular connective covered with one layer of cubical or polyhedral slightly
granular cells. Fatty degeneration is not entirely missing but the abundant
large clear cells of other adenomas are not found. In some cases the cell
layers are multiplied and malignant features appear. The course of these
tumors is slow and they seldom display malignant clinical qualities. In a
case of Keyes, Sr., the patient, 49 years of age, complained chiefly of hema-
turia. The kidney was removed and the disease did not recur. Manasse's
two cases were found at autopsy.

FIG. 329. — Papillary adenocarcinoma of kidney.

The multiple tumors have been regarded as the sequel of inflammatory
and regenerative hyperplasia. From this point of view the true neoplastic
nature of the simple forms may be doubted, as done by Sudeck and Hanse-
mann. Yet these growths pass insensibly into true and sometimes active
adenomas or adenocarcinomas.

(2) Papillary adenomas and adenocarcinomas with granular cells occur
not only in sclerotic kidneys but frequently in otherwise normal organs. The
tumors are single or more often multiple, and appear as solid white masses
in cortex or medulla. The solitary tumors may reach considerable dimensions,
but the very large growths composed of clear cells are not duplicated in this
variety. Fatty changes and hemorrhage are usually wanting, but many of
the tumors are locally aggressive and invade the kidney diffusely, perforate
the pelvis and capsule, and extend into the lymphatics. Invasion of the
veins is less prominent than with other renal growths.

TUMORS OF KIDNEY 727

On gross anatomical features this group of tumors has often been divided
into nodular and infiltrating forms, the former being adenomatous the latter
adenocarcinomatous. Yet the transitions are frequent and occur in the
same tumors. With increasing malignancy the encapsulation, which is
seldom distinct, becomes obliterated. The whole organ may thus be much
enlarged while retaining its form.

The structure presents several variations of the papillary type. Usually
the connective tissue appears in thin strands, frequently branching, covered
by one or more layers of opaque granular cells. The vascularity is much less
than in most other renal growths, so that the gross appearance has been
described as snow white. The cells somewhat resemble those of the convo-
luted tubules, but the resemblance is seldom sufficiently distinct to impress
such an origin. Nevertheless not a few observers claim to have traced the
growth from renal tubules (Waldeyer, Manasse, Stoerk).

In some cases the cells are extremely small, the papillae minute, and the
resulting structure in section j resembles in part an alveolar growth and
suggests an embryonal origin. Sudeck argued that all the tumors are
essentially alveolar. Wiecheselbaum and Greenish found two distinct types
with transitions. I have seen rare tumors with both types of structure in
adjoining areas, but find that the alveolar growths, as a rule, differ markedly
from the papillary, suggesting different conditions of origin.

In the malignant growths, the cell layers multiply, adjoining papillae
fuse, and the renal tissue is invaded, as papillary, alveolar, or diffuse
carcinoma.

(3) The malignant transformation of cystadenoma is described by Klebs,
Ziegler, Ricker, and others. These tumors are single or multiple, well
encapsulated, and sometimes of large dimensions. The papillary and cystic
character is evident on gross inspection, and the cyst may contain consider-
able fluid with blood and fatty detritus. The capsule may be invaded and the
parenchyma may be infiltrated by secondary nodules, or the malignancy may
be demonstrated by an unexpected recurrence. The structure presents
coarse trabeculae, of vascular connective tissue, covered by cubical or cylin-
drical granular or clear epithelium which is usually in a single 'layer, but
in many areas becomes multiple, atypical in form, and produces pseudo-
alveoli. Characteristic tumors of this type are rare.

Alveolar Adenocarcinoma. — -Although the early writers uniformly
recognized an alveolar adenoma of renal origin, the advent of Grawitz' theory
led many to refer the majority of alveolar growths to an adrenal source.
Only a superficial acquaintance with the morphology of renal tumors could
favor such an interpretation, since alveolar adenomas form a highly character-
istic and important group of renal growths which are wholly different from
the adrenal derivatives. In this group also the derivation from preformed
renal tubules has been traced by Waldeyer, Manasse, Stoerk and others.

The structure may almost exactly reproduce that of the renal cortex.
Stoerk has shown that regenerating tubules may multiply and ramify,
producing localized tumor-like nodules resembling adrenal rests. Most
observers have been unable to trace alveolar adenomas to preformed tubules
and believe that these growths are chiefly of embryonal origin. In accord-
ance with this view is the fact that the renal carcinomas in children are chiefly
of alveolar type. Stoerk found foci of spindle-cells in alveolar adenoma, sug-
gesting a relation to adenosarcoma. Weigert, in a congenital case, observed
abortive glomeruli associated with alveolar adenoma. In adults both embry-
onal and adult types of alveolar adenoma are observed, and the resemblance
to adult tubules is occasionally so striking as to indicate that an embryonal

728

NEOPLASTIC DISEASES

origin is not constant. Finally the islands of displaced renal cortex in the
capsule or cortex of the kidney, described by Albarran, were of alveolar type
and are believed to have given rise to alveolar tumors. Several forms of
small adenomas previously described also present themselves as possible
sources of larger adenocarcinomas.

The varieties of alveolar adenomas which present sufficiently distinct clin-
ical and structural features to warrant recognition are somewhat numerous.
They may be conveniently described in the following classes:

(a) Adenocarcinoma of infants.

(b) Embryonal adenocarcinoma of adults.

(a) Adenocarcinoma of Infants. — Compared with the mixed tumors
pure epithelial growths are rare in children. Of 170 cases Albarran found
four adenomas, seven carcinomas, two adenocarcinomas, and four adrenal

FIG. 330. — Adenocarcinoma of adult kidney, reproducing convoluted tubules.

tumors. In the literature attention is seldom given to the recognition
of carcinoma in infants and many cases have doubtless been included in the
literature of congenital sarcoma. It is quite possible that some of the
infantile adenocarcinomas are related in origin to the congenital mixed
tumors, as Weigert's cases, in which there were abortive glomeruli, but others
appear to be of more adult type and probably arise from portions of well-
differentiated renal blastema. A relation to the congenital cystic kidney
is also probable. Von Kahlden has shown that marked epithelial overgrowth
may occur in this condition. The scope of the structure is illustrated in
the following cases:

Weigert described small bilateral renal tumors in a stillborn fetus which projected
slightly beneath the capsule. They were composed of well-formed alveoli resembling

TUMORS OF KIDNEY 729

renal tubules, and of vascular foci in which loose polyhedral cells surrounding capillaries
recalled the structure of imperfect glomeruli. A large adenocarcinoma, interpreted as a
later stage of Weigert's tumors, is described by Barth. It was as large as a child's head,
replaced most of the kidney in a child of five years, had caused hydronephrosis and was com-
posed of alveoli, cords and diffuse growth of polyhedral cells. Perthes describes three
large tumors in children, of adenomatous and carcinomatous structure. The resemblance
of the acini to renal tubules was noted. In Malcolm's case the tubules were separated by a
delicate stroma and the tumor, a malignant adenoma, was lacking in embryonal characters.
In Manasse's alveolar carcinoma (Case VIII) the resemblance to renal epithelium was also
noted. The most malignant of the growths show central softening.

Small cysts may appear in the adenomatous growths, as in the cases of Iliot described
by Kelynack, in which the structure resembled thyroid gland, and in Edmund's case.
Some of the tumors reach a very large size, especially the malignant adenoma involving
the whole kidney.

FIG. 331. — Embryonal tumor of renal blastema in the kidney of a child.

Metastases are comparatively rare. Even the actively growing very
cellular carcinomas may be free from secondary growths (Bokai).

(b) Embryonal adenocarcinoma of adults is a rare but characteristic
tumor. It is probably of the same origin as some of the malignant adenomas
of children, which it resembles in structure.

In a case in the New York Hospital the patient, a woman of 35 years, complained of pain
for one year and hematuria for 3 months before operation. The tumor, 24 X 14 X 8 cm., was
well circumscribed laterally but fused gradually with the remnant of kidney. It was solid,
lobulated, cream colored, and moderately soft. There were no metastases. Section
showed a uniform structure of large alveoli lined by large granular, cylindrical or cubical
cells with darkly staining large nuclei. Many of the alveoli contained homogeneous
acidophile material. In some foci the alveoli were indistinct. The embryonal character
of the cells and structures was pronounced.

(c) Tubular Adenocarcinoma and Carcinoma of Adults. — In this group are
included the majority of malignant alveolar tumors of the renal epithelium.
They are clearly separable from the carcinoma with clear cells, from papillary
carcinoma, and from adrenal growths. The structure is uniformly alveolar

730

NEOPLASTIC DISEASES

or tubular, adult in type, and resembles the renal parenchyma. These
tumors probably originate from well-differentiated renal blastema or from
adult cortical tubules. Waldeyer, Manasse, and others claim to have traced
the development of such tumors from the renal tubule cells, but most obser-
vers have not succeeded in this task. Sharkey believed he could trace the
origin of his tumor to the glomerular epithelium. Beneke also has observed
tumor-like hyperplasia of glomerular epithelium. It seems more probable
that the growths develop from misplaced renal tissue or from the well-known
types of tubular or alveolar adenoma, but Albarran's early case (166) was
as well diffused as a tuberculous lesion, and the outlines of the cortex were
unaltered.

While there are many records of tumors of this group they are distinctly
less frequent than other forms of renal carcinoma. They arise from any

FIG. 332. — Embryonal adenocarcinoma of renal blastema.

portion of the kidney and may be located chiefly in the cortex or pelvis, which
are widely distended, or beneath the capsule, or they may be extrarenal.
Very early circumscribed but non-encapsulated tumors are described by
Albarran. In Brault's case a very small tumor was associated with metas-
tases. Most of the tumors reach considerable and sometimes large dimen-
sions. The adenomatous tumor may long remain encapsulated but infil-
trating growths may greatly enlarge the kidney while preserving its form.
Fatty changes, hemorrhage, and necrosis are not prominent, but the solid,
tabulated, opaque texture serves to distinguish most of them from adrenal
growths and papillary carcinoma. Small cysts containing gelatinous mate-
rial are not infrequent, and in a group of cases the abundance of such material
has led to the designation as colloid carcinoma (Newman, Dickinson, Schuep-
pel). The highly malignant tumors infiltrate the kidney diffusely, perforate

TUMORS OF KIDNEY

731

pelvis and capsule, invade both veins and lymphatics, and produce metas-
tases in many organs.

The structure presents many variations but usually follows that of certain
segments of the renal tubules. That they are actually derived from such
portions of the tubules, while possible, cannot at present be claimed.

The convoluted tubules were reproduced to a remarkable degree in a case
of A. Frazer's, kindly placed at my disposal. The tumor was a large solid
circumscribed growth presenting mainly large alveoli and tubules lined by
high cubical granular cells exactly duplicating those of the convoluted tubule
of the adult organ. Numerous variations from this structure appeared in
more actively growing hemorrhagic and degenerating portions of the growth,
and in some foci the growth was diffuse.

FIG.

333. — Embryonal tumor of renal blastema,

glomeruli

vith production of abortive tubules and

The smaller renal tubules are simulated by many small alveolar adeno-
carcinomas and carcinomas, but the size of the alveoli seems to depend on
the tissue of origin (adenomas), the rate of growth and associated fibrosis,
rather than on any inherent capacity to reproduce normal renal structures.
In some tumors the alveoli are quite small, and lined by small flat cubical
epithelium. Or the cells are larger and form small compact groups with
no definite lumen. Invasion and replacement of preformed tubules may
determine the structure of infiltrating growths. Tumors composed of small
alveoli are relatively frequent and are depicted by Albarran, Stoerk, and many
others. Diffuse growth derived from such structures may simulate various
types of sarcoma. Markedly elongated tubules lined by high cylindrical
cells of opaque granular type are also encountered. Striking variations in

732 NEOPLASTIC DISEASES

structure are frequently observed in the same tumors, including especially low
papillary projections into distended alveoli, collections of secretion, giant-
cell formation, and peculiar cell inclusions.

EMBRYONAL ADENOMYOSARCOMA

Whatever its origin and its interrelations with other renal tumors may
prove to be, the embryonal sarcoma of infants is one of the most characteristic
neoplasms of the kidney. Its rather frequent occurrence in infants, the com-
plex embryonal structure, rapid growth to very large size, fatal course, and
obscure origin, render it a specific clinical disease and a topic of much theo-
retical interest. Hedren has extracted many of the case reports up to 1907,
but includes many simple embryonal tumors which do not certainly belong
in this group.

The great majority of cases are observed in the first three years of life,
it is rarely found after the loth year, but Hedren reports a bilateral tumor at
54 years, while Schaffer describes an early stage of the disease in the single
kidney of a deformed fetus. This kidney was twice the normal size, presented
abortive renal structures, islands of cartilage, and areas of smooth and
striated muscle. Several reports are of bilateral tumors.

Gross Anatomy. — The tumors lie within a distended renal capsule, their
position may suggest an origin from any part of the kidney, mid-cortex,
upper pole, papillae (Manasse) or pelvis, and while usually sharply separated
from the remnant of the organ, they may fuse insensibly with it (Busse),
or a thin rim of renal tissue may inclose a large segment of tumor. The growth
may be entirely extrarenal (Broch, Brandt, Borst).

The large size of these tumors is a notable feature, since at any given
age they are usually the largest of the renal growths, and this volume is
attained rapidly. In several cases the largest diameter has reached 35-
37 cm. (Hoisholt, Jenckel), while in a subject of 34 years Muus found a
tumor of 40 cm. Heineke's tumor weighed 3580 gr.

The growth is often solid, opaque, and variously subdivided into lobules
or areas by preponderance of glandular, fibrous, muscular or very cellular
tissue. The larger tumors are usually cystic and some approach the appear-
ance of the congenital cystic kidney. Hemorrhage and necrosis are late
complications. Extensions and metastases are exceptional, but in Merck el's
case a tumor thrombus extended in the vena cava to the heart. The liver
is the most frequent seat of metastases. Pulmonary metastases have been
observed in several cases, in Brandt's 5 months after extirpation of the tumor.
Ribbert's tumor extended along the spine.

The embryonal structure is the most distinguishing feature and presents
a great variety of tissues usually suggesting abortive renal elements. The
usual composition is of isolated tubules of high cylindrical or cubical cells
with indistinct lumina, surrounded by broad zones of indifferent spindle-
cells, on which is based the designation of adenosarcoma. Either tubules or
spindle-cells may be in excess, the tumor approaching embryonal adeno-
carcinoma or sarcoma.

Occasionally a tuft of spindle-cells projects into an invaginated tubule, like
an abortive glomerulus. Both spindle and cubical cells may be very £ mall
and numerous, producing a structure of round-cell or alveolar sarcoma.
Multilobed giant-cells may be prominent. Cysts are usually lined by cubical
epithelium. Squamous epithelial nests with keratohyalin were found by
Muus, and Jenckel saw cysts lined by squamous-cells. Most of the cells
are rich in glycogen.

TUMORS OF KIDNEY 733

Smooth or striated muscle-cells are usually present in some portions
of the tumors and either may make up the bulk of the growth. Some have
derived the latter from the former, but Hedren maintains that the two types
are separate, the striated cells first appearing in the usual tubular form of
the embryo. The cellular connective may by edematous or myxomatous,
and often contains elastic fibers. Fat tissue appears in single cells or definite
lobules. Cartilage appears in the form of small isolated islands, rather more
frequently in older subjects. In one case islands of bone were observed
(Hedren). The metastases are usually of round-cells, but Blau reports
striated muscle-cells in the lung.

FIG. 334. — Topography of Wilms embryonal tumor of kidney. Epithelial tubules lying
in masses of spindle and polyhedral cells. Striated muscle cells in centre.

Histogenesis. — The interpretation of the origin of renal mixed tumors
has passed through several phases and covered all apparent possibilities.

An origin from an aberrant sex cell has been deemed necessary by Ribbert,
who interpreted some of the epithelial rosettes as neuro-epithelium and who
emphasizes the presence of all three germ layers.

Wilms places the period of the embryogenic disturbance later, but con-
siders that the originating tissue must be defined early, must involve ecto-
derm and mesoderm, and include nephrotome, sclerotome, and myotome.

The earliest conception was that of Cohnheim and Birch-Hirschfeld
who assumed an origin from the Wolffian body. Busse points out that no
Wolffian remnant has ever been found in the kidney, so that this interpre-
tation has been generally abandoned. Birch-Hirschfeld's service was
chiefly in emphasizing the existence of a definite group of embryonal mixed
tumors.

734 N EOF 'LA STIC DISEASES

Busse and Muus place the origin at a still later teratogenic termination
period and see no reason why all the structures observed may not be derived
from the renal blastema. This view attributes a prominent part to meta-
plasia, thus accounting for adult squamous epithelium, striated muscle,
cartilage and bone. In this respect it is in accord with modern tendencies,
which are not in favor of the rigid specificity of germ layers. It also serves
to explain why some of the tumors approach the type of simple embryonal
adenocarcinomas of the kidney, of which I have seen one striking example.
It accords further with the gradual fusion of some tumors with renal paren-
chyma, and permits considerable latitude in the exact period in the differen-
tiation and growth of the renal blastema at which the tumor may arise. On
the whole this view is the most acceptable, as well as the simplest of the pro-
posed hypotheses. Hedren was much impressed by the presence of bone in
his unique case, which he could not accept as of metaplastic origin, and con-
cludes that embryological data and casuistic studies are inadequate to estab-
lish any single origin of the renal mixed tumors.

In addition to the typical embryonal sarcomas and their recognizable
atypical forms, there are other renal tumors whose structure suggests a
relation with the main group.

Quiescent masses of fat and cartilage are not infrequently observed in
the kidney (Hansemann, Borst). Fibromyomas, single or multiple, of
cortex or capsule (Busse, Larkin), fibre myo-osteosarcoma (Hildebrand),
fibrolipomyoma (Busse), and myxoliposarcoma, are recorded. In all of these
renal epithelial elements are missing. Apparently pure carcinomas of the
kidney occur in infancy (Birch-Hirschfeld). All of these observations
suggest that the embryonal kidney is subject to a variety of developmental
disturbances resulting in tumor growth and that no single source of these
anomalies should be assumed to exist.

RENAL TUMORS OF ADRENAL TISSUE. HYPERNEPHROMA

In 1883 P. Grawitz formulated the conception that certain tumors
of the kidney were derived from adrenal rests. In this group he included the
so-called lipomas of the cortex, angioma cavernosum, various myomas, as
well as the adenomas and adenocarcinomas of Klebs, Sturm, Sabourin, and
(1884) of Weichselbaum and Greenish. The argument favoring this view
was quite ably prepared. The chief evidence consisted in: (i) The location
of the tumors under the capsule where adrenal rests are found. (2) The
character of the cells, which differed markedly from renal epithelium in their
high content of fat without signs of degeneration. (3) The sharp encapsu-
lation separating the tumors from the renal parenchyma. (4) The resem-
blance of the structure to that of the adrenal. (5) The presence in the small
tumors of a fibrous core and a more cellular glandular cortex. Even when
not encapsulated the tumor was sharply separated from the renal parenchyma,

Grawitz theory was soon endorsed by Chiari, Horn, Lubarsch, Beneke.
Ambrosius, Marchand, and many others, and came to be generally accepted.
Sudeck in 1893 first offered objections, and in recent years other contrary
views have been frequently expressed, by Stoerk, Zehbe, Wilson and Willis,
Ipsen, Glynn, and others. It is now evident that the scope of Grawitz'
tumors was much too widely extended, and it has become necessary to
determine anew whether adrenal tumors of the kidney exist and how they
can be identified.

On these questions it may be said that the presence of adrenal rests in
the kidney is fully attested, although they are probably less frequent than

TUMORS OF KIDNEY

735

many have supposed. It also appears that certain tumors arise from these
rests, although clear descriptions of their structure have not been fully given.
Finally, recent studies have demonstrated that a large proportion of the
reported hypernephromas are renal adenocarcinomas.

Occurrence of Adrenal Rests (Pick, Goupel, Lit.). — The adrenal cortex is developed
from the mesothelium of the Wolffian ridge, as are also the ovary and testis, while the
medulla is of neuro-ectodermal origin and belongs to the sympathetic system, although
mingled with the neuro-epithelium are derivatives of the cortical cells. According to
Aichel the interrenal bodies of lower vertebrates and the adrenals of higher vertebrates
arise from the Wolffian body funnels, which are of mesothelial origin. Marchand's

FIG. 335. — An adrenal tumor of the kidney.

adrenals' in the broad ligament of the female and along the spermatic cord of the male,
arise from segmental tubules of the Wolffian body and correspond to the suprarenals of
lower vertebrates.

The renal cortex, on the other hand, is formed from the renal blastema, a mass of
indifferent mesothelium which lies some distance below the adrenal and is separated from
it by the Wolffian body.

The adrenal is at first larger than the kidney because of the hypertrophy of the fetal
cortex, which atrophies and is replaced after birth by the adult cortex derived from a rim
of small cells (Elliott, Armour). The position of the early adrenal is not at first favorable
to the inclusion of its tissue in the kidney, as shown by Wilson. Yet after the second month
it is closely applied to the kidney and surrounds a large portion of the renal body (Peter).
Inclusions in the kidney may therefore reasonably be assumed to result. The occurrence
of diffuse adrenal tissue without encapsulation is described by R. Meyer. That the adult

736 NEOPLASTIC DISEASES

peritoneal epithelium is capable of developihg foci of adrenal tissue is suggested by Pick
and Poll. Total subcapsular location of both adrenals, portions remaining on the kidney
after decapsulation, are recorded by Klebs, Grawitz, Weiler, and Ulrich. Fusion of
adrenal in the renal capsule and intralobular inclusion of rests surrounded by renal paren-
chyma are described by Grawitz and Ulrich. Interlobular rests connected with the adrenal
by a strand of fibrous tissue are more frequent conditions. Most of the adrenal rests con-
tain only cortical tissue, but medullary tissue also was found by N. Pitt, Grawitz, and
Manasse.

Yet it appears clearly that adrenal rests in the kidney are much less frequent than the
supposed adrenal tumors. Glynn could find only about 17 in the literature and obtained
none in 1500 kidneys. Yet Lubarsch in 300 autopsies found eight adrenal rests in the
kidney. On the other hand such rests are relatively frequent in other situations (March-
and); in the neighborhood of the epididymis, in 76.5 per cent, of newborn children (Wiesel);
on the under surface of the liver, in 92 per cent, of cadavers (Neusser); in 90 per cent, of all
bodies (Holmes); on the broad ligament and spermatic veins of 24 females (Aichel). In
adults they are much less common and many observers find them in only a small proportion
of cases, as Schmorl in 4 of 510 livers; Hanau, about spermatic veins, in 5.9 per cent, of
children under five years. They are occasionally found in the testis (Dagonet, Michael,
Meyer, Kirkbride); pancreas (Ribbert); transverse colon (Nicholson). The facility with
which different observers are willing to identify adrenal rests doubtless explains the
varying results.

FIG. 336. — Adrenal adenoma in kidney.

It must be admitted also that tumors of misplaced adrenal tissue outside
of the kidney are distinctly rare, although the diagnosis of such an origin
is frequently made on insufficient grounds. The location of adrenal rests
in the kidney is chiefly in the upper pole, but not exclusively between the
renculi, as i? sometime? claimed. On the other hand the tumors commonly
attributed to these rests occur with about equal frequency in all segments
of the organ.

Notwithstanding these discrepancies it is clear that adrenal rests occur
with moderate frequency in the kidney, where they may give rise to tumors.

Gross Appearance of Adrenal Rest Tumors. — The anatomical features
commonly attributed to Grawitz' tumors apply to a large group of renal
growths. They are large well-circumscribed, yellowish, fatty and vascular
tumors, prone to hemorrhage, necrosis and cyst formation. A segment of
intact kidney is usually found connected with the tumor. Grawitz empha-
sized especially the presence of a central fibrous area surrounded by a more
cellular cortical portion, but in most descriptions of hypernephroma these
features have been absent or disregarded. Yet the true adrenal tumor of
the kidney, at least in its early stages, regularly presents such distinguishing
landmarks (Fig. 335). It also as a rule lacks the markedly lobulated sub-

TUMORS OF KIDNEY

737

divisions, numerous small cysts filled with gelatinous or bloody material,
and gradual merging with the renal parenchyma, which belong to renal
adenocarcinoma with clear cells. The adrenal tumor is usually more solid,
although cysts form from necrosis and hemorrhage. The malignant growths
invade the perirenal tissues, peritoneum and lymph-nodes, more readily
than renal carcinoma. Both invade the renal pelvis and the large veins,
but metastases are earlier and more widespread with adrenal growths.

Many so-called renal hypernephromas actually arise in the adrenal
gland and, invading the kidney, fuse the two organs in a diffuse mass. When
the adrenal cannot be found the renal origin of the tumor at once becomes
doubtful.

Structure. — The scope of the structure attributed to adrenal hyper-
nephroma should be controlled by the known structure of tumors of the
adrenal itself, as seen in the human subject. Observations on tumors of
the adrenal in lower animals cannot safely be used as criteria.

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FIG. 337. — Adrenal tumor of kidney. Note the broad sheets of cells without alveolar

formation.

From this standpoint is it necessary to eliminate all tumors with distinct
lumina and especially those of papillary structure. There remains a con-
siderable number of trabecular, or solid, or diffusely growing or sarcomatoid
tumors which differ essentially from renal adenocarcinoma.

The simplest structure reproduces one or more zones of the adrenal cortex.
Some resemble the hyperplastic nodules of the adrenal itself (struma supra-
renalis). The cells are arranged in small circular groups separated by fine
strands of connective tissue (zona glomerulosa). This structure may be
uniform in tumors several centimeters in diameter. Or the elongated cords
of the z. fasciculata may predominate. The characteristic cytoplasm is not
clear but slightly granular with numerous lipoid globules and glycogenic
granules, yielding a foamy texture. Hydropic degeneration may consider-
ably enlarge the cell borders. The attachment of the cells to the stroma is
loose and the palisade arrangement of rigid cylindrical cells of renal car-

738

NEOPLASTIC DISEASES

cinoma is absent. Tumors of this type may be designated as adrenal ade-
noma of the kidney.

A peritheliomatous structure is presented by certain 'adrenal tumors, but
this type is extremely difficult to distinguish from similar structures in renal
carcinoma. Section of many portions of the tumor and attention to the
gross relations are then of much value. Peritheliomatous structures are
more atypical and malignant than the adenomatous. The cells are loosely
attached, lacking the clear mosaic appearance of renal carcinoma, and present-
ing a granular and vacuolated texture. Large granular giant-cells may form,
and some tumors are composed almost exclusively of giant-cells, both in
the original tumor and in metastases.

A trabecular arrangement is followed in some adrenal tumors of the kidney
in which the granular and fatty cells appear in broad anastomosing sheets

FIG. 338. — Adrenal medullary tumor of kidney.

supported by vascular stroma. These tumors also approach the type
of some renal carcinomas, but the absence of lumina or papillae, and the
smaller size and granular characters of the cells strongly indicate their
adrenal nature.

The most malignant forms of adrenal tumors of the kidney present
a carcinomatous or sarcomatous structure. The cells appear in small groups
(alveolar sarcoma) or grow diffusely. In well-nourished areas the tissue
may resemble over-cellular liver tissue. Giant-cells may be very numerous.
The form is polyhedral or round or elongated. In some cases the meso-
blastic tendencies, emphasized by Adami, yield areas of large spindle-cells
and the appearance is distinctly sarcomatous. The cell borders are indis-
tinct and the cytoplasm is still more granular and opaque and less fatty.
Areas of pigmented cells, doubtless representing the chromaffine substance
of the medulla, may be present, as in cases described by Weichselbaum and

TUMORS OF KIDNEY 739

Greenish, Ambrosius, and Manasse, and in one case of the writer's. Lassagna
describes a bilateral carcinosarcoma presenting both ganglion-cells and chro-
maffine pigment.

All the above structures are duplicated by tumors of the adrenal gland.
Whether other observed types of malignant adrenal tumors contribute
any portion of the so-called round-cell or alveolar sarcomas of the kidney
remains to be shown.

Differentiation between Adrenal and Renal Tumors. — The debate over
the structure of adrenal tumors of the kidney has been continuous since
1893, when the question was opened by Sudeck, and was accelerated by
Stoerk's publication in 1908. It concerned chiefly the significance of lumina,
the evidence of a papillary structure, and the chemistry of the cells.

The presence of lumina in adrenal tumors has been maintained by Grawitz,
Marchand, Askanazy, Dobbertin, and Manasse. In the normal adrenal
lumina are described by Kolliker, Stilling, and Eberth. In the adrenal of
the horse and cow, lumina appear to be constant. Yet in the human adrenal,
adrenal rests, and adrenal tumors, lumina are conspicuous chiefly by their
absence, while their occasional presence is hardly sufficient ground for
assuming that tumors of the kidney, in which lumina are the predominant
feature, are derived from adrenal tissue. Pseudolumina may form by central
degeneration of tumor cords, but this origin cannot explain the well-defined
structure described by Manasse. Dobbertin's tumor was an embryonal,
alveolar and papillary tumor, of uncertain origin in a child. Winkler of ten
speaks of lumina in his adrenal tumors but depicts only pseudolumina caused
by degeneration. It is also possible that certain adrenal tumors are derived
from renal rests. Beneke and Ulrich describe renal tubules in the adrenal
cortex. Ricker found groups of renal tubules in the adrenal joined to the
kidney by cords of connective tissue, and concludes that hypernephroma
may have a mixed adrenal and renal origin. The presence of lumina therefore
is a somewhat uncertain criterion on which to separate adrenal from renal
growths, but it cannot be questioned that a predominance of this feature
tells strongly against an adrenal origin. Yet small adrenal adenomas may
show an irregular alveolar structure.

The same considerations apply to the papillary structures of supposed
adrenal rest tumors. The markedly papillary character of renal carcinoma
is not approached in any authentic case of human adrenal growth. Never-
theless a certain papillary structure which is less pronounced than in renal
carcinoma, may appear in adrenal tumors which are chiefly of perivascular
type. Winkler describes such a structure in the pulmonary metastases of a
bilateral adrenal growth. A low papillary growth may be present also in
small adrenal adenomas. In and about cystic cavities which form in
adrenal carcinoma from hemorrhage and softening localized papillary growth
may occur.

The characters of the cells in adrenal growths differ distinctly from those
of most renal tumors. In the former the cytoplasm is foamy, granular, and
interspersed with lipoid granules. In most tumors the granular character
increases and the fatty appearance diminishes with the increase in malig-
nancy. In the renal tumors the cells are remarkably clear throughout,
resemble vegetable cells, and contain large globules or crystals of fat with
hydropic fluid, and little or no granular material. Lubarsch thought the
abundance of glycogen a strong diagnostic point in adrenal growths, but it
may be equally abundant in renal tumors. Glycogen is scanty in the normal
adrenal. Hydropic degeneration is usually missing in adrenal growths
(Zehbe) but very marked in Grawitz' tumors.

740 NEOPLASTIC DISEASES

Fat is present in both renal and adrenal tumors, and in both the lipoids
consist chiefly of cholesterin esters (Panzer) and are doubly refractive
(Lohlein, Stoerk). The fat content in Ipsen's cases ran from 4 to 10.7
per cent, while that of the horse's adrenal was 30.8 per cent. Sisson finds
the fat very unevenly distributed in Grawitz' tumors, but quite uniformly in
adrenal growths.

The loose relations of the cells to one another and to the stroma in many
adrenal growths contrasts with the rigid cell borders and coherence of the
cells in renal papillary carcinoma. Areas of diffuse growth, of indifferent
spheroidal cells, and of spindle-cells are practically unknown in the renal
tumors but are frequent in adrenal growths. Giant-cells form in both
varieties of tumors, perhaps to a greater extent in those from the adrenal.
Pigmented cells belong to adrenal tumors. Fraser points out that the
primary structure differs markedly in adrenal from that of renal tumors,
and that while secondary structures due to malignant change or degeneration
may cause the renal to resemble the adrenal growths, the primary structures
of both types are distinct. Hence the diagnosis must be based only on the
primary structure and not on non-specific secondary changes. Many
sections from various portions of the tumor may be required to detect the
primary structure.

Among miscellaneous data may be mentioned the fact, pointed out by
Stoerk, that Grawitz' tumors while very frequent in the kidney are very rare
in the adrenal. Ellis collected 157 in the kidney, three in adrenal, two in liver,
and one in uterus. Garceau mentions 176 in the kidney, while Woolley
could find only 22 in the adrenal. Glynn points out that abnormal sex
characters are commonly present with adrenal growths, but invariably
absent with Grawitz' tumors. Wells failed to find adrenalin in a typical
Grawitz' tumor.

Croftan observed that a watery extract of the adrenal caused rapid
decolorization of starch blue from action of iodine, and transforms starch
or glycogen into maltose or dextrose, while injection of this extract into
dogs and rabbits produces glycosuria. He employed this test for the
recognition of adrenal tumors of the kidney. Results of the test in the hands
of Korber and Winkler were not uniform. Ellis found the reaction in a
variety of tissues.

Conclusions. — Sufficient evidence has been adduced to prove, in the
writer's opinion, that the group of adrenal tumors of the kidney differs, as
a whole, quite distinctly from the renal adenocarcinoma with clear cells.
The main distinctive features of the adrenal growths are the central fibrous
core and exact reproduction of the adrenal by benign growths, and the
general mesoblastic tendencies of the malignant forms. Chromaffine cells
are not infrequently present. For an alveolar or papillary structure it is
extremely difficult to establish an adrenal origin in man. Yet the opponents
of Grawitz' theory seem to have gone too far in practically eliminating the
adrenal rest as a source of renal tumors. In atypical cases of both varieties
it may be impossible to establish a positive differentiation.

Tumors of Extrarenal Adrenal Rests.— The distribution of adrenal
structures outside the kidney corresponds to the location of groups of tumors
which present a structure suggesting an origin from adrenal tissue. Three
main divisions of aberrant adrenal tissue are found :

(a) Along the suprarenal vein, solar plexus, and inferior surface of the
liver ;

(b) Along the internal spermatic vein, in the broad ligament and about
the uterus, ovary, and tube, in the female;

TUMORS OF KIDNEY 741

These adrenal rests are usually of comparatively simple structure, pre-
senting only cortical tissue, but in several instances pigmented medullary
tissue is present. The absence of pigmented cells is not a certain indication
of entire lack of medullary elements, since pigment is late in appearance
even in the normal adrenal. From the usual construction of the rests only
cortical tissue can be expected in the tumors. In the rare cases of hyper -
plasia of aberrant adrenal tissue described by Marchand, Gunkel, and Pick,
only cortical tissue was apparent. Yet Chiari's and Schmorl's tumors con-
tained brownish or yellow pigmented cells.

The tumors attributed to these rests have often shown such striking
resemblance to adrenal adenoma as to leave little doubt of their true
nature. In others the structure has been less specific, often peritheliomatous,
or carcinomatous, and the derivation from adrenal tissue must remain
doubtful. In some reported cases, especially in the liver, ovary, and testis,
the adrenal origin is highly questionable. Thus, Pepere's hypernephroma
of the liver is clearly an hepatic adenoma, while some of the supposed hyper-
nephromas of the ovary and testis can equally well or better be interpreted as
atypical forms of well-known carcinomas of these organs.

In general the tumors are well encapsulated, of large size, cystic or
solid, of light yellow color, with a tendency toward necrosis and hemorrhage.
They possess considerable malignancy and local extensions and general
metastases are frequent.

Hepatic Hypernephroma. — Schmorl who reported finding four examples
of adrenal rests in the right lobe of the liver, also described a small yellowish
tumor in this region presenting the structure of adrenal cortical adenoma.
Larger malignant tumors probably of the same nature are recorded by Vecchi
and Noyes.

Peritheliomatous structures in hepatic tumors have often been regarded
as of possible adrenal origin. An angiosarcoma of the pancreas was so inter-
preted by Ribbert and Kronlein.

Lateral Retroperitoneal Tumors of Adrenal Pests. — The retroperitoneal
tissues above and below the kidney and extending into the pelvis are the
seat of a wide variety of tumors of sarcomatous and carcinomatous types.
Goebel has tabulated 101 cases, illustrating the wide scope of this group of
tumors. They include benign connective-tissue growths, lipoma, fibroma,
fibromyomas, and ovarian cysts, various types of sarcomas, rare carcinomas,
teratomas, and cysts, and four adrenal rest tumors.

Chiari's case, the first reported definite extrarenal hypernephroma, was
a large tumor lying below the kidney on the quadratus lumborum, reaching
the true pelvis, and extending into the mssocolon and along the crural
vessels. The gross and microscopical structure was rather typical of adrenal
adenocarcinoma. Weiss described a very similar case. Goebel's tumors
both grew through the mesocolon in the peritoneum or abdominal wall.

Adrenal Tumors of the Broad Ligament, Ovary, Tube and Uterus. —
Peham has described two large cystic and solid, yellowish tumors of the ovary,
•which presented a structure recalling that of hypernephroma. Scudder's case
of bilateral ovarian tumor, of very similar structure, does not strengthen the
probability of an adrenal origin. The rare tumors of the corpus luteum
offer a strong resemblance to hypernephroma and certain fatty and hydropic
ovarian carcinomas closely resemble adrenal growths.

In the broad ligament Weiss and L. Pick have each described large yellow-
ish, hemorrhagic and necrotic tumors, displacing uterus and ovary, and
exhibiting many microscopical features of hypernephroma. In a large tumor

742 NEOPLASTIC DISEASES

attached to the fundus uteri, Eastwood describes rather typical reproduction
of the zona glomerulosa of the adrenal, as well as alveoli filled with colloid,
as in the thyroid gland.

Hypernephroma of Spermatic Cord and Testis.- — Adrenal tumors of the
testis are described by Chevassu and Debarnardi, but their exact nature
appears rather uncertain.

EPITHELIAL TUMORS OF RENAL PELVIS AND URETER

The renal pelvis and the ureters are the seat of tumors very similar to
those of the bladder. They take the form of :

(1) Papilloma

(2) Papillary epithelioma (epidermoid carcinoma)

(3) Alveolar carcinoma.

Of 54 such tumors collected by Albarran and Imbert 22 were benign
papillomas, 16 epitheliomas and 16 carcinomas. Savory and Nash have
tabulated 49 cases. The tumor occurs chiefly between the ages of 35 and 65
years, much more frequently in males, and in 8 of 53 cases there were calculi.

(1) Papilloma is a benign growth which affects any portion of the renal
pelvis or ureter. In 7 cases both were involved, while in 6 the ureter was
the primary seat, especially the upper or lower orifices. Pelvis and ureter
throughout were affected in the cases of Lancereaux, Fenwick, and Hebb.

The tumors are usually multiple and may be extremely numerous, covering
the entire mucosa with fine vegetations. Often there is one large composite
tumor and several small polyps scattered over pelvis and calices (Kohl-
hardt) . Albarran holds that multiple tumors are often the result of implan-
tation, but it seems more probable that in cases of very extensive distribution
the tumors develop all along the genito-urinary tract, as the result of factors
affecting the entire mucous membrane. In the cases of Murchison and of
Neelson, the bladder was involved with pelvis or ureter, and Murchison's
case was bilateral. The tumors are villous or wart-like, attached by a
narrow pedicle and expanding in fan shape. Very fine branching growths
collapse on removal and require floating in water for restitution of the
original form. The great vascularity is a source of hemorrhage, which is
the chief symptom. Incrustation with salts and association with calculi is
frequently observed, and the intervening mucosa may be the seat of chronic
pyelitis sometimes cystic (Stoerk). Various grades of hydronephrosis often
result from partial occlusion, chiefly by ureteral tumors. The structure
presents elongated branching blood-vessels sometimes accompanied by
smooth muscle-cells, covered by multiple layers of transitional epithelium.
The tumor-cells are cubical, cylindrical or much elongated and spindle
shaped, but the form and arrangement are orderly and typical. At the bases
of the tumors there is round-cell infiltration.

While the course of these tumors is usually benign, not a few of them have
recurred in malignant form after curettage or incomplete removal. They
are distinctly capable of developing recurrences from implantation in the
wound. In Tikhoff's case the recurrence developed locally as alveolar
carcinoma, 10 years after operation. Very suggestive is the case of Drew — •
villous papilloma of pelvis invading the kidney, simple papillary excrescences
throughout the ureter, and a large papilloma at the vesical orifice.

(2) Papillary epithelioma produces more numerous and more compact
tumors than the benign papilloma. They appear as closely set, opaque,
warty outgrowths which are usually found to cover a considerable area.
Both pelvis and ureter may be involved, as in the cases of Rayer, Drew,

TUMORS OF KIDXEY 743

Israel and Poll, or a recurrence of a pelvic tumor may later appear in the
ureter (Israel, Fenwick). Pelvis, ureter and bladder may be simultaneously
involved (Rayer, Drew, Israel). Even in early stages of the growth
there is a tendency toward encroachment on the submucous tissues and
renal parenchyma. In a case pictured by Kuster the entire visceral layer of
mucosa was involved by low warty growths and the renal cortex was per-
forated. It is sometimes difficult to determine in the gross whether the
original growth is renal or pelvic (Graupner). In advanced cases the
pelvis may be distended and obliterated and fused with surrounding tissues,
and the kidney may either be invaded and deformed, or multiple cysts may
distend the cortex in hydronephrosis.

Finally there is a form of diffuse infiltrating carcinoma of the kidney,
the organ being much enlarged but not greatly deformed, which probably
originates as papillary carcinoma of the pelvis (Graupner, Hildebrandt,
Beneke, Milne). A case of this type, which first suggested a diagnosis of
endothelioma, is described by Beneke and Namba and attributed to a trauma.
Yet the neighboring lymph-nodes were tuberculous.

Metastases are often observed in adjoining nodes, adrenal, peritoneum,
liver, lung, and in Kischenky's case, in the femur. Mesenteric, aortic and
perirenal nodes may be invaded (Rayer, Drew, Volcker). Along the genito-
urinary tract extension occurs by '(a) lateral encroachment of the tumor
through the lumen, submucosa, or mucosa of the ureter; (b) by the develop-
ment of new tumors over increasing segments of the mucosa; and (c) accord-
ing to Albarran, by implantation.

The structure presents two distinct types: (i) simple papillary epithe-
lioma, suggesting a relation to benign papilloma and (2) squamous-cell
carcinoma.

(1) Papillary epithelioma shows overgrowth of the cell layers of benign
papilloma, atypical cell forms, and infiltrating qualities. In infiltrating
tumors the papillary structure is soon lost and the growth is alveolar or
diffuse or scirrhus.

The transformation of benign into malignant papilloma has been made
clear by Albarran. In Battle's case simple papilloma- curetted from the
pelvis soon recurred with malignant structure. Pantaloni observed a recur-
rence in malignant form in the scar after nephrectomy for a uniformly
benign papilloma. In portions of chiefly benign papillomas, especially at the
base, atypical overgrowth is sometimes observed. The long duration of
symptoms preceding the discovery of a malignant papilloma suggests the
development of a slowly growing benign tumor followed by malignant
transformation. Yet benign papillomas appear to have existed for 6, 12,
and 27 years (Battle, Albarran, Pantaloni) and the malignant properties
have developed only after incomplete extirpation.

(2) Squamous-cell carcinoma of the pelvis was described by Kundrat
in 1891 and later cases have been reported by Rundle, Graupner, Kischensky,
Beisenbruch, and Scheel. These remarkable tumors are usually of large
size when discovered, but Battle observed squamous changes in a small
villous tumor of the pelvis and Rundle found the upper ureter invaded by a
squamous carcinoma of moderate dimensions. In other cases the pelvis
has been distended and the wall infiltrated by a bulky growth. The kidney
is either transformed into large cysts by hydronephrosis or infiltrated and
destroyed.

The squamous changes are very pronounced and much of the growth
may be composed of epithelial pearls many of which are hornified or calcified.
In Schmorl's case distant metastases showed the same structure.

744 N EOF LA STIC DISEASES

That the pelvic and ureteral epithelium is capable of extensive epidermi-
zation is well attested by the reports of Wendel of numerous cases of leu-
koplakia, usually associated with calculi. Rokitansky described a very
advanced condition, with much scaly desquamation, as "cholesteatoma."
Ziegler found marked epidermization in pyelitis calculosa, and Beselin re-
ported an advanced case with tuberculous pyelitis. Yet all cases are not
associated with calculi or leukoplakia, so that the excessive hornification
must be regarded as a tendency inherent in the growth.

| In a case studied by the writer in a woman of 58 years, the kidney and tumor measured
14 X 19 cm. The tumor involved chiefly the extrapelvic fat but had occluded the lower
half of the pelvis, along which it invaded the kidney. The renal cortex was thinned out
over several large smooth- walled cysts. The ureter was destroyed down to the bladder.

FIG. 339. — Epidermoid carcinoma distending the renal pelvis. Alveolar growth of small
polyhedral cells with abrupt and extensive pearl formation.

There were metastases in aortic and mesenteric nodes and in the uterus. The main bulk
of this large tumor was composed of hornified and slightly calcified epithelial pearls sur-
rounded by a moderate number of spindle or cubical granular epithelium. The transition
from one to the other type of cell was very sharp.

(3) Alveolar carcinoma of the renal pelvis is not clearly distinguished
from papillary epithelioma, which in advanced and malignant cases may lose
its papillary character and present the structure of alveolar or diffuse or
scirrhus carcinoma. Hildebrandt describes a large tumor of pelvis and
kidney, the pelvic portions of which were papillary, the renal being scirrhus.
Yet Albarran describes papillary adenoma with cylindrical cells in pelvis
and ureter, and Giordano found chiefly cylindrical cells in a pelvic tumor,
while several others have appeared to show no trace of papillary but exclu-
sively glandular and alveolar carcinoma (Hedenius, Wirsing, Hektoen.

TUMORS OF KIDNEY 745

Hartmann, Israel). In Grohe's case the structure resembled thyroid gland
and he attributed its origin to the tubular glands of the pelvic mucosa.

The early pelvic and ureteral tumors are described as flat and infiltrating
rather than papillary. The advanced tumors are large, infiltrating and
highly malignant.

TUMORS OF THE RENAL HILUS

The tissue of the renal hilus gives origin to several forms of simple and
of complex tumors, which may be distinguished from tumors of renal paren-
chyma, or pelvis, or adrenals, and for which special embryological errors
appear to be responsible. Tumors of the hilus develop about the renal
vessels and the ureter, which are soon compressed, and the kidney is often
found stretching over the tumor mass as a shell incloses a nut. The tumors
are often bilateral. Most of them are observed in children, but not a few
appear in adults.

Lipoma of the hilus is not infrequent. It may be difficult to separate
from hypertrophy of the fat tissue which follows atrophic conditions of the
kidney. The hilus fat tissue is also the seat of a chronic productive inflam-
mation in which the fat is infiltrated with lymphocytes and plasma-cells,
and thickened by new connective tissue, so that it is much increased in bulk.
Hollen described a well-circumscribed lipoma.

Angiolipoma surrounding the vessels and pelves of both kidneys is
described by Salomon.

Myxoma and myxosarcoma of the hilus produce bulky masses which
infiltrate the surrounding tissues and cause displacement, stretching, and
atrophy of the kidney. In four large tumors of this type I have found con-
siderable admixture of actively growing fat tissue.

Schluter reported a large myoma which had caused nearly complete
atrophy of the kidney.

Diffuse Sarcoma of Hilus and Renal Pelvis. — A peculiar form of sarcoma
of the hilus and pelvic tissue has been described by de Vecchi and by Salomon.
The tumors were bilateral and occurred in infants under two years of age.
The tumor- tissue encircled the ureter, great vessels, pelvis, and papillae,
but was well demarcated from the renal parenchyma. The structure was
complex, presenting areas of round, spindle, and giant-cells, which invaded
and destroyed the fat and muscle-tissues, de Vecchi found areas of chromaf-
fine cells which he regarded as a portion of the neoplasm derived from mis-
placed chromarfine tissue, but Salomon interpreted these cells as remnants
of the normal paraganglia or adrenal structures of this region which had
resisted destruction by the tumor. Both authors were inclined to regard
the tumors as derived from remnants of the nephrotome or sclerotome and
therefore related to the Wilms' tumors of the kidney, but the grounds for
this interpretation are not clear.

CHAPTER XXXVIII
TUMORS OF THE ADRENAL

The embryology of the gland and the very variable histology of its tumors
render it difficult to choose a satisfactory terminology of adrenal growths.
Since the adrenal cortex is of mesothelial origin, neoplasms of this tissue may
be designated as mesotheliomas. The tendency of many of these tumors to
reveal mesoblastic or sarcomatous properties also supports the suggestion
of Adami and Woolley that recognition of this fact be granted by employing
the term mesothelioma. Yet the acquired epithelial characters of the gland-
cells predominate in most of the growths, which behave as adenomas or
carcinomas. In others the structure of epithelial alveoli is mingled with
areas of spindle-cells as in carcinoma-sarcoma. In a well-known group the
cells are large, round, and atypical and the structure presents itself as round-
cell sarcoma. Yet there is very good reason to believe, as pointed out by
J. H. Wright, that all the round-cell sarcomas of children are derived from
the nervous elements of the sympathetic. Hence they may properly be
called neurocytoma. Of these some show definite ganglion-cells and nerve-
fibers, and have been called neuroma^ or glioma ganglionare. Finally, there
are rare tumors composed of chromaffine cells and although these cells are
originally derivatives of the neural elements, their acquired characters
dominate the neoplastic process and demand for them a separate classi-
fication.

The entire group falls into two divisions (i) cortical and (2) medullary,
in which the following special forms are observed.

ADRENAL TUMORS

Cortical: (a) Hyperplasia, nodular or diffuse

(6) Adenoma

1. glia-tissue or

2. chromaffine cells.
(6) Neuroma ganglionare

(d) Suprarenal chromatophoroma.

Hyperplasia. — Various grades of focal hyperplasia of cortical tissue are
well known but rather rare conditions in the adrenal. All gradations exist
between simple focal hyperplasia and true adenoma and the distinctions
between them are not always emphasized. Letulle observed both conditions
in the same adrenal. Virchow described the group as struma suprarenalis.

The nodules appear as pinhead or pea-sized masses of light yellow or
brownish color, sharply circumscribed but not encapsulated. Larger masses
of apparently the same significance may reach the size of a cherry and form
a well-defined projecting tumor.

Diffuse hyperplasia of the adrenal is also observed. It affects the cortex
and is usually associated with feminine pseudohermaphroditism (Glynn,
Lit.). In these cases the adrenal may be as large as the kidney (Marchand,
Febiger).

The structure reproduces that of the cortical zones. The cells and

746

TUMORS OF THE ADRENAL 747

cell groups are often larger than normal and may be irregularly arranged.
The tumors are usually very fatty and have been mistaken for lipomas, but
usually they present the structure of the zona glomerulosa or reticularis.

Letulle has shown that nodular hyperplasia of the adrenal may be asso-
ciated with a similar condition in the liver and occurs in a variety of diseases.
Sex abnormalities, as overgrowth of hair and genital organs, are observed
occasionally with nodular hyperplasia but especially with definite tumors of
the adrenal.

Adenoma of the adrenal is distinguished from nodular hyperplasia by its
atypical and neoplastic structure. From the presence of adenomatous
areas in portions of malignant adrenal growths it is evident that many of the
latter arise from the former. Adrenal adenoma is comparatively rare,
Kelynack finding three cases in 1500 autopsies. In some of the cases of
pseudohermaphroditism the process in the hyperplastic adrenals approaches
adenoma.

The tumors are usually single but may be multiple and bilateral. They
form projecting masses of yellowish or reddish color, well circumscribed from
the cortex of the gland but often deforming or destroying the organ. Hemor-
rhage and central softening may occur. They may reach a considerable
size, weighing 2-4 ounces while retaining the adenomatous structure. A
fibrous stroma is nearly constant and may be abundant, rendering the tumors
quite firm and fibrous (fibro-adenoma). More often the stroma is fine and
vascular. Rarely the tumors are surrounded by a definite capsule. The
structure may reproduce exactly that of the adrenal cortex, with increase in
the size of the cells, hyperchromatism of nuclei, and often with marked fatty
changes. Or the cells may be smaller, more numerous, granular, and free
from fat. Irregular alveolar structures with lumina and low papillary
growths are described by Kelynack in benign tumors. Lumina surrounded
by cylindrical cells are also described in Manasse in adrenal adenoma, and
this structure appears to be very frequent in horses.

Rolleston described a brownish fibro-adenoma as large as a walnut.
Extensive fatty changes may produce a structure resembling lipoma. Auvray
and Pfeffel described a large tumor, in a case of pseudohermaphroditism, as
adeno-angiolipoma. In a few reported cases the cells were markedly pig-
mented but these tumors were probably medullary.

The limits of growth of adrenal adenoma are restricted. In pure form
they do not reach large dimensions or produce metastases and most of them
are encountered at autopsy. Malignant transformation into adenocarcino-
ma or still more atypical growth appear to be of relatively common occurrence.

Carcinoma. — Malignant tumors presenting epithelial characters are much
the most frequent of adrenal growths. Winkler observed 10 such cases
to three sarcomas, and suggests that even the sarcomas arose from cortical
epithelium. Rolleston and Marks, however, interpreted only 9 of 26 col-
lected cases as carcinoma or malignant adenoma, but they assume that sar-
coma may arise from the cortical epithelium. The average age of incidence
in 9 cases was 44 years. Winkler observed 2 cases, at 19 years, and at
66. Several of his cases gave a history of trauma.

The tumors are usually found at autopsy, of large size, involving the
whole of the adrenal, adherent to or fused with the kidney and bound to
neighboring structures by many extensions.

The earlier tumors are smaller and imbedded in the enlarged adrenal,
of which the outline may be partly retained. At all stages they are soft,
yellowish and prone to hemorrhage and necrosis. Central softening may
yield cysts of large size but the very cellular tumors are usually rather solid.

748 NEOPLASTIC DISEASES

Early and widespread extensions and metastases are a prominent char-
acteristic of adrenal carcinoma. Although there are some reports of a
stationary tumor persisting for months or years before active growth occurred,
most of the adrenal carcinomas progress rapidly from the first symptom.

The local extensions invade the kidney and perirenal tissue so that it
may be difficult to separate the tumor from the kidney. The adrenal is
often obliterated. The suprarenal and renal veins are early invaded as in
hypernephroma. The renal pelvis may be distended by tumor masses
(Winkler). The peritoneum is often the seat of numerous implantations.
The opposite adrenal is frequently involved, and there are extensions to the
spleen, liver, and abdominal organs. The lymphatics are invaded with
enlargements of retroperitoneal, mesenteric, and thoracic nodes. The intra-
venous growths may reach in a solid column to the right heart (Gerber),
but usually they break up and give origin to very numerous distant metas-
tases. Hardly any organ of the body may escape secondary deposits,
but they are most frequent in liver, lungs, and brain. The frequency of bone
metastases in tumors of supposed adrenal origin has long been emphasized
but in most of the reported cases the tumor arose in the kidney and its
exact nature was not fully determined. In cases of fully verified adrenal
carcinoma bone metastases are infrequent. They occurred in 3 of Winkler's
10 cases. In 48 cases of various malignant adrenal tumors collected by
Hartmann and Lecene, bone metastases were demonstrated in only i, while
the liver was involved in 23; lungs, 9; preaortic nodes in 8; peritoneum, 5;
stomach, pancreas, heart and brain, occasionally.

The structure of atypical adrenal carcinoma is essentially specific but
there are atypical forms which are difficult to separate from sarcoma.

(a) Adenocarcinoma or adenoma malignum is a type which resembles
adenoma but shows atypical areas of malignant character and yields mstas-
tases. Yet the arrangement of cells is orderly and reproduces the alveoli
of thez. glomerulosa or the anastomosing sheets of enlarged columns from the
z. fasciculata. The diffuse growth of atypical cells as in true carcinoma
is missing. There is usually considerable vascular stroma. Lumen for-
mation is rare. The cells closely resemble the fatty granular cells of the
normal gland but are large and the nuclei are hyperchromatic. Various
secondary changes result from necrosis and hemorrhage, including especially
the formation of giant-cells, cysts, and pigmentation.

As interpreted by Rolleston and Marks, the group of malignant adrenal
adenoma includes a large proportion of the malignant tumors, and transi-
tional stages to carcinoma are so frequently found in these growths that a
sharp separation from other types is impossible. Clinically they are fully
malignant, although Winkler described a very large tumor of this type
without extensions.

(b) Fully developed carcinoma also presents several peculiarities of
structure. A prominent type, often encountered, shows chiefly large granu-
lar and fatty cells in perivascular arrangement. This structure is but
slightly removed from the vascular adenocarcinomas but is usually more
active, atypical, and malignant. By softening of central lines of cells the
structure may assume a pseudopapillary type.

Giant-cells of large size may become very numerous in tumors which are
chiefly perivascular carcinomas. Almost the entire tumor and its metas-
tases may be composed of giant-cells. Such structures have been inter-
preted as sarcoma, as in Affleck and Leith's case. They are fully paral-
leled by giant-cell types of hepatoma. Carcinosarcoma is a complex struc-
ture seen in not a few adrenal carcinomas (Adami, Woolley). Certain

TUMORS OF THE ADRENAL 749

areas of these growths may present any one of several carcinomatous types,
as alveolar or perivascular, while in other large areas or sheets the cells are
elongated, spindle shaped, compact, and granular. It appears possible
that the spindle form represents a recrudescence of mesoblastic tendencies,
but in many cases such cells occur owing to purely local factors.

Diffuse carcinoma appears in the most malignant forms of adrenal car-
cinoma. The cells lose all resemblance to adrenal parenchyma, and appear
as rounded or polyhedral granular cells notably free from fats and glycogen.
They grow diffusely or in small groups, rapidly penetrate surrounding
tissues and produce bulky metastases. That some of the so-called sarcomas
of the adrenal are highly atypical growths derived from the renal parenchyma
appears quite possible.

The course of malignant adrenal tumors is usually rapid and fatal. In
several cases the usual course has been interrupted by a successful extirpation
(Hartmann, Lecene, Lit.). Beginning with signs pointing to a growth in
the region of the kidney, there usually follow, pain, palpable tumors,
asthenia, and cachexia. Pigmentation of the skin was stated by Fox to be
very rare, but this symptom and others of the Addison complex appear more
frequently in recent reports. Winkler reports two cases of well-developed
Addison 's disease associated with cortical tumors of the adrenal. In a
series of cases various disturbances ol the sexual characters, hirsuties, pseudo-
hermaphroditism, precocious development of the genitals, and obesity, have
been associated with adrenal tumors. It has been clearly shown by Glynn
that these sexual and nutritional disturbances are observed only with cortical
tumors, hyperplasia, adenoma, or carcinoma.

MEDULLARY ADRENAL TUMORS

Tumors of the adrenal medulla include three well-defined types:

(1) Neuroma ganglion are.

(2) Neurocytoma. Neuroblastoma.

(3) Chromamne cell-tumors. Paraganglioma.

Virchow refers to the occurrence of multiple nodules in the adrenal which
he assumed to be gliomatous.

While pure examples of each of these tumors are observed there are
many transitions between them, and in Wahl's case all three were repre-
sented in portions of the same tumor. The more adult neoplasms occur
chiefly in adult or elderly subjects, the malignant growths are practically
limited to children, while the chromamne tumors are often associated with
some phase of neurofibromatosis. All these features accord with the origin
of the tumors, which arise from the sympathetic anlage which goes to form
the adrenal medulla, and the varying structure of the tumors indicates an
origin at successive stages of the differentiation of the sympathetic neuro-
blasts. Similar tumors have been reported, and will doubtless be recognized
more frequently, throughout the entire distribution of the sympathetic
system and its chromafTine glands (Herxheimer, Wahl, Lit., Dunn, Lit.).
The great majority occur in the adrenal medulla and in the abdominal
sympathetic.

(i) Neuroma ganglionare is a rare tumor in the adrenal and belongs in
the group of ganglionic neuromas which arise throughout the sympathetic
system.

A small glioma composed of medullated nerve-fibers and proliferating
ganglion-cells in the adrenal was described by Weichselbaum in 1881, and
similar cases have been reported by Dagonet in a subject of Addison's

750

N EOF LA STIC DISEASES

disease, by Schmidt and by Bruchanow. Schmidt's tumor arose from the
suprarenal plexus and only partly involved the gland. These tumors may
reach considerable dimensions, but they are not locally aggressive and metas-
tases are absent. They probably arise from well-differentiated sympathetic
nerve tissue. The structure shows a preponderance of medullated and non-
medullated nerve-fibers, among which lie groups of more or less well-formed
proliferating ganglion-cells. Many of these are of relatively small size and
approach the form of indifferent polyhedral cells. Others are large and

FIG. 340. — Drawing of neuroblastoma of right suprarenal, viewed from anterior aspect,
The outline of the flattened residue of the suprarenal body is distinguishable on the front
of the upper part of the tumor. The hemorrhagic character of the tumor is visible through
the thin capsule. The kidney is seen below and behind the lower pole. (After Dunn,
J. P.B., 18.)

multipolar and may contain lipoid pigment. Dagonet's tumor contained
much fibrous tissue and some smooth muscle-cells. Ohse's tumor appears to
have developed largely within the adrenal in a child of five years and was more
cellular than others of this group.

(2) Neurocytoma. — Marchand, 1891, described a cellular tumor of the
adrenal in an infant of nine months and interpreted the structure as a repro-
duction of the anlage of the sympathetic nerve tissue of the organ. A fuller
description of the structure and origin of these tumors was furnished by Kus-
ter in 1905. In a child of 14 weeks the right adrenal was transformed into a

TUMORS OF THE ADRENAL

751

tumor as large as a watch, the medulla of the other adrenal showed early
stages of the same growth, while the liver was extensively invaded. In a
second case, in an adult, the tumor was as large as the fist, but metastases
were absent. The tumors were sharply circumscribed from the cortex,
gray, with dark vascular areas. The structure presented very numerous
cell nuclei without definite cytoplasm, very often arranged in the form of
rosettes. Some of the cells were larger, better defined, and resembled the
polyhedral cells of the medulla. The matrix was' chiefly granular but in
the adult case fine fibrils were demonstrable. The stroma supported fine
blood-vessels. Kuster interpreted the tumors as of neuro-epithelial origin,
and Wiesel supported this general view, pointing out that in the development

FIG. 341. — Neurocytoma of adrenal in an infant. Note bulky masses of glia fibrils.

of the adrenal just such rosettes of cell nuclei appear in the sympathetic
anlage. From them are developed both ganglion-cells and chromaffine
cells. Lapointe and Lecene in describing a typical case demonstrated glia
fibrils in the matrix and concluded that the tumors arise in misplaced portions
of adrenal nerve tissue, but not in the normal anlage that forms the sym-
pathetic elements, which yield tumors with medullated fibrils and ganglion-
cells. Yet it seems that there are transition forms between the two groups,
indicating a common origin.

The resemblance between the cellular "gliomas" and the so-called con-
genital sarcomas and lymphosarcomas of the adrenal immediately became
obvious and Kretz in 1903 suggested that a series of lymphosarcomatous
tumors of the liver were derived from the sympathetic formative cells.
In 1910 J. H. Wright pointed out these resemblances in detail, concluded
that the adrenal and hepatic round-cell sarcomas of infants and many other

752 NEOPLASTIC DISEASES

territories, were probably of neurogenic origin, and he proposed for them the
term "neurocytoma."

This conclusion has been fully justified. The grounds for assuming the existence of
true mesoblastic sarcomas of the adrenal have never been adequately established. There
is no evidence that the stroma or blood-vessels contribute to these growths. Of traces of
fetal blood formation the adrenal preserves none. The existence of lymph-follicles in the
normal adrenal is not proven. Dagonet describes groups of lymphocytes in the cortical
zones but derives the parenchyma from these cells. The lymphocytes, lymph-follicles,
and plasma-cells occasionally seen in the adrenal are probably the result of circulatory and
nutritional disturbances (Oberndorfer). The diagnosis of sarcoma has been based on the
presence of indifferent round-cells, the origin of which has not as a rule been considered.
Yet in many cases the supposed sarcomas have presented the typical rosettes of neuro-
epithelium, while the clinical and anatomical characters are so uniform as to indicate a
single origin. Hence the work of many clinical observers who have shown that adrenal
"sarcoma" appears in certain characteristic clinical types is not reduced in'value by the
demonstration of the true origin of these tumors. Not a few of them appear to be of
bilateral origin (F. Hoist, Sabrazes, Husnot).

In recent years the retroperitoneal malignant neurocytomas of infants
and similar tumors in many other regions have frequently been recognized
and the structure has repeatedly been analyzed in detail (Landau, Anitschow,
Symmers, Wahl, Dunn). These histological studies have extended the
scope of the tumor so that it is necessary to include in this group many if
not most of the retroperitoneal round-cell sarcomas of infants, and many
embryonal and peculiar growths of cervical, thoracic and peripheral nervous
system, while a few cases have been found in the brain. The structure
varies in the degree with which nerve elements are developed, but in the
most immature types are imperfect rosettes, very numerous but ill-defined
fibrils giving an abundance of hyaline stroma, or many hyaline globules
staining with eosin. The hyaline globules resolve themselves into bundles
of imperfect nerve fibrillse connecting groups of neurocytes. Various other
structures may be interpreted as imperfect ganglion-cells, axis-cylinder
processes, or glia fibrils. Falk and others attribute the excess of fibril-
lar material to the activity of sheath cells which differentiate from the
tumor-cells and lay down nerve-fibers. The fibrils do not stain well by Wei-
gert's neuroglia stain, nor by Mallory's method, yet they may be detected in
formalin sections stained by eosin and hematoxylon. Landau secured excel-
lent results with iron-hematoxylon and Van Gieson's stain. Pick and Bielsch-
owsky stained the fibrils by the latter's method, which is not al\v ays successful.
Dunn, by means of Bielschowsky's and Levaditi's stains, was able to show
that the great bulk of the fibrillar material is composed of naked axis cylin-
ders. The fibril] ae forming the rosettes may resist all the specific stains.
The metastases are usually of round-cells only, with or without fibrillar
material, but in the cases of Miller and of Jacobsthal the secondary tumors
contained ganglion-cells.

In a recent case of the writer's, in a child of two years, the tumor first appeared on the
inner side of the left thigh below Poupart's ligament and grew rapidly to enormous dimen-
sions. It destroyed all the muscles of the thigh from knee upward, invaded and filled the
pelvis, destroying the muscles and invading kidney and adrenal. The retroperitoneal
nodes were extensively involved, and by way of the lymphatics the lungs were largely re-
placed by very numerous masses originating from the walls of bronchi and vessels. The
liver escaped. The tumor appeared to originate from the femoral sympathetic plexus.
The structure of the main tumor was that of round-cell sarcoma with indistinct alveolar
arrangement and occasional excess of hyaline stroma. In the lungs there were many ro-
settes surrounding hyaline globules and great excess of hyaline stroma in which many fine
fibrils were discernible. In many areas there were occasional large isolated multipolar
cells suggesting abortive ganglion-cells. The fibers in material fixed in formalin failed to
take Bielschowsky's stain, but were well defined by picroacid-fuchsin.

TUMORS OF THE ADRENAL 753

Clinical Types of Adrenal Neurocytoma. — (a) Adrenal Sarcoma in Infants
with Cranial Metastases (Hutchinson's Type). — Hutchinson described a
peculiar clinical syndrome in 13 cases of adrenal sarcoma occurring in children
from three months to nine years of age. The disaese begins spontaneously or
after trauma, with ecchymosis of one or both eyelids, soon followed by exoph-
thalmos, a tumor of the orbit and temporal region, with extensions to the
auricular and submaxillary nodes. The orbital tumor reaches large dimen-
sions, while an abdominal growth may be discovered only at autopsy. The
adrenal growth may be as large as a walnut or a child's head, but shows little
tendency toward local extension. Secondary growths appear also in ribs,
spine, and long bones, as well as in liver and other organs.

The structure of the tumors is usually described as round-cell sarcoma,
but in two -cases the diagnosis was hypernephroma (Aisenstein, McCarty),
and in one, melanotic carcinoma (Reimann — Chiari).

In the case of Tileston and Wolbach the tumor contained many rosettes
very similar to those observed in retinal and other gliomas. These authors
accept the adrenal origin of Hutchinson's tumors because the structure was
identical in all, while in six cases only adrenal, lymph-nodes, and bones were
involved.

There is thus no doubt that certain adrenal tumors in children follow
Hutchinson's type, but it appears also that other tumors, hypernephroma,
etc., may produce the same syndrome. Moreover, all round-cell tumors
of the adrenal do not produce orbital metastases.

(b) Congenital Sarcoma of Adrenal and Liver in Infants (Pepper's Type). —
The prominence of the hepatic metastases gives a somewhat striking clinical
character to a group of cases described by Pepper. The symptoms are those
of a rapidly enlarging abdominal tumor caused by diffuse and nodular growths
in the liver and adrenal. The other organs were not involved. One or
both adrenals may be affected and the tumors may reach large dimensions
with little tendency toward local invasion except to the liver. The duration
varied from 10 days to 16 weeks.

Structurally the tumors were described as round-cell or lymphosarcoma.
Winkler describes a case in an infant of two years in which the adrenal and
kidney were destroyed and there were bulky metastases in liver, lungs, skull,
musculature, and many lymph-nodes. Hence the presence of hepatic
metastases does not exclude them in other organs.

Much light has been thrown on the various anatomical and clinical
characters of these tumors by the study of P. S. Frew. He points out that
the medullary origin is indicated by the frequent persistence of a portion
of adrenal cortex along one segment of the tumor. It is quite evident, as
emphasized by Glynn, that the structure differs entirely from that of the
cortical growths. Frew regards the entire group as a type of medullary
carcinoma which extends along the lymphatics and yields secondary growths
in different territories, depending upon which adrenal is primarily involved.
The lymphatics of the left adrenal pass out with the vein at the lower pole
of the gland and join with the renal vein and its lymphatics, which have
rich connections with the lumbar and preaortic nodes. Tumors of the left
adrenal accordingly invade the regional nodes extensively, passing (a)
downward along the iliacs to the pelvis and groin, (b) across to the mesenteric
nodes, (c) upward to the hilus of the liver and thence into the liver by the
portal spaces, (d) through the posterior mediastinum, (e) along the inter-
costal lymphatics, and (f) through the deep cervical chain along the carotid
artery to the base of the skull. Hence with left-sided tumors deposits occur
in the above locations, especially in the ribs and cranium (Hutchinson's

754

NEOPLASTIC DISEASES

type). Secondary growths occurred in the substance of the liver in four of 2 2
cases and only in very young subjects succumbing to very rapid growths
(Pepper's type). The lungs were never involved with tumors of the left
side.

From the right adrenal the vein and lymphatics pass from the upper pole
and join the vena cava and main lymphatic trunk. This portion of the
adrenal is uncovered by peritoneum and is in contact with the bare area of
the liver. Hence local lymphatics are less involved, while the extensions
are to the surface of the liver (20 of 29 cases); the pleura and lung (9 of 16
cases in which the disease extended beyond the diaphragm); and to the right
cervical nodes with right-sided exophthalmos. The tumors of the right

gland were also more confined to the
abdomen (12 cases), reached a larger size,
and tended to involve the kidneys by
direct extension into the pelvis (n cases).
These rules were followed by the neuro-
cytomas of Kuster and Lapointe and
Lecene.

(c) Medullary Tumors with Adrenalin
Content and Nephritic Symptoms. — In a
male subject of 47 years, suffering from
active nephritis with glycosuria, albumi-
nuria, cardiac hypertrophy and hyper-
tension, and snowing finely granular
dark red kidneys, Orth found a medullary
tumor of the right adrenal, 7 X 4% cm.
A watery filtrate of the tumor gave a
green color when treated with ferric
chlorid, and contracted the living frog's
pupil, showing the presence of adrenalin,
while an extract from a secondary car-
cinoma in the adrenal failed to give these
reactions. Orth concludes that the car-
diac hypertrophy was referable to over-
production of adrenalin by the tumor.

The structure of this growth was
identical with many of the round-cell
sarcomas occurring in children. The
small round-cells he regarded as fore-runners of the chromaffine cells, while
others resembled the larger polyhedral cells of the normal medulla. Vaquez
and many others have noted high arterial tension with adrenal tumors

(Ellis, Lit.).

(3) Medullary Chromaffine Cell Tumors. — Nodular hyperplasia of the
pigmented cells is not infrequently observed in the adrenal, and appears in the
form of small brownish tumors as large as a pinhead or bean (Schmorl).
Such nodules are more common in the cow (Stilling) and a pigmented tumor
in the cow's adrenal is described by Zanfroginni.

Definite pigmented tumors of the adrenal medulla have been described
by Berdez, Manasse, Susuki, Kawashima, and Laignel-Lavastin. Obser-
vations on tumor growth of chromaffine cells extend, however, over most of
the territory known to contain elements of the chromaffine system.

Weichselbaum found chromaffine cells in a renal alveolar adenoma which
may have been derived from the adrenal. This observation is not infre-
quently repeated. In a tumor of moderate size occupying the whole of the

FIG. 342. — Medullary tumor of
adrenal.

TL'MORS OF THE ADRENAL

/oo

medulla of the adrenal I found very large polyhedral nonpigmented cells in
alveolar arrangement. The tumor was evidently derived from the chro-
maffine cells of the medulla. A similar peculiar structure appears in certain
renal tumors. Two small pigmented tumors penetrating the upper pole of the
renal cortex are mentioned by Wiesel and Stoerk. Stangl found a hard
brownish tumor at the bifurcation of the aorta, \\hich he derived from the
pigmented cells of ZuckerkandFs organ. Monckberg describes a tumor at the
angle of the jaw, and another in the left hyoid region, containing scanty
pigmented cells yielding chromaffine reaction, which he derived from the car-
otid gland. For this entire group of tumors Alezeis and Peyron propose the
name uparaganglioma."

FIG. 343. — Structure of tumor of chromaffine cells of medulla of adrenal.

The tumors in the adrenal have been of relatively small size, usually
as large as a walnut, but Susuki's tumor measured 10 cm. in diameter. They
are sharply demarcated from the cortex, of which a portion usually remains
at one segment. The substance is soft, cellular, and vascular, with areas of
hemorrhage and necrosis. Manasse found the large venous sinuses invaded
but without metastases.-

The structure presents small groups or a diffuse growth of round, oval,
spindle, or polygonal cells most of which are small. Giant-cells with single
or multiple nuclei also occur. The pigment is irregular in distribution
but gives the morphology and the many special staining reactions devised
for chromaffine substance. Homogeneous acidophile cell inclusions are usu-

756 N EOF LA STIC DISEASES

ally present. In Susuki's case some of the larger cells approached the type
of sympathetic ganglion-cells. The stroma is composed chiefly of capillaries.

An interesting physiological relation of this tumor appears in several
cases which occurred in subjects of cutaneous neurofibromatosis and pig-
mentation of the skin (Susuki, Kawashima, Herxheimer).

Adrenal Melanoma. — Small brownish benign cortical tumors of the adren-
al are described by Lucksch. They occurred in adults, were composed of
cortical cells containing pigment resembling melanin, and they seem to form
a probable source of the malignant pigmented tumors of the adrenal.

Primary bilateral melanotic malignant tumors of the adrenal are de-
scribed by Davidsohn, Goldzieher, Tuczek, and Maclachlan. The tumors
occurred in adults, were of moderate size, and sometimes produced extensive
metastases, but primary sources in the skin or choroid were missing. The
origin of these tumors it is difficult to determine. Not a few of the typical
adrenal carcinomas contain areas of pigmented cells of the adrenal type.
Davidsohn thought he recognized the structure of the zona fasciculata in a
mesenteric metastasis, claimed to have demonstrated adrenalin in this tissue,
and derived the tumor from pigmented adrenal cortical cells. Tuczek
found the pigment a true melanin and not a lipochrome as is found in the
adrenal cortex. He derived his tumor from the pigmented ganglion-cells
of the medulla, which contain melanin. Maclachlan concluded that the
adrenal melanoma arises from the wandering chromatophores which are
said to exist in the loose tissue about the adrenal. Yet the tumors seem to
involve the whole organ, which long preserves its form.

CHAPTER XXXIX
TUMORS OF PROSTATE

Hypertrophy of Prostate. — In about 33 per cent, of men over 60 years of
age, and occasionally much earlier, but never over 70 years, the prostate
becomes notably enlarged (Moullin). Greene and Brooks believe that the
condition may begin in youth, becoming noticeable only in later life. The
process probably begins in middle life (Gross, White), but very early cases,
collected by Belfield, appear to be of uncertain nature and probably
neoplastic.

The growth affects one or both lateral lobes, or the anatomical median
lobe, or the glandular tissue surrounding the orifice of the urethra, producing
growths of variable configuration. Obstruction to the urethra is caused
especially by enlargement of the tissue about the urethra which, as Home
(1811) showed, produces a valvular, polypoid or ring-shaped tumor at this
point (Home's lobe). Lesions originating at this point may spread to the
trigone, producing low or bulky intravesical growths. The dimensions are
often considerable, Gross reporting a prostate weighing 288 gm. Tortuosity
of urethra, retention of urine, and hypertrophy and sacculation of bladder,
are frequently observed, and dilatation of ureter and renal pelvis may result
from torsion of the vas deferens where it crosses the ureter (Tandler, Zucker-
kandl). After reaching a certain size most cases remain stationary, and
in these fibrosis may occur. Or a tendency toward fibrosis may be prominent
from the beginning.

The enlarged gland is hard or soft, depending on the prominence of con-
nective tissue and fibrosis or of gland tissue. On section there is diffuse
smooth translucent tissue, or nodular masses some of which may shell out
of their capsule. Many dilated alveoli may yield a spongy or cystic appear-
ance.

The structure showrs two main types (i) diffuse growth of connective
tissue with islands or strands of smooth muscle and (2) glandular overgrowth.
Brooks found fibrous overgrowth the predominant process in 41 of 58 cases.
The connective tissue is cellular, edematous, infiltrated with lymphocytes
and large hydropic cells, or firmer, fibrous, or hyaline. The latter is often
a late stage of the former. Atrophic glands may be included in the new
tissue. Rarely there is a definite increase of smooth muscle-cells, usually
in foci resembling small myomas. More often the smooth muscle is atrophic.
The true prostatic myoma of Virchow should be separated from prostatic
hypertrophy. The cases of hypertrophy in which there is pure overgrowth
of smooth muscle are extremely rare (Halle, Albarran, Ciechanowski).

The glandular overgrowth yields normal prostatic alveoli, or the cells
may be more numerous, appear in two or three layers, or in papillary pro-
jections into enlarged lumina. Many areas are composed of cystic alveoli
lined by flat cells or partly filled by low papillary projections. Desquamation
of lining cells, retained secretion, concretions and round-cell infiltration of
stroma are nearly constant, and while the structure varies in different areas,
the whole picture indicates a chronic catarrhal and productive inflammation
with unusual epithelial overgrowth.

758

NEOPLASTIC DISEASES

Occasionally the multiplication of small alveoli is extensive, secretion is
missing, the stroma scanty, the cells hypertrophic and the condition assumes
an adenomatous character.

Rarely the alveoli are rilled with atypical large or small hyperchromatic
cells, lateral sacculations form, and the process passes into carcinoma.
The frequency of this change to carcinoma is at present uncertain. It has
been observed by Klebs, Socin, Kaufmann and others and Greene and Brooks
find that it occurs in 5 to 10 per cent, of cases of prostatic hypertrophy. Halle
and Albarran found suspicious changes which they designated as adenocarci-
noma in 14 of 100 cases, and they note the frequency with" which elderly
men, long suffering from prostatic hypertrophy, die with symptoms of cancer.
I have repeatedly seen miniature carcinomas, as judged by structure, in

FIG. 344. — Focus of atypical proliferating alveoli in chronic prostatitis. Carcinoma in

other portions of prostate.

portions of enlarged prostates. The carcinomatous change probably begins
rather early and sharply, if it is to occur at all.

Etiology. — The older authors looked for predisposing and exciting factors,
in gout, syphilis, horse-back riding, alcoholism, sedentary habits, constipation,
gonorrhea, strictures, and stone.

Later histological studies led many to conclude that prostatic enlarge-
ment is a tumor process, and chiefly a myoma, occasionally adenomyoma, or
adenoma. Velpeau likened the tumor to myoma uteri. Yet the prostate
is not the homologue of the uterus and the histology and history are not
that of myoma. Although Casper found 19 myomatous cases in 24, later
interpretations have shown that true myomatous prostates are very rare.
More or less isolated or pedunculated myomas arise in the prostate, but
the structure of the new fibromuscular tissue in ordinary hypertrophy is
that of a simple overgrowth and quite different from that of uterine or other
myomas. Several features stand against the neoplastic theory for the
glandular hypertrophy. This process begins diffusely or in multiple foci,

TUMORS OF PROSTATE 759

it is associated with periglandular fibrosis, and the process is self-limited.
The structure is not that of a neoplasm, and when true adenoma of the
prostate arises in the course of hypertrophy it presents a very different
structure. In my material adenoma is rare in enlarged prostates.

An inflammatory origin has been maintained by most recent observers,
but is firmly opposed by Thompson, Frische, and many experienced clinicians.
Ciechanowski attributes the condition to chronic posterior urethritis chiefly
of gonorrheal origin; and he emphasizes the constant presence of inflammatory
lesions. The inflammation begins in the ducts, and causes first partial or
complete occlusion. The retained secretion leads to enlargement of alveoli,
newgrowth of epithelium, perialveolar fibrosis, and hypertrophy of muscle
fibers. Exudative changes may be limited to portions of the enlarged
gland, while other areas show chiefly cellular overgrowth. This distribution
is not inconsistent, as some assume, with the inflammatory hypothesis. A
centrally located inflammatory process leads to hypertrophy of glands, while
a peripheral localization tends toward glandular atrophy and fibrosis (Cie-
chanowski, Rothschild). Greene and Brooks and Motz also find the ducts
occluded, and trace the progress of overgrowth to infection and retained exces-
sive secretion. My own material all indicates the presence of an inflamma-
tory element, but it is not clear that the inflammation is always primary.
In this respect the inflammatory theory is distinctly in need of further sup-
port. That all cases are not gonorrheal is shown by Keyes, who in 433 cases
of hypertrophy found only 18 giving a history of previoas prostatitis. Yet
he places the proportion of males who have had gonorrhea as high as 80 per
cent. While the histology of the process may perhaps be satisfactorily
explained as a result of productive inflammation in a peculiar organ yet the
clinical data cannot be so readily dismissed.

Launois and Guyon find that all prostates of elderly men showperiacinar
fibrosis, hypertrophy and diminution in number of muscle-fibers, disorder of
gland tissue, and arteriosclerosis. Hypertrophy or atrophy may follow.
In line with this theory stand the speculations regarding a functional dis-
turbance in the gland. Furbringer suggests that the marked overgrowth
is a compensatory process following senile insufficiency and Rovsing assumes
that there may be increased rather than senile failure of functional capacity.
There appears to be a relation to testicular function but its details are not
clear. White, Moullin, and others find that prostatic hypertrophy recedes
after castration, but this event has been too exceptional to establish this
method of surgical treatment (Keyes). There does not appear to be any
complete parallel inflammatory condition in other glands, but in the thyroid
a very similar process results from functional disturbance, and involution
of the breast approaches in some cases the type of prostatic hypertrophy.
Considerable importance attaches to these various hypotheses, since some-
where in this field must be found the key to the unusual glandular over-
growth which often exceeds the limits of productive inflammation. It may
become possible to divide the cases into inflammatory and true hypertrophic
forms, as suggested by Young and Geraghty,but at present it seems necessary
to assume that the condition results from a combination of both factors.

Carcinoma of Prostate. — -Until recently carcinoma of the prostate was held
to be a rare disease, forming 0.27 per cent, of the carcinomas in men, accord-
ing to Gurlt, or 0.418 per cent, in Heimann's series. Probably through more
careful examination of apparently simple hypertrophies of the gland and more
accurate diagnosis, carcinoma of the prostate now appears more frequently.
Engelbach, 1888, collected 114 reported cases of malignant tumors. E.
Kaufmann personally observed 22, Wolff collected reports of 8q carcinomas

760

N EOF LA STIC DISEASES

and 22 sarcomas. Since there is some uncertainty in the diagnosis of both
these tumors, present statistical data are still open to revision.

Etiology. — -The chief condition predisposing to prostatic cancer is chronic
hypertrophy. Notable examples of the transformation of simple hypertro-
phy into carcinoma are recorded by many observers. The evidence in these
cases usually consists in a long history of hypertrophy in cases presenting
as carcinoma, and about 10 per cent, of prostatic cancers give such a history
(Wolff, Kaufmann). Likewise the careful study of enlarged prostates
reveals early cancerous changes in about 19 per cent. (Albarran, Halle,
Greene, Brooks). From these data one may safely conclude that early or
suspicious cancerous changes in the prostate are much more frequent than

'?••&%'

FIG. 345. — Adenocarcinoma of prostate.

is the established disease. A satisfactory elimination of previous hyper-
trophy has not commonly been attempted, so that the relation of the two
processes still remains to be determined.

The chief age of incidence, like that of hypertrophy, is the seventh decade,
when 68 per cent, of the cases occur, bat the disease has been observed
between 40 and 50 years. Wolff collected six cases under 40 years, at least
one of which (Biliroth's) was probably true glandular carcinoma in a subject
of 30 years. A rapid carcinoma with regional metastases in a youth of 17
years is reported by Gardiner and Cummins.

An influence of heredity is not apparent, and the antecedent personal
history is usually declared negative. Wolff saw carcinoma develop after
incomplete removal of an enlarged prostate. The susceptibility of workers
in anilin products to bladder tumors does not appear to extend to the pros-

TUMORS OF PROSTATE 761

tate, bat Kaufmann's case of "lympho sarcoma" occurred in an anilin
worker.

Gross Anatomy. — In the early stages carcinoma may appear in simple or
multiple foci of firm opaque texture, in an hypertrophied organ. Usually
the whole organ is enlarged, hard, and fixed, but one lobe is frequently the
chief or sole seat of the disease, while the pars intermedia only was affected
in the cases of Billroth and Tyson. The disease may also arise in the glands
of the prostatic urethra. To what extent the seminal vesicles are the primary
seat of carcinoma involving the prostate is uncertain. Berger, Fenwick and
Walter describe carcinomas which appeared to originate in the vesicles but
the exact source of these tumors is questionable. Guelliot's case of vesicle
cancer in a man of 50 years failed to involve the prostate or bladder. Kauf-
mann's tumor in a man of 87 years diffusely invaded the prostate but a
larger mass involved both vesicles. Arising in an atrophic gland the pros-
tate may remain small while metastases become general (Jolly, v. Reckling-
hausen, Hebb). A markedly indurated prostate in a man over 50 years of
age producing urinary retention is highly suspicious of carcinoma, especially
if it is very hard and not very large. When with the indurated prostate
there is induration along the seminal vesicles with pain and hematuria the
presence of carcinoma is practically certain (Young).

The capsule resists invasion, but is commonly penetrated first along the
seminal vesicles. Per rectum the enlarged gland usually presents a hard
nodular surface, and extensions to neighboring structures and lymph-nodes
with fixation of the organ may be detected. In advanced cases a bulky tumor
fills the pelvis, fuses the organ with neighboring tissues, or invades bladder,
rectum, and lymph-nodes.

The bladder is invaded in 57 per cent, of cases (Kaufmann). Frequently
the invasion passes through the lymphatics, producing multiple or confluent
submucous nodules or diffuse infiltration in the fundus (32 per cent.) . Direct
invasion through the trigone, simulating primary vesical cancer, is also com-
mon. Belfield has described a bulky tumor filling the bladder. In late
stages the secondary vesical tumors may ulcerate with hemorrhage, or per-
forate the wall, producing peritonitis (Tyson, Engelhardt) or a rectovesical
fistula. The bladder may become hypertrophied and sacculated. The
ureters are invaded from the vesical wall as in bladder carcinoma, or occluded
by nodules at the orifices, or compressed by enlarged lymph-nodes.

The seminal vesicles are early invaded on one or both sides and may be
obliterated. Rarely the urethra is involved by submucous infiltration
usually by way of the lymphatic connection with the seminal vesicles, and
the growth may extend well along the urethra and into the corpora caver-
nosa (Tailhelfer, Kaufmann).

Diffuse prostatopelvic carcinoma (Guyon) results from diffuse invasion
which binds prostate, seminal vesicles, bladder and rectum in a firm mass
to the pelvic bones. Here the chief symptom may be obstipation. Frisch
observed perforation of the obturator foramen and a large perineal tumor.

Lymphatic Extensions. — According to Sappey, the prostate is very richly
supplied with lymphatics. They arise in the glandular lobules and pass
chiefly backward and anastomose with the rectal vessels. Two main trunks
on each side drain the peripheral plexus, the inferior trunk passing outward
to a lymph-node lying on the lateral wall of the true pelvis. The superior
vessels pass upward along the wall of the bladder, communicating with
lymphatics in the muscle-tissue and leading to a chain of nodes on the external
iliac vessels. There are rich connections between the vessels of prostate
and seminal vesicles. The vesical mucosa is very poor in lymphatics, but

762 NEOPLASTIC DISEASES

in the trigone small vessels may be infected from the pen-urethral tissues
which in tarn communicate with those of the seminal vesicles. From these
relations it appears that urethral invasion must be by retrograde transport,
that invasion of seminal vesicles is early, that secondary growths readily
form in the pelvis, while metastases in the f undus of the bladder do not early
reach the mucosa or ulcerate.

The extent of lymphatic invasion in prostatic carcinoma varies extremely
but is less than with many carcinomas. As a rule only the regional nodes
are involved, especially those of the true pelvis in close relation to the seminal
vesicles. The frequency of invasion of the inguinal nodes (16 per cent.) must
be referred to lymphatic connections with the seminal vesicles, pelvis and
urethra, and retrograde transport seems to occur in these cases (Courvoisier).
From the true pelvis extensions are along the great vessels, iliac, lumbar,
vena cava, to mesenteric and retroperitoneal nodes, liver and kidneys.
Further extensions to the thoracic and cervical nodes are not infrequently
observed. The supraclavicular nodes may be involved (6 per cent.) with
or without invasion of other cervical chains, and with freedom of the thoracic
duct (Carlier) . Very general lymphatic invasion is described by Baumgarten,
and extensive visceral metastases by Kaufmann. The organs involved in
22 cases were, liver 10, kidneys 3, adrenals 3, pancreas 3, peritoneum 4,
lungs 9, pleura 12, dura 5, brain, heart, thyroid, spleen i in each.

Skeletal metastases of markedly osteoplastic character occur in a notable
group of prostatic carcinomas (Silcock, Thompson, Recklinghausen, Cour-
voisier). Similar osteoplastic processes are observed, especially with mam-
mary carcinoma, and with tumors of stomach, gall-bladder, thyroid, etc.,
but the early and frequent occurrence and extensive distribution belong
chiefly to the prostatic disease. Kaufmann calculated that about 70 per cent,
of prostatic carcinomas cause skeletal metastases, as compared with 37
per cent, for thyroid carcinoma (Limacher) and 14 per cent, for mammary
cancer. Of 16 cases with skeletal metastases Kaufmann found more or less
osteoplastic tendency in 14, and from the literature he collected 20 cases
with extensive growth of bone.

In these cases the prostate may be relatively small and fibrous, the local
extension moderate, the organs free, while the bones are the seat of wide-
spread osteoplastic carcinoma. Under these circumstances the prostatic
tumor may be overlooked. More often the pelvis contains a bulky tumor
involving prostate, vesicles, and bladder, and the viscera are also invaded.
The spinal column, pelvis, long bones, skull, ribs and sternum, scapula,
and clavicle have been affected with extensive thickenings, deformities,
excavations, and fractures. The new bone may be diffuse, obliterating the
shafts and marrow cavity, or periosteal and stalactite, and the structure is
spongy or eburnated. The osteoplastic process predominates over the osteo-
clastic, but both may be equally prominent. Severe anemia may result
from destruction of bone-marrow (Schmorl, Braun).

The histological process is described by Recklinghausen as carcmomatous
osteitis. The tumor-cells lodge in the small venous sinuses, cause stasis
and hemorrhage, which is followed by reactive growth of fibrillated, osteoid
and finally osseous tissue. The tumor-cells become inclosed in the bone,
assuming the function of osteoblasts, and bony tissue may be most abundant
in very cellular areas of tumor-cells where connective tissue is wanting
(Wolff, Braun, Sasse). Participation of connective tissue osteoblasts is also
observed (Erbsloh). Extensive resorption of the new bone by osteoclasts
may follow the plastic process. Schmorl refers to a similar lesion in the
lungs as metastatic osteosarcoma.

TUMORS OF PROSTATE 763

Axhausen attributes the osteoplastic process entirely to the chemical
influence of the carcinoma cells. The transformation of epithelial tumor-
cells into bone-cells, accepted by Wolff, and Kaufmann, he did not observe.
There is little actual newgrowth but chiefly an absorption and redeposit
of the old. Cyanotic hyperemia (Recklinghausen), inflammatory changes
in the marrow (Lenziger, Kaufmann), and primary bone necrosis (Askanazy),
he finds of secondary importance. Lacunar resorption by osteoclasts
furnished by the connective tissue is the chief factor in the absorption process,
and the new bone forms in the connective tissue both by a metaplastic and a
neoplastic process.

^ The course of prostatic carcinoma varies from that of rapid cases occurring
chiefly in middle life and terminating within a few months, to the more

FIG. 346. — Carcinoma of prostate, involving one half of the prostate, without much
enlargement, but giving distant metastases.

prolonged cases, which extend over three years or more. Wolff in 46 cases
found 39 per cent, lasting less than one year, 28 per cent, one to two years,
8.7 per cent, two and one-half years, 24 per cent, three years or more.

Sarcoma is much more rapid and has usually proven fatal within six
months, but firm spindle-cell sarcomas may continue as long as two years.
Lymphosarcoma is usually of very short duration.

The clinical course of prostatic carcinoma is very notably dependent on
the structural type of the tumor, so that different forms appear as radically
different diseases.

(1) Adenoma or adenocarcinoma arising on chronic prostatitis may give
the symptoms of chronic hypertrophy and the carcinoma be discovered
only in the extirpated gland.

(2) Adenocarcinoma, usually arising on hypertrophy, may give a large,
hard, » nodular prostate, which exists for many months before involving

764

N EOF LA STIC DISEASES

lymph-nodes. Eventually it produces local extensions, and finally it general-
izes. Jt isof ten extirpated, and regularly recurs.

(3) Fully developed carcinoma, alveolar or diffuse, may fail to cause
much enlargement of the gland, prostatic symptoms are moderate, and the
disease is overlooked, or the metastatic tumors are regarded as primary,
or the condition is discovered at autopsy.

Structure. — Malignant epithelial tumors of the prostate appear in three
structural types, adenoma, adenocarcinoma, and carcinoma.

(i) Adenoma. — -A pure adenoma of the prostate is rare. Diffuse cir-
cumscribed areas of adenomatoid overgrowth occur in many cases of chronic-
ally enlarged prostate, and at times this process becomes more pronounced

.. ,'>$#&&£%

^:-.:^ %<'*--

*:>*P*?SSfe:. i '-'.i **rs iS* — .* **"* • w<*.

''•^^^ ^:^^

i!f^%*ir"
^ f-M,

p:- i^ -tt&.i
%%^^l^gfk

FIG. 347. — True adenoma in an enlarged
prostate.

FIG. 348. — Malignant adenocar-
cinoma of prostate.

and assumes the characters of adenoma. Yet such areas usually form only
a small portion of the enlarged prostate and grade off into inflammatory
overgrowth. When a true adenoma develops in the prostate it appears
always to be locally aggressive and in this respect is malignant. More often
it passes freely into adenocarcinoma or carcinoma.

I have examined one case in which the tumor exhibited throughout a
rather uniform structure of malignant adenoma. It formed a partly circum-
scribed mass, 3 cm. in diameter, lying in a prostate successfully removed for
chronic hypertrophy. The lymph-nodes were free. The structure presented
compact groups of small alveoli lined by high cuboidal clear epithelium with
hyperchromatic nuclei. The stroma was reduced to a trace. In some foci
the outlines of the alveoli were indistinct, the cells more atypical, and

TUMORS OF PROSTATE

765

the growth almost diffuse. The tumor capsule was infiltrated with small
groups of cells without definite lumen. The remaining portions of the
prostate showed the changes of interstitial and glandular hypertrophy.
A somewhat similar case is described by Ciechanowski as adenoma malignum,
and this term seems properly applicable to the condition.

(2) Adenocarcinoma is the structure assumed by many malignant tumors,
but it rarely occurs in pure form, passing readily into alveolar carcinoma.
Kaufmann found no exception to this rule and my own material is of the
same character. Not infrequently one finds large alveoli of typical adeno-
carcinoma scattered in wide fields of diffuse or small alveolar carcinoma and
it is evident that the latter represents a more rapidly growing derivative
of the former structure, of which transitions may often be clearly traced.

FIG. 349. — An area of adenocarcinoma in a chronically enlarged prostate.

The typical adenocarcinoma presents large spaces filled with masses of
somewhat atypical cells forming numerous secondary alveoli. The size of
these cells varies from large, clear prostatic epithelium, to small granular
acidophile cells, and the carcinomas derived from them present corresponding
variations. The simplest form of adenocarcinoma is the structure usually
observed in the suspicious or precancerous areas of chronic hypertrophy,
but compact groups of small alveoli, as in malignant adenoma, also occur in
these cases, and occasionally multiple layers of atypical cells completely
fill the alveolus and the structure passes directly into solid carcinoma. Con-
siderable difficulty may be met in interpreting single fields presenting these

766 NEOPLASTIC DISEASES

various structures, but as a rule the usual signs of malignancy, as atypical cell
form and excessive multiplication of alveoli, leave no doubt as to the nature
and tendencies of the process.

Pure adenocarcinoma is doubtless not so active and aggressive as alveolar
carcinoma and its presence probably signifies that a preliminary period of
relatively slow growth has preceded the more malignant carcinoma with
which it is usually associated. The change to carcinoma is so nearly con-
stant that the later course of the disease is practically identical in the two
conditions. Adenocarcinomatous structures are rarely observed in extensions
and metastases.

(3) Carcinoma of the prostate presents many variations in structure.
A pseudo-alveolar type is assumed when very numerous small groups of
cells, inclosing a definite lumen, are closely packed together and infiltrate
stroma, gland, capsule, and nodes. This is really a more malignant form of
adenocarcinoma. Usually the cells grow loosely, forming small groups or
large masses, or diffuse fefiltrations, in which case the growth is indistinguish-
able from carcinomas from other sources. When the cells are small and
cytoplasm scanty the structure closely resembles round-cell sarcoma and it is
probable that some reported cases of prostatic sarcoma are of epithelial
origin. In McKenzie's case,, observed in this laboratory, the general struc-
ture was identical with that of lymphosarcoma and it was only after repeated
and very careful search in various sections that the clear evidence of its
carcinomatous nature was obtained.

Hydropic swelling, formation of giant-cells, collections of colloid material
inclusion of fatty crystals, and round-cell infiltration of stroma, are commonly
observed, but it is noteworthy that extensive necrosis of prostatic carcinoma
is very rare. Schlagenhaufer finds much doubly refractive lipoid material
(cholesterin esters) in the cells of prostatic carcinoma, which he interprets
as a sign of exaggerated functional activity of these cells.

Scirrhus carcinoma is observed in rare cases in which the prostate remains
small and hard, as well as in foci of cellular tumors (Thompson, Barton,
Matthias, Berger, Kaufmann). Boyd designated a case as colloid scirrhus.

Squamous Epithelioma. — In the upper anterior portions of the fetal
prostate the ducts are lined by squamous epithelium up to the third month of
life or later (Aschoff, Schlachta). In chronic suppurative prostatitis Schmidt
finds extensive squamous epithelial metaplasia and in a prostate from a man
°f 53 years he described beginning acanthoma. Klebs and Marchand de-
scribe acanthoma of the prostatic urethra, and acanthoma of the prostate
is reported by Beyer and Buchal.

Sarcoma of the Prostate. — -Sarcoma rarely occurs in the prostate and
many of the reported cases are of uncertain nature. Kaufmann collected
only 24 authentic cases but discards many others for lack of microscopical
report. Three occurred in infants under one year, seven others in the first
decade, and only seven from 30 to 73 years.

The only well-defined variety of prostatic sarcoma is the rhabdomyo-
sarcoma, which is also a probable source for any genuine mesoblastic round-
cell tumor that may exist. Few of the older reports of sarcoma are of any
value for critical analysis. While true spindle and round-cell tumors prob-
ably arise from mesoblastic elements in children, it is highly probable that
most of the cases reported as such, especially in adults, are diffuse carcinomas.

Round-cell sarcoma is the most frequent and the least definite form and
no uniform description will apply to it. Socin describes a bulky tumor
between bladder and rectum, in an infant of 8 months, which was soft, vas-

TUMORS OF PROSTATE 767

cular, cystic and composed of diffuse small, round and polyhedral cells with-
out uniform stroma.

Kaufmann's case was a large myxomatous round-cell sarcoma in a
child of 1 1/2 years. In adults 18, 21 and 35 years, round-cell sarcomas are
reported by Oliva, West, and Hughes. These tumors are difficult to dis-
tinguish from lymphosarcoma and from rapid atypical carcinoma. Thus
Graetzer and Dupraz found- an alveolar structure closely resembling carci-
noma. Dupraz's tumor occurred in a man of 73 years, and gave osteoplastic
metastases. Kapsammer reports as lymphosarcoma a very rapidly growing
tumor arising from an old stricture of the bulbous urethra and invading the
urethra. He refers to two other cases of round-cell prostatic tumors, in
which an origin from Cowper's glands was suggested.

Lymphosarcoma in adults is described by Coupland, Kaufmann and
others. In Kaufmann's case in an anilin worker the prostate was much
enlarged, fused with seminal vesicles, tumor folds projected into bladder,
regional nodes with one exception free, while visceral metastases were wide-
spread, and the cervical lymph-nodes were involved.

The existence of a true lymphosarcoma of the prostate is not satisfactorily
proven. The structure of the gland does not favor the occurrence of such
tumors. One of the cases most fully described is Kaufmann's, but there was
nothing in the gross anatomy of this case to distinguish it from ordinary
diffuse carcinoma and the metastases were exactly as one would expect in
carcinoma, the regional nodes being practically free. The structural de-
tails were inconclusive. In Lefmann's case the cutaneous metastases suggest
sarcoma but the lymph-nodes were only slightly involved by very numerous
metastases. Since studying McKenzie's case of pseudolymphosarcoma I
have come to doubt the existence of lymphosarcoma of the prostate.

Rhabdomyo sarcoma occurred in three cases described by Kaufmann, two
in infants, one in an adult of 26 years. The tumor grew rapidly to large
dimensions. In the adult there were invasion of prostatic veins and wide-
spread metastases, especially in the bones, with pernicious anemia.

The tissue was chiefly composed of spindle-cells and resembled ordinary
cellular spindle-cell sarcoma with myxomatous tendencies. Round-cells
also were abundant. The specific elements consisted in fusiform, round and
tubular structures, presenting various stages of differentiation of striated
muscle-fibers from which all the tumor elements were derived. It is obvious
that the distinction between simple spindle-cell sarcoma and myosarcoma
may be difficult. Veil's spindle-cell tumor with large polymorphous cells
and growth into gland tubules, strongly recalls the myosarcomas. Of the
nature of the embryogenic disturbance which gave origin to these tumors
there are no indications.

Spindle-cell sarcoma occurs chiefly in children and produces a bulky tumor
destroying the prostate and compressing adjoining organs. Tordens de-
scribed a tumor as large as the child's head, arising from the left lobe, reach-
ing the navel, of myxomatous character and partly cystic. Other soft sar-
comas were also myxomatous, while the firm tumors are free from this
element (Isambert, Marsh, Wind). An angiosarcomatous structure occurred
in Matthias' case. A rapidly growing tumor in a child of 2 years, composed
of adenoma and sarcoma, is mentioned by Birch-Hirschfeld. That the
spindle-cell sarcomas arise from the prostatic stroma is strongly indicated
by their structure.

The seminal vesicles were the primary ^eat of a round- and spindle-cell
sarcoma, with metastases in mesentery, kidney, and heart muscle, described
by Zahn.

CHAPTER XL
TUMORS OF TESTIS

In the testis more notably than in any other organ it is possible to main-
tain a single embryogenic origin of the great majority of tumors. It appears
that all the common and nearly all the rarer tumors of this organ arise from
totipotent sex-cells, and that the monodermal forms of these growths repre-
sent one-sided developments of tridermal teratomas. Very rarely the stroma,
duct-cells, interstitial cells, and adult seminiferous tubules give origin to
characteristic growths. Whether any of the malignant epithelial tumors may
originate from fully differentiated cells of rete, epididymis, or testis, it remains
for future observations to determine. It is, therefore, of advantage to discuss
testicular tumors from the point of view of their teratomatous origin and to
trace their derivatives as far as may be possible. Later it may be necessary
to reduce the scope of these teratomatous derivatives.

TERATOMA TESTIS AND ITS DERIVATIVES

Historical. — In 1696 Saint Donat identified a rudimentary skull and pigmented optic
cups in a testicular tumor and thus established the fetal character of some of these growths.
In 1803 Prochaska found fetal limbs, and in 1833 Andre de Perrone observed hair, teeth,
and bones in testicular tumors. The tridermal composition was first pointed out by John-
son who distinguished ectodermal cysts lined by squamous-cells, entoderm with columnar
ciliated cells and mesodermal tissues. Numerous later observations have furnished a
nearly complete series of fetal organ rudiments which may be encountered (Ohkubo, Lit.).
Astley Cooper (1845) described the cystic tumors under the term hydatid disease, and Curl-
ing divided the growths into benign cystic, and malignant solid types. With the aid of the
microscope he detected that cancer regularly begins in the rete. Langhans' work with
Kocher marked a distinct epoch, since with the aid of microscopical sections he was able to
classify the tumors on structure. He classed many of the apparently simple tumors with
teratoma, recognized the carcinomatous nature of the "alveolar sarcomas," and suspected
that a large proportion of all tumors of the testis were of teratoid origin. Wilms advanced
this work showing that all the complex tumors are tridermal and dividing them into adult
cystic embryomas and more solid embryoid teratomas. Later, Wilms, Ribbert, Pick,
Ohkubo, and Chevassu showed that one element of the teratoma may overgrow the others,
producing simple growths, and that many tumors called adenoma, sarcoma, carcinoma,
chondroma, myxoma, etc., contain scanty traces of all three germ layers and are teratomas.
The writer's study led to the conclusion that all the common tumors of the testis are of
teratomatous nature, while pure adenoma, fibroma, myoma, and sarcoma are rare.

Varieties of Teratoma Testis. — Three main varieties of the tumor occur:

(1) Adult embryomas or teratomas

(2) Embryoid, teratoid, or mixed tumors

(3) Embryonal malignant tumors.

Numerous intermediate cases connect these types; the same tumor
may present several structures; and some peculiar forms call for special
description. Indeed the variations in structure and course of these neoplasms
are so numerous and definite as to require their description as distinct clinical
and pathological conditions, connected only by a single etiological factor.

(i) Adult and complex embryomas constitute a relatively small group,
characterized by the presence of definite rudimentary organs which may be so
arranged as to resemble a parasitic fetus.

768

TUMORS OF TESTIS

769

The typical testicular dermoid is a sharply circumscribed tumor lying
within the tunica, separated from the testicular tissue by a capsule and fused
with the rete. On section the growth presents a large cyst containing hair
and sebaceous material and lined by epidermis. A protuberance containing
the main body of the embryo projects into or fills the cyst, and itself exhibits
numerous small cysts and the various organ rudiments. The tumor is thus
encysted by a continuous layer of epidermis wrhich covers the embryo as
well as the inner surface of the capsule.

In other cases the embryo is fused with the capsule and the dermal
tissues appear in the form of solid portions, while multiple cysts occur at
different points of the tumor.

A'n.

Cff,

FIG. 350. — Structure of an encysted embryoma of testis. (After A. Midler.) Ho,
Testicular tissue in capsule. H, Skin and appendages. Pep, Squamous epithelium. Ath,
Cystic cavity containing sebaceous matter. CN ', Central nervous system. Gl, Glia tissue.
Nep, Neuro-epithelial cell groups. Resp, Respiratory tract. Krn, Hyaline cartilage. Oe,
Esophagus. Ch, Choroid plexus.

Microscopical study reveals an extensive series of organ rudiments belong-
ing chiefly to the cephalic extremity. The cutaneous covering presents hair,
sebaceous and sweat-glands and fat tissue, with islands of smooth muscle-
tissue. Beneath lies brain tissue in which cellular and fibrillar layers may
be discerned. Choroid plexus, dura, and pia have been traced in connection
with cerebral tissue, and wide canals lined by flat-cells have been inter-
preted as ventricles or central canal. Amyloid concretions, or brain sand,
may be present. Bony plates are often found about the brain rudiment and
in Geinitz' case these plates consisted of two lamellae inclosing diploe and
marrow arranged as a skull. Cavazanni found nucleated red cells in the
marrow. Adult ganglion-cells in the course of nerve-trunks represent the
sympathetic system. Isolated groups of ganglion-cells, neuro-epithelium,
and glia-tissue may also be found.

Many other organ rudiments have occasionally been observed. Optic
vessels with choroidal and retinal pigment cells have frequently been seen.
Mammary gland tissue, normal or fibro-adenomatous, is described by Chev-

770

NEOPLASTIC DISEASES

assu, Durr, and many others. Striated muscle bundles were first recognized
by Senftleben, and Koslowski found cardiac muscle arranged about four
chambers as in the heart.

FIG. 351. — Teratoma testis. Tissue resembling liver cords.

Chevassu and Picque thought they could identify liver-cells and cords.

Rudiments of lung have been interpreted by Schlagenhaufer, Pepere, and

Gessner. Chevassu pictures charac-
teristic renal tubules and glomeruli.
Gessner described ovarian tissue. The
writer found a fibromuscular organ with
mucous lining, which resembled stomach
or uterus.

A buccal cavity is located by a
superficial area of mucous membrane
an(^ kere have been found in rare cases
bicuspid and molar teeth embedded in
a bony mass (Wilms, Heinen). Che-
vassu and Ohkubo identified salivary
glands. The respiratory tract is repre-
sented by canals lined by columnar or
ciliated cells and supported by islands
of cartilage.

The intestinal tract appears in the
form of canals lined by cuboidal mu-
cous cells forming crypts. The cellular
lymphoid mucosa may be thrown up
into villi. A double layer of smooth
muscle surrounds these canals.
FIG. 352.-c7nstruction of a tera- 1 Ohkub° detected crystalline lens,

toma testis. C, Carcinoma with lym- spleen, and adrenal. Thyroid tissue is

phoid stroma. D, Epidermoid cysts. E, extremely rare, and Szulcewski mter-
Epididymis. F, Fat tissue. M, Fibro- prets tissue of this type as a form of

?rCTUnyroi0drgt"snSue *' Re™™ °* "^ mucous degeneration, but I have de-

scribed four lobules of adult thyroid
resembling the normal organ in the minutest details.

The stroma supporting these organ rudiments may be of adult type or

TUMORS OF TESTIS

771

show various forms of overgrowth of connective tissue, or blood- and lymph-
vessels.

FIG. 353. — Teratoma testis. Embryonal carcinoma with overdevelopment of lymphoid

stroma.

FIG. 354. — Teratoma testis. Detail of Fig. 352. Embryonal carcinoma with lymphoid
stroma in an organ resembling adult thyroid.

Not all the definite rudimentary organs are confined to typical adult tera-
tomas. Many are definable in the more embryonal solid tumors, where they

772

NEOPLASTIC DISEASES

are reduced to irregular canals or cysts lined by various types of epithelium,
to neuro-epithelial cell groups, and to different glandular structures.

The clinical course of the adult teratoma is usually slow. Many of the
tumors are present at birth and slowly enlarge until they are removed
between the tenth to fortieth years. (Tilanus, Kalning, Macewen, Boeckel).
In these cases no malignant changes are present.

Rarely adult teratomas terminate with the development of malignant
neoplastic processes, which lead to local recurrence after operation and to
general metastases. In a tumor described by the writer, containing adult
dermoid cysts, uterus and thyroid, much of the tumor was surrounded and

•

FIG. 355. — Teratoma testis. Adenocarcinoma. Neuro-epithelial cell groups.

infiltrated with embryonal carcinoma with lymphoid stroma. The patient
died of internal metastases. The source of the carcinoma is undetermined.

(2) Teratoid, Embryoid, or Mixed Tumors. — A large proportion of testicular
tumors are composed of more or less embryonal structures, derived from all
three germ layers, but arranged in such confusion as to eliminate any resem-
blance to an embryo. These tumors have been described under many terms,
but Wilms showed that they belong in a single group of tridermal growths
which he designated as embryoid or teratoid.

In gross appearance the tumors are of moderate or large size and solid or

TUMORS OF TESTIS

773

riddled with many small cysts. They develop from the rete and are well
encapsulated, the testicular tissue being stretched over them in a thin layer
included in the capsule. Occasionally they arise in the tunica. The section
is very varied, depending on the proportions of cysts, cartilage, cellular
areas, hemorrhage, and necrosis.

In structure the cysts are lined by squamous or cylindrical cells and there
may be many islands of squamous-cells, while the solid portions contain
masses of embryonal cartilage, osteoid tissue, cellular connective and smooth
muscle. While these tissues may be comparatively adult in type and the
tumor quite benign, there is a prominent tendency for the derivatives of one
germ layer to overgrow the others and to exhibit true neoplastic and malig-

FIG. 356. — Embryonal carcinoma of testis. (' Seminome' of Chevassu.)

nant qualities. Thus the solid areas often show cellular foci composed of
embryonal connective and myxomatous tissue, or very cellular masses of
smooth muscle-cells, either of wrhich may compose the bulk of the tumor and
give origin to metastases.

Neuro-epithelial cell groups may be very abundant and carcinomatous
areas of this origin may develop. Entodermal derivatives may be prominent,
in the form of small cysts or alveoli lined by cylindrical cells. In many of
these cysts the type of epithelium may suddenly change, as from squamous
to cylindrical. Adenocarcinomatous foci derived from the cyst lining are
frequently seen and these areas grade into various structural forms of
carcinoma.

(3) Embryonal Tumors of the Testis. (i) Sarcoma Testis. Seminome
(Chevassu). — -Embryonal carcinoma with lymphoid stroma.

The most frequent tumor of the testis is composed of large round or poly-

774

X EOF LA STIC DISEASES

hedral cells of embryonal type, lying diffusely or in large alveoli. The stroma
is often richly infiltrated with lymphocytes. Through the demonstration by
Wilms, Ohkubo and others that many of these tumors contain teratoid
elements, the suspicion first stated by Langhans, that the tumors are teratoid,
has been confirmed. Yet Chevassu, Debarnardi and others derive this tumor
from the spermatoblasts or their embryonal equivalents and separate this
group from the teratomas with which they are so often associated.

Several considerations forced the writer to conclude that this common
tumor of the testis is always a one-sided development of a teratoma and is not
derived from the adult spermatoblasts.

(i) The characteristic structure is often seen in teratomas, adult or
embryonal. (2) In a very early embryonal carcinoma I found minute
traces of cartilage, entodermal alveoli, and squamous epithelial cell groups.
(3) The rapid growth of the malignant embryonal element gives unusually
favorable opportunity for the overgrowth and suppression of other elements.

^r^^^^^^^^^^^$Wr:^^'^.
^,../,.5^,.^.,-^^;,,-.

|i|^$^ "";'"£V- ' "•, r/i" •;;-.'•' : V^f":^5

$S$ ltl%: S5SK8

,>.:.•*. * ..• « ?>»w.JJr«* •»•*.# j* , , **v *-<•- t ^^.,*V «*,.•• —..*.«* * »-.?v/^ »****•. * i*.« •*!?*• v '

FIG. 357. — Teratoma testis. Embryonal carcinoma. Spontaneous regression.

(4) The only known tumor of the adult spermatoblasts is very different from
the embryonal carcinoma. Barring the possibility of unrecognized forms of
metaplasia, the teratomatous relations of our tumor seem to be demon-
strated. It remains possible that the embryonal carcinoma may arise from
spermatoblasts incited to growth by the presence of a teratoma. The
occurrence of extratesticular carcinoma speaks against this possibility (Kos-
lowski, the writer).

The embryonal carcinoma is a rapidly growing, soft, opaque, often necrotic
tumor arising in the rete and invading and destroying the testis. A portion
of the organ may persist as a thin layer in the capsule, where it is found
atrophic. The tumors reach a considerable size and then undergo central
necrosis, often complicated by hemorrhage, ulceration or suppuration.

Excision in the early stage may permanently eradicate the disease, but
usually there is local recurrence, metastases in the upper abdominal nodes,
lungs, brain, and other organs. Chevassu reported 22 recoveries after one
year from castration in 59 cases of embryonal carcinoma, and 13 after later
periods. No case died after three years immunity. Of 55 mixed tumors
only six remained well for two years, four others showing no recurrence

TUMORS OF TEST IS 775

after six months. The rapid course of recurrences is notable. Definite
chorioma appears to be uniformly fatal.

Structure. — The structure is usually characteristic but shows several varia-
tions. As a rule one finds large round or polyhedral cells with vesicular
hyperchromatic nuclei lying in wide sheets or diffusely. The cells are
rich in glycogen. The stroma may be very scanty, or strands of lymphoid
tissue may be prominent, or more fibrous bands may produce alveoli. Defi-
nite lymph-nodules may form in the stroma. Necrosis is common. A form
of regression may be observed with atrophy of tumor-cells and formation of
granular or cellular interstitial tissue.

Embryonal adenocarcinoma is a somewhat distinctive type of testicular
tumor. It grows rapidly, is very vascular, and is often the seat of extensive

FIG. 358. — Embryonal carcinoma of testis, with lymphoid stroma.

hemorrhage. Encapsulation is usually as marked as in adult teratoma, and
while traces of teratomatous elements are not infrequently found this
structure may be nearly pure carcinoma. It is sometimes associated with
chorioma. The structure presents irregular alveoli lined and traversed by
rows of large cuboidal cells with large hyperchromatic nuclei. Or the alveoli
may be indistinct, the cells smaller and more undifferentiated and the
structure may even resemble lymphosarcoma.

Chorioma Testis. — This remarkable form of teratoma has passed through
several stages of study and interpretation. In 1868 Waldeyer observed poly-
poid tumor masses, extending from a testicular teratoma into the pelvic
veins, which he compared in appearance with hydatid mole. A typical case
was described by Breus, 1878, in which the polypoid masses extended into the
heart. In the French literature a series of these cases was reported under
the term "sarcome angioplastique " by Malassez and Monod, Carnot and

776 NEOPLASTIC DISEASES

Marie, and others, who also noted the resemblance to hydatid mole. Mac-
Callum likewise interpreted his case as lymphendothelioma. In 1902 Schlag-
enhaufer, Wlassow, and Steinert, all pointed out the exact resemblance of this
tumor to chorioma, traced the origin of the syncytial masses from epithelium
of the testicular growth, identified glycogen-holding Langhans' cells, noted
the hemorrhagic character of the metastases, and showed that chorioma tes-
tis reproduces exactly the essential features of chorioma uteri. Warthin and
Gabarini have reported cases in which there was hypertrophy of breasts with
secretion of colostrum, thus adding physiological features of pseudogestation
in the male. While Risel denies the origin from a true chorionic element in
the teratoma and points out that syncytial masses may form from any epithe-
lial structure, there is no doubt that the general significance of chorioma testis
has been correctly interpreted by Schlagenhaufer. The course and structure

FIG. 359. — Teratoma testis. Tumor composed of adenocarcinoma with cylindrical cells.

of chorioma testis is an exact duplicate in all details of that of the uterine
tumor, which is not the case with the pseudochoriomatous growths of mis-
cellaneous epithelial origin to which Risel's criticism applies.

The testicular tumors giving origin to chorioma are usually small and
may be overlooked during life. They are described as soft, succulent,
cystic, or hemorrhagic. In Kanthack's case the tumor was composed of many
small cysts of various types. A large cystic tumor chiefly of adult type
was found by Steinert. In one case (Blatteis), I found the small original
tumor largely destroyed by hemorrhage and presenting the structure of
embryonal adenocarcinoma with several areas of syncytium. In another
case the testis was very slightly enlarged but the rete and cord presented a
continuous series of pea-sized dermoid cysts. On section a small focus
of proliferating syncytium was discovered in the rete. In the gross this
area appeared as a hemorrhagic spot. There were bulky metastases of
complex structure in the mediastinal and cervical nodes, dermoid cysts and

TUMORS OF TEST IS 777

chorioma in the lungs, and a single large tumor resembling a placenta in the
liver from which fatal hemorrhage occurred. Steinert's case also gave
complex metastases in mediastinum, lungs, and liver, among which chorioma
was prominent.

The exact origin of the syncytial cells is not clear. Pick has traced
them to the neuro-epithelial cell groups. In two cases I have found the

FIG. 360. — Teratoma testis, composed of epidermoid structures and a dark central
nodule of chorioma. In the body of the testis are nodules of large cell embryonal carci-
noma. Same case as Figs. 361 and 362.

minute foci of chorioma in a very limited field and lying in or nearadeno-
carcinomatous areas of which the cells showed none of the features of neuro-
epithelium. Nor was there any special relation to blood-vessels. No
gross chorion-like structures have been identified in the testis. Moreover
similar cells may appear in tumors which have not yielded choriomatous

FIG. 361. — Teratoma testis. Same case as Fig. 362. Choriomatous metastasis in liver
resembling a chorion and giving rise to fatal hemorrhage.

metastases. Hence it would appear hazardous to attempt the diagnosis of
chorioma testis in the absence of pulmonary or hepatic metastases.

Certain apparently primary tumors of the liver in males have been
described as chorioma for which no satisfactory source has been determined.
It seems probable that these are either primary carcinomas of the liver-
cells simulating chorioma, or metastatic chorioma of the testis, the primary
tumor having been overlooked.

778

NEOPLASTIC DISEASES

Metastases of Teratoma Testis.— Nearly all varieties of the embryonal
and mixed tumors may prove malignant and give rise to metastases which
are often of complex types. The course and character of these metastases
present many interesting features.

The retroperitoneal nodes at the celiac axis are often involved through
the lymph-channels of the spermatic veins, and an epigastric tumor is often
the first sign of recurrence. This form of recurrence is especially common
with the highly malignant embryonal carcinomas.

FIG. 362. — Metastases in lung and cervical lymph-nodes from a small teratoma testis,
shown in Fig. 361. The lung shows whitish epidermoid cysts and dark nodules of chorio-
carcinoma.

From this point there may be rapid progress upward, so that mediastinal
and even cervical tumors may divert attention and become the largest tumors
in the body. Invasion of the spermatic and iliac veins, with continuous
tumor growth extending as far as the heart, has been observed both with
chondrosarcoma (Paget) and chorioma. Discontinuous metastasis by way
of the veins is most frequent, and gives rise to tumors of lungs, liver, brain,
kidney and stomach.

TUMORS OF TESTIS 779

The structure of the mestastases may reproduce several features of the
original growth, or only one. As a rule the individual secondary tumors
represent a single germ layer in either adult or embryonal form. Well-
formed adult ectodermal cysts may appear in the lungs and chondromatous
nodules may exhibit adult characters.

In the retroperitoneal and thoracic nodes one may find many adult
and embryonal structures reproducing in a remarkable degree the original
tumor. Yet the derivatives of the germ layers are usually distinct, showing
that each embolic cell group has produced only its own kind. In a case
of chorioma testis I found three entirely separate groups of metastases in
the lungs, one composed of chorioma, another of epidermoid cysts, and a
third of "myxosarcomatous tissue. The chorioma appeared also in the liver,
while the two latter tissues made up the bulk of the mediastinal tumors.

In a case of embryonal adenocarcinoma there was local recurrence,
tumors of abdominal and thoracic nodes, very extensive diffuse invasion
of both lungs, large tumors of the brain, and seven globular tumors of the
gastric mucosa, from the central excavations of which fatal hemorrhage
occurred. In Westenhofer's case the hepatic metastases had the structure
of lymphosarcoma. Steinert describes combined tridermal metastases in the
liver, which contained encapsulated nodules composed of cysts lined by
cylindrical cells backed by a muscularis, and associated with epidermis,
cartilage and bone. The presence of such structures in one compact
metastatic tumor it is difficult to refer to any other source than to emboli
of undifferentiated cells capable of producing all three germ layers. Further
observations are needed to elucidate the questions here involved.

4. Miscellaneous Tumors of the Testis, Tunica and, Cord, and Their Relation
to Teratoma. — The study of teratoma testis has greatly narrowed the scope of
pure simple tumors of this organ, and reduced their numbers to a compara-
tively few cases whose real nature often remains uncertain. In no other organ
has the principle of the overgrowth of one element of a teratoma been
proven to be so predominant, and while it is possible to carry this principle
too far, the data seem to demonstrate its great importance in the interpre-
tation of tumors of this region. Hence tumors which are apparently of
other origins must be scrutinized carefully.

Fibroma. — Fibroma of the testis is very rare but apparently pure cases
are described by Curling and Kocher. These were large, firm, cystic or
calcified tumors of very slow growth. Fibromas of the tunica albuginea are
reported by Fergusson and Pean.

A large fibroma, 14 X 9 cm., replacing the testis is described by Chevassu.
It contained pseudocysts and sarcomatous areas and the author was unwilling
to eliminate a teratomatous origin.

Plexiform fibroma of the cord is described by Ehrendorfer. Fibrolipoma
of the spermatic cord is a well-recognized tumor which Kolisko regards as
of teratomatous origin.

Chondroma. — Cartilage is nearly constantly present in the testicular
teratoid tumors and often forms the bulk of the growth. It occurs in the
form of adult or embryonal hyaline masses of small size or large dimensions.
Neumann found bone in one case. Myxoma may arise from imperfect
formation of cartilage.

The tendency of cartilage to overgrow other elements of the tumors
has long been recognized. Kocher accepted as pure chondroma only five of
the 28 cases described by Dauve, adding three of his own, but later writers
(Ribbert, Ohkubo) question the existence of pure chondroma testis apart from
a teratomatous origin. Paget's case of malignant chondroma is now gener-

780 NEOPLASTIC DISEASES

ally regarded as a teratoma (Wilms, Ohkubo). Cartilaginous metastases in
lungs or lymph-nodes occurred in his and Kocher's cases. Since the origin of
these tumors appears to be in the rete, since many are cystic and occur in
infants, and since it is practically impossible to eliminate teratomatous
elements by microscopical study, it seems necessary to assume that all these
tumors are of teratomatous origin.

Myxomatous areas are frequently present in mixed tumors of the testis
and may form the bulk of the tumor. Most reported myxomas have been
associated with chondroma, sarcoma, adenoma, or cystoma and clearly
belong in the teratoid group. Kocher and Wilms could find no cases of
pure myxoma.

Myoma.- — Smooth muscle-tissue is nearly constant in the mixed tumors
but seldom forms a prominent part of the tumor, nor does it commonly
present blastomatous changes. Reports of leiomyoma testis are likewise
rare. Nepveu's case contained both smooth and striated muscle and was
probably of teratoid nature. Leiomyoma of epididymis or vas is described
by Trelat, following trauma, and by Hericourt. It is assumed that these
tumors arise from the cremaster internus muscle.

Striated muscle is rarely seen in testicular tumors, but in a few cases it
has been present in abundance, usually with cartilage and epithelial canals,
thus demonstrating its teratomatous relations. Mixed tumors of this
type are described by Arnold, Kocher, Ribbert, Chevassu, Wood and others.
Apparently pure rhabdomyoma attached to the lower pole of the [tunica
albuginea and probably derived from the gubernaculum of Hunter, are
described by Rokitansky and Neumann.

The scope of myoma and myosarcoma of the testis is not yet determined.
Neumann and Ribbert found many spindle- and round-cells which were
not clearly separable from the muscle-cells, and Neumann suggested that some
spindle-cell sarcomas may be of myogenous origin. Benenati describes
striated muscle, large spindle-cells lacking striation, and round-cells, in a
testicular tumor with metastases containing only the round-cell tissue.

Sarcoma. — Spindle-cell sarcoma of the testis has rarely been reported
and it is difficult to determine the true nature of these cases. Chevassu,
out of 126 testicular tumors, found only one which appeared to be purely
sarcomatous. Yet the cells were of mixed type, spindle and round, and
since there were also alveoli lined by epithelioid cells, the opinion is expressed
that the tumor might be of teratoid origin. The probability that teratoid
elements have been overlooked in these cases is shown by Wilms, who on
re-examining an old tumor called plexiform spindle-cell sarcoma, found also
cysts lined by cylindrical or squamous-cells and an island of cartilage under-
going mucoid degeneration.

In view of these observations considerable doubt surrounds the interpre-
tation of other so-called spindle-cell sarcomas. Some of these tumors
contained myxomatous areas, and cell groups of uncertain nature
(Ehrendorfer). Others contain many giant-cells suggesting a myomatous
element (Kocher, Krompecher). Or both these structures are combined
with spindle-cells (Debarnardi). There is no doubt that tumors composed
chiefly of spindle-cells occur in the testis, but their true nature and the pos-
sible relation to myoma and teratoma remain uncertain.

Adenoma. — Adenoma of the testis has been described in two cases by
Chevassu and Pick. They were found in undescended organs, one of them
in an hermaphrodite. The tumors appeared as pinhead or bean-sized yellow-
ish nodules in the body of the atrophic testis. Some small cysts resulted
from dilation of alveoli. They were composed of regular tubules lined by

TUMORS OF TESTIS

781

cylindrical cells about 15 micra in height, with finely granular cytoplasm and
compact nuclei and arranged in palisade fashion. The transition from nor-
mal tubules was followed step by step. Chevassu likens the tubules to those
of a sweat-gland.

While adenoma of the testis appears in many older reports it is now evi-
dent that the authors were dealing with teratomas.

Interstitial Cells.— Tumors or tumor-like hyperplasias of the interstitial
cells of the testis are rare conditions observed in undescended and atrophic
testes, in which the atrophy of tubules is associated with moderate hyperplasia
of the large cells of the stroma. These tumors are usually limited to very
moderate dimensions, but in Kaufmann's case it measured 9X6 cm. They
are well encapsulated and of rusty brown color due to the lipoid pigment
in the cells. The structure exhibits alveolar groups of large polygonal cells

FIG. 363. — Adenoma of testicular tubules. (After Chevassu.)

closely resembling the interstitial cells. Neoplastic characters may be dis-
tinct (Durck). Cases of this characteristic- type are described by Che-
vassu, Pick, and Kauf mann.

Waldeyer (1872) derived certain plexiform angiosarcomas from the inter-
stitial cells and Hansemann (1895) attributed certain alveolar sarcomas to the
same origin.

Adrenal Tumors of the Testis. — Rarely a solid carcinoma of the testis
presents a structure recalling that of adrenal carcinoma or perithelioma.
Debarnardi has described such a tumor and attributed its origin to an adrenal
rest. It occurred in a child of 10 months and involved the upper pole of the
testis and extended up the cord. As the testis and rete were intact it was not
strictly a tumor of the testis but rather of the epididymis and cord. The
structure was complex, presenting sarcomatous and adenocarcinomatous
areas.

The occurrence of adrenal islands in and about the testis has been fully
demonstrated by Marchand, Wiesel, and Kirkbride, and such cell groups may
well give origin to tumors.

782

NEOPLASTIC DISEASES

In Debarnardi's case, and in others of my collection, in which the question
of adrenal origin arose, the structure presented alveoli of large polyhedral
cells which lacked the embryonal character of the ordinary carcinoma and
resembled adrenal carcinoma. A perithelial structure was not promi-
nent, nor were the gross features strongly indicative of adrenal nature. In
one case the tumor proved to be secondary to a tumor in the adrenal. The
structure of perithelioma appeared also in a recurrence of embryonal carci-
noma. Further observations would appear necessary to establish the exist-
ence of a testicular carcinoma of adrenal origin.

Lympho sarcoma Testis.— An apparently distinct group of lympho-
sarcoma of the testis was described by Malassez in 1877 and later by Tala-
vera and other French observers. More recently Chevassu has shown that
the majority of these tumors are embryonal carcinomas, but his further claim
that true lymphosarcoma in the testis is always secondary must be ques-

**N

V,*fcJ2?;-

FIG. 364. — Island of adrenal tis-
sue in testis of newborn infant.
(After Kirkbride.)

FIG. 365. — Epidermoid in rete testis of newborn
infant. {After Kirkbride.)

tioned. Curling observed the disease in 1866 and Ehrendorfer described a
typical case with cutaneous metastases, and recent cases are reported by
Debarnardi and by the writer. The disease is distinguished by its develop-
ment in most cases, in both testicles, by its occurrence chiefly in children, by
its rapid course, and by multiple metastases in the skin. The structure is
that of a diffuse tumor composed of embryonal large round-cells resembling
large lymphocytes, lying in a reticular stroma.

The origin of lymphosarcoma of the testis would naturally be referred to
lymphoid tissue of the normal organ but no such structures are commonly
present in this organ. It seems possible that the tumor may be derived from
some elements of a.teratoma of which the rapidly growing cells lose all differ-
entiation. Areas of such embryonal round-cells may occasionally be seen in
teratomas. Yet there are no definite observations which may be used in sup-
port of the hypothesis that lymphosarcoma of the testis is of teratoid nature
and its origin remains quite undetermined.

Etiology.- — The study of the formal genesis of teratoma testis, quite as
much as any other teratoma, has contributed important data in the field of
teratology. The questions involved almost exactly duplicate those of tera-

TUMORS OF TESTIS

783

toma ovarii, but the testicular group is distinguished by the wide variety of
simple tumors derived from the parent teratoma.

Virchow held that the testicular mixed tumors arise from the normal ele-
ments of the organ, in which theory he attributed to metaplasia a very wide
scope. While modern views greatly restrict the field of metaplasia, it may
still be well not to ignore entirely the possible influence of this factor in the
structure of mixed tumors. The idea that metaplasia alone can account for
the organic structures of these growths cannot, however, be entertained, and
since the entire series is connected by abundant intermediate types which
demonstrate their single origin, the theory of metaplasia has been abandoned.
The testicular embryomas, for the same and other reasons, must be excluded
from the group of fetal inclusions. The results of the various forms of double
embryos are seen in the sacral and cephalic teratomas, where the conditions

FIG. 366. — Embryonal carcinoma of testis. So-called alveolar sarcoma.

are favorable for the separation or attachment of multiple embryos, but these
conditions are not provided in the testis.

The Marchand-Bonnet theory of origin, from polar bodies or isolated blas-
tomeres, is less satisfactory for the testicular growths and their peculiar
derivatives than for any of the fields to which it may conceivably apply.

An origin from some member or members of the sex-cell series is now gener-
ally accepted as applicable to the testicular tumors. This theory fully
accounts for the predilection of teratomas for the sex glands and for the pecul-
iarities of these growths as compared with extragenital teratomas. The
exact form of this originating sexual cell cannot well be determined, but the
conceptions held have included every stage from an original sex blastomere
down to the adult spermatoblast. Unless one chooses to distinguish essen-

784 NEOPLASTIC DISEASES

tially between adult embryomas and embryonal mixed tumors, for which
there are no adequate reasons, the entire group must be derived from a
cell commonly present in the testis. Hence a nearly mature spermatoblast
or its near antecedents are most probably the source of the tumors.

Cavazzanni distinguishes between the benign congenital embryomas of
early life and the malignant tumors of young adults following trauma. Both
arise, he thinks, in cell groups of much more limited potencies than an ovum,
probably from remnants of the Wolffian body. Yet his bilobed teratoma
exhibited, in one lobe, tumor structures which he interprets as essentially
different in origin from those of the other lobe. A misplacement of spermato-
blasts with incomplete development would strengthen the sex-cell theory
and these conditions are provided at the junction of tubules and rete where
the tumors regularly arise and where Kirkbride finds much disorder in the
structure of the embryonal and fetal testis. Teratoma testis is also partic-
ularly prone to develop in atrophic undescended organs.

Why one teratoma grows slowly and produces adult tissues, while another
develops rapidly and remains embryonal in type, cannot readily be explained
and this variation may possibly call for a wide difference in the stage of develop-
ment of the originating cell. A more obvious factor is probably found in the
influence of the blastomatous process which is usually added to the embryonic
growth. Such a process at once interferes with the orderly progress of simple
embryonal growth and converts the embryo into a true tumor. Beginning
early, the blastoma may completely suppress the embryo, or if late the
embryo may reach the limit of its growth before the blastoma assumes serious
proportions. The reported cases illustrate both of these relations.

The incitement to growth seems to have been furnished in many instances
by trauma and while it is difficult to establish an essential connection, the
traumatic theory is in accord with experimental data showing that trauma
may readily excite spontaneous growth of ova.

Undescended testes are unusually prone to develop malignant tumors, of
which Bulkeley has collected 59 cases. In three the tumors were bilateral
(O. C. Smith).'

CHAPTER XLI

TUMORS OF LUNG

CARCINOMA OF LUNG

Primary tumors of the lungs have long attracted much clinical and
pathological interest. Bayle, in 1810, vaguely described pulmonary cancer,
and Stokes, 1842, recognized several varieties of the disease. Eber-
mann as early as 1857 collected 72 cases, one occurring before the age of
nine years. Jaccoud. appears first to have sharply distinguished the disease
from phthisis. Behier pointed out the prominence of pressure symptoms
and the frequent invasion of supraclavicular nodes. Bennett's Lumleian

FIG. 367. — Carcinoma of lung.

Lectures in 1872 dealt fully with the clinical aspects, from an analysis of 39
cases. Rokitansky recognized several gross varieties of the pulmonary
lesions but the earliest microscopical studies were those of Langhans,
Marchiafava, and Malassez, 1871 to 1876.

The more detailed interest and knowledge date chiefly from the later
studies of Wolf, 1895, and Passler, 1896. Since that time the literature
has grown to very considerable proportions, so that Adler in 1911 was able to
tabulate 374 cases of carcinoma and 90 of sarcoma. Since 1912 Scotland
Forman find reports of 120 new cases.
50 785

786 X EOF LA STIC DISEASES

Etiology.— Primary malignant tumors of the lung form about i per cent,
of all cancers. Among 16,578 cancer autopsies from various Continental
sources 168 pulmonary cancers were recorded (compiled from Karrenstein
and Adler). Kaufman places the proportion much higher, at 1.83 per cent.
It is evident that increased attention has greatly augmented the list of
observed cases. Knierim (1909) reported that at Leipsic, during nine years,
66 cases of bronchial carcinoma, 7 acanthomas, and two alveolar tumors
had been observed.

Males are much more frequently affected than females, 71.9 per cent,
to 24.8 per cent. Alder gives the following analysis of age incidence:

10-20 years 6

20-30 years 10

30-40 years 30

40-50 years 78

50-60 years 113

60-70 years 94

70-80 years 23

80-90 years 2

356

Horn observed an adenocarcinoma in a girl of 18 years. A congenital
multiple tumor appears to have been encountered by McAldowie in an infant
of five and one-half months, while Nuscheler reported a case in a girl of seven
years, and Werner described a small cell carcinoma in a female of 19 years.
Sarcoma occurs at somewhat earlier ages, chiefly between 30 and 40 years,
and six cases have been reported in the first decade. The right lung is
more frequently affected than the left. Of 106 cases Perrutz located 35 per
cent, on the left side, 54 per cent, on the right, while 10 per cent, were bilateral.
The chief etiological factor is tuberculosis. Of Wolf's 31 cases 13 were
associated with tuberculosis. Squamous-cell carcinoma developing in the
wall of a tuberculous cavity is described by Schwalbe, Friedlander and
Perrone. Wolf found tuberculous lesions throughout diffuse carcinoma, or
surrounding tumor-masses. In the old scleroses, atelectases, and reparative
lesions of tuberculosis may be found many alterations of bronchial and pul-
monary epithelium, marked by considerable cellular overgrowth. Oertel
points out that the association may be accidental, at other times the two
processes exist in symbiosis, while rarely tuberculosis appears to inhibit
the carcinoma. Several cases in which there was active miliary tuberculosis
with carcinoma suggest that the malignant process may light up latent
tuberculous foci (Wolf).

Rupture of anthracotic nodes into the bronchi is held by Wolf as re-
sponsible for some cases of bronchial carcinoma. A history of chronic
bronchitis has often preceded bronchial carcinoma, and the lesions of chronic
bronchitis often present very marked overgrowth of bronchial epithelium.

In chronic interstitial pneumonia also, the overgrowth and metaplasia
of alveolar epithelium is sometimes excessive. Menetrier offers evidence
to show that primary sclerotic lesions in the lung may lead to cancer, and this
view is supported by Ribbert. Yet many alveolar carcinomas appear to have
developed in previously normal parenchyma.

Trauma has figured prominently in the history in many series of cases
and sometimes the relation between the two has been rather striking
(Auf recht) .

In many carcinomatous lungs anthracosis is extremely marked and in the
much quoted cancer of the Schneeberg miners this condition has been held

TUMORS OF LUXG

787

chiefly responsible for the disease. While some of these cases have proven
to be tuberculosis or other infectious granuloma, a few must be accepted
as primary carcinoma. In a recent case Arnstein found chiefly squamous-
cell carcinoma of bronchial origin, while portions of the tumor contained
spindle-cells which also appeared in the hepatic metastases.

Classification. — -Tumors of the upper third of the trachea are relatively
common, but they closely resemble laryngeal growths with which they are
usually grouped. The lower portion of the trachea is very rarely the seat
of tumors.

Among pulmonary tumors are considered the growths arising from the
bronchi and pulmonary parenchyma.

According to histogenesis three groups of pulmonary carcinoma must
be recognized, as rising from (a) bronchial epithelium, (b) bronchial mucous
glands, (r) alveolar epithelium.

FIG. 368. — Beginning carcinoma of bronchial mucosa. (After Langhans, V. A., 53.)

To a considerable extent these tumors are distinguished by gross anatomical
features and probably also by certain clinical characters. It is however not
possible to separate all advanced cases, especially of the more malignant
types, and the specific features belong chiefly to the earlier stages of the
tumors.

(a) Bronchial Carcinoma of Lining Epithelium.— Carcinoma of the bron-
chial lining epithelium produces extensive changes in the bronchial mucosa,
advancing along the walls of the bronchi, septa, and pleura, but seldom pro-
ducing a diffuse tumor of the lung. The process usually begins at or below
the bifurcation and extends toward the trachea above and the smaller bronchi
below. The bronchi may be filled with papillary projections over a wide area,
while the walls are thickened and the parenchyma invaded. Wolf describes
a case in which the lower half of the trachea and both main bronchi were

788

N EOF LA STIC DISEASES

filled with papillary masses and encased in dense connective tissue infiltrated
with tumor-cells.

Domeny found the main bronchus of the left lower lobe occluded
by a protruding tumor-mass, while the mucosa was the seat of large carcino-
matous ulcers. Packward describes a large tumor involving the two lower
tracheal rings and both bronchi and extending through the lung to the pleura.
There were numerous bronchiectases. A distinctly polypoid tumor of the
right bronchus with pulmonary metastases is recorded by Merklen and
Girard.

Excavation of the superficial tumor-tissue and bronchiectasis are fre-
quently established and lead to the formation of one or several cavities filled
with mucopus and walled by disintegrating tumor-tissue. In tuberculous
bronchiectatic cavities one or many polypoid tumors may project into or fill
the cavity, while the walls are infiltrated by tumor-tissue. Localized stenos-
ing and ulcerating tumors may surround bronchi of the first or second order

FIG. 369. — Relations of a squamous-cell carcinoma of bronchus. (After Ernst.')

and on account of their limitation to the hilus may readily be overlooked
(Kaufmann, Harbitz).

In advanced stages a main tumor-mass surrounds the hilus and large
bronchi, while ulcerating and usually dilated bronchi form cavities in the
centers of tumor-masses in the affected lobes. Extension to the pleura is
frequently observed in the form of widespread lymphatic injection or of
very marked thickening. The ribs and chest wall may be eroded.

Secondary complications greatly alter the picture. The remaining lung
tissue becomes emphysematous, atelectatic and sclerosed, or pneumonic
areas appear in the terminal stages. Putrefaction of retained mucus, pus,
and tumor detritus often excites fatal gangrene. Large vessels are eroded with
fatal hemorrhage. The tumor process extends into mediastinum, pericar-

TUMORS OF LUNG 789

dium, auricles, and great veins. Serous or bloody pleural effusion is very
frequent.

The structure of this type of bronchial carcinoma is that of squamous-cell or
cylindrical cell alveolar carcinoma. While the squamous-cell tumors usually
maintain a uniform structure throughout, the cylindrical cell growths often
vary extensively both in the type and in the arrangement of the cells. Thus
many histological varieties of carcinoma are represented in these bronchial
tumors. Watsuji calculates that 32 per cent, of all pulmonary carcinomas
are squamous.

Wolf found eight acanthomas and seven cylindrical cell tumors among
15 of bronchial origin. The cylindrical cells are arranged in small or large
groups or they grow diffusely. Adler describes a very cellular growth,
medullary carcinoma, which it was difficult to separate from round-cell
sarcoma. Harbitz describes a bilateral gelatinous tumor with bronchiectatic
cavities, of which the structure was adenocarcinomatous. He also found
high cylindrical cells, with mucoid changes, proliferating in small bronchi
which formed the centers of multiple tumor nodules.

Horn's tumor in a young subject was also adenocarcinomatous and
grew from a broad pedicle into a bronchiectatic cavity penetrating large and
small bronchi. Chiari described a cylindrical cell tumor of distinctly
papillary structure. Ernst's papillary tumor contained hornifying squamous
epithelium.

Fibrocarcinomatous areas are often observed in old lesions and in the
pleura, while in some contracted organs the lesion is chiefly of this type.
Spindle-cell areas are occasionally observed and in Hodenpyl's and Arn-
stein's cases this form persisted in metastases. It is highly probable that
certain so-called spindle-cell sarcomas of the lung are atypical carcinomas.

(6) Bronchial Carcinoma Arising from Mucous Glands. — In a consider-
able series of cases, tumors of this origin have yielded somewhat characteristic
gross and microscopical features, which are: limitation chiefly to the walls
and especially to the submucosa of the bronchi; relatively intact condition
of the bronchial lining; stenosis rather than dilatation of the bronchi;
often considerable infiltration of the parenchyma; and a structure of glandu-
lar carcinoma recalling that of the bronchial mucous glands. Typical cases
of this group are described by Langhans, Beck, Fuchs, Ebstein, Ehrlich,
Rondeau, Decreton, Kretschmar, Wolf, and others. Hansemann considers
that most bronchial cancers arise from the mucous glands.

A very early stage is described by Langhans. The lower 4 cm. of the
trachea and 2% cm. of the bronchi presented very numerous nodular eleva-
tions of the mucosa chiefly on the posterior aspect, while submucosa and
adventitia were diffusely thickened. The mucous lining itself was intact.
The changes were most advanced at the bifurcation of the trachea, where the
nodules projected 7 mm. into the lumen and caused a ring-like constriction.
There were no metastases. The nodules proved to be markedly hyperplastic
and carcinomatous mucous glands. The solid alveoli were composed of
small polyhedral or cylindrical cells and extended through the layers of
mucosa and submucosa down to the cartilage.

A tumor of the size of a cherry of glandular carcinomatous structure and
with numerous metastases is described by Lehmkuhl. An advanced but
characteristic condition is reported by Domeny. The tumor surrounded'and
compressed the larger bronchi with sclerosis, atelectasis, atrophy, and contrac-
tion of the lung. The pleura was much thickened and the hilus nodes were
invaded. There was marked thickening of the bronchial mucosa with stenosis
but, while the mucosa was thrown into folds, its ciliated lining was everywhere

790 NEOPLASTIC DISEASES

intact. In another case the chief lesion was bronchial stenosis. Rondeau
describes a markedly contracted and sclerosed right lung in which the bronchi
were almost completely occluded, while the pleura was 4-6 cm. in thickness.
The indurated tissues and pulmonary lymphatics were infiltrated with
adenocarcinoma in which the alveoli contained colloid masses. A sharp
limitation of the peribronchial tumor from the parenchyma is mentioned by
Beck, Meunier, and Ducreton. Gelatinous changes were prominent in
several cases, and the presence of much mucoid material led Willert to desig-
nate his tumor as carcinoma myxomatodes. Others have referred mucoid
carcinomas to the bronchial lining epithelium and to the alveolar epithelium
(Harbitz, Le Sourd).

The structure presents an adenocarcinoma or alveolar carcinoma recalling
the mucous glands of the trachea and bronchi. The alveoli may be regular,
lined by two or more layers of cubical cells, and dilated or compactly filled.
The cells are usually of small size and cubical or polymorphous, while high
cylindrical and squamous-cells are missing. Highly malignant tumors may
yield alveolar or diffuse and atypical carcinoma. The secretion of mucus is a
prominent feature and, while not wholly limited to mucous gland cancers, is
strongly indicative of this origin. In many cases the mucous secretion is
limited to single cells, but it may fill or distend alveoli and lead to pronounced
gelatinous or even cystic changes (Coats). From this typical structure there
are many variations, corresponding to the duration and malignancy of the
process and its secondary changes.

(c) Carcinoma arising from the pulmonary alveoli is either (i) diffuse or
(2) multiple and nodular. In the diffuse form one whole lobe or the whole
lung is uniformly consolidated, while cavities may form from necrosis. The
lesion may resemble organizing pneumonia or croupous pneumonia in gray
hepatization (Levene, Pepere), and there are indications that the condition
may really follow an atypical acute pneumonic process (Loser, Cahen). The
pleura is usually involved, and local and general metastases are frequent.

In the nodular form one or both lungs are the seat of many poorly defined
tumor foci from miliary to marble size or larger. Even the small nodules
may show necrotic areas, and the lesions are not always readily distinguished
from tubercles (Marchiaf ava) . The larger tumors may be solid or cystic.

The structure of the diffuse tumors presents partial or complete filling of
the air vesicles with cuboidal, cylindrical, or flat-cells. The walls of the
vesicles may be preserved or obliterated by diffuse growth or by inflammatory
processes. Domeny and others describe diffuse carcinomas of the paren-
chyma largely composed of squamous-cells. Extensive inflammatory changes
may reduce the proportion of cells and give excess of new connective tissue.
Kretschmar in a diffuse tumor described a papillary structure with cylindrical
cells. Extension through the lung occurs by way of the air passages, septa,
lymphatics, and blood-vessels, which may be found infiltrated by tumor-cells
(Edlavitch).

The structure of the nodular tumors was clearly pictured by Malassez,
and presents groups of slightly dilated air vesicles filled with papillary projec-
tions of cylindrical cells. The central spaces may be occupied by desqua-
mated cells, mucus, or necrotic material (La Sourd). Multiple tumors
composed of high, cylindrical or goblet cells of adenomatous type and without
metastases are reported by Kelly. A combination of high cylindrical cells
in papillary arrangement and solid masses of polygonal cells was observed
by Knierim and attributed to a dual origin from alveolar and bronchiolar epi-
thelium. B jornsten found many cystic tumors of both lungs in a child of nine
years, of which the structure was that of papillary cystadenoma proliferum.

TUMORS OF LUXG 791

The metastases of pulmonary carcinoma are usually very numerous and
widespread but vary greatly with the grade of malignancy. The vascularity
of the organ and the frequent invasion of blood-vessels facilitate dissemi-
nation, while the abundant lymphatic channels lead to infection of the
bronchial nodes in a high proportion of cases and to early extension through-
out lung and pleura. The tumors extend also along the lumen of the bronchi
replacing the mucosa, but Stilling's conclusion that aspirated tumor par-
ticles produce secondary growths may be doubted. In 374 cases Adler
reports invasion of bronchial nodes in 117, mediastinal 45, tracheal 26, cervi-
cal 23, retroperitoneal 23, and in many other regions less frequently. The
liver was invaded in 103 cases, pleura 52, pericardium 39, heart 30, kidney 58,
adrenal 38, spleen 18, brain 53. The bones were involved 57 times and often
extensively, the ribs, spine, skull, and sternum suffering in the order named.
In a case reported by Turnbull and Worthington the bones were the sole seat
of metastases. Metastases were absent in 33 cases.

Few organs fail to appear as possible sites of secondary growths, which
have been noted in skin, finger tip, nasal septum, eye, bladder, tubes, ovary,
uterus, pancreas, thyroid, spinal cord, and hypophysis. Deposits in the vol-
untary muscles w^ere observed in nine cases and in one case they were found
only in this tissue.

Histogenesis. — 'The exact sources of pulmonary carcinoma have been
traced in detail by many observers who have shown that these tumors aris.e
from the bronchial mucosa, the bronchial mucous glands, and the alveolar
epithelium. The impression of Schottelius that the pulmonary endothelium
gives rise to carcinomatoid tumors has not been verified.

Comparatively few cases have furnished any opportunity to trace the
beginnings of pulmonary carcinoma. On the other hand when the evidence
of histological structure, gross anatomy, and clinical history is combined, the
conclusions regarding histogenesis may be regarded as reasonably certain and
acceptable.

An origin from bronchial lining epithelium is indicated by extensive
involvement of the bronchial mucosa and by invasion chiefly along the bron-
chial tree. Papillary projections from atypical proliferation of lining epi-
thelium were observed by Reinhard and Chiari and speak strongly in favor
of an origin from this epithelium. A high papillary structure, as in Chiari's
case, has a similar significance. While cylindrical cells may be present in all
forms of pulmonary carcinoma, the presence of very high cylindrical cells
and their persistence in metastases accords best with an origin from the
bronchial mucosa (Chiari, Tillmann, Peck). In a case of alveolar carcinoma
with high cylindrical cells Ravenna traced the rather sharp transition of the
bronchial lining into the tumor-tissue.

Bronchial papillomas are probably a source of malignant tumors. Such
growths are much less frequent in the bronchi than in the trachea. Siegert
described such a tumor at the bifurcation and assumed that it arose from a
misplaced fetal remnant. Werner described a bronchial papilloma with
ciliated cells. The great majority of squamous-cell tumors arise from bron-
chial epithelium. Squamous metaplasia of the bronchial mucosa has been
shown to be of frequent occurrence in tuberculosis and other pulmonary
lesions, and this change probably precedes the development of carcinoma in
many instances (Grifiini, Kitamura, Haythorn).

E. Froelich found extensive bronchial pachydermia with squamous-cell
cancer. It is especially in and about tuberculous cavities that squamous
alterations are observed and in these situations squamous-cell cancer is most
frequent.

792 N EOF LA STIC DISEASES

In many cases squamous epithelium is mingled with cuboidal and cylin-
drical cells, as in Kretschmar's case, indicating that the metaplasia may take
place in the established tumor. In a bulky tumor of bronchial origin Henrici
found non-keratinizing squamous mingled with cylindrical cells, while in the
main branches there were papillary projections and foci of squamous
metaplasia.

Bronchial malformations appear to be connected with the origin of certain
tumors which are characterized by a cystic or papillary structure and by
abundant secretion of mucus. Stoerk describes cases of cystic malformation
of the lung in infants which he refers to two types of embryogenic disturb-
ance: (i) overgrowth of misplaced and fetal portions of the bronchial tree;
(2) overgrowth of areas of fetal bronchiectasis resulting from inflammation
and leading to occlusion of bronchus and retention of mucus. He reports a
spongy fetal cystic adenoma replacing the middle lobe of the right lung,
and presenting many cavities lined by bronchial epithelium. The septa were
deficient in elastic fibers and contained many glandlike alveoli. Some
tumors of children and adults seem to belong in this series. Aschenborn
found the right lung in a boy of 12 years replaced by a cystocarcinoma con-
taining several large cysts and eroding the ribs. Linser found a large cystade-
noma with cellular stroma reproducing fetal bronchi in a boy of 13 years.
Couvelaire described a large cystadenoma in a newborn infant with many
adenomatous alveoli branching off from abortive bronchi. Dionisi's tumor
recalled the structure of thyroid gland. Lohlein describes a sharply cir-
cumscribed tumor of the right upper lobe exuding much mucus from cystic
cavities which were dilated interlobular bronchioles. The structure was of
papillary projections of cylindrical epithelium into spaces filled with mucus.
This tumor was interpreted as originating from an area of fetal atelectasis.
Weichselbaum's small coarsely papillary adenosarcoma in the lung of a
woman of 67 years may represent a late development in a malformed
bronchiole.

The bronchial mucous glands have been shown to give origin to a well-
defined group of pulmonary growths. In a multiple nodular submucous
carcinoma of trachea and bronchi Langhans traced an unbroken series of
hyperplastic glands, showing extensive overgrowth of saccules, their disloca-
tion between the layers of connective tissue, the loss of membrana propria,
and finally breaking up into infiltrating cords of tumor-cells. Beck and
Rondeau also were able to trace the transition from hypertrophic to neo-
plastic glands in more advanced tumors. In most cases the diagnosis of
bronchial gland origin has been based on gross anatomy and microscopical
structure. The tumors are often distinctly glandular but many other histo-
logical varieties probably arise from this source (Ehrich, Fuchs, Passler). A
large scirrhus tumor with small round or cubical cells is referred by Wolf to
the bronchial glands.

In the pulmonary parenchyma it is difficult to distinguish the parts
played by vesicular and by bronchiolar epithelium, and in many instances
tumors appear to arise from both sources. In a multiple nodular tumor
Malassez described groups of slightly widened alveoli lined by papillae of
low cylindrical epithelium, but he was unable to determine whether the cells
were alveolar or bronchiolar. Since alveolar epithelium readily changes to
cuboidal in atelectatic foci, it is clear that tumors with such cells may origi-
nate in the alveoli. By exaggeration of the papillary structure and fusion of
adjoining foci some more diffuse tumors may perhaps be safely traced. Thus
Knierim describes a diffuse tumor of the mid-lobe exuding much mucus and
resembling a confluent lobular pneumonia. There was mucus in outlying

TUMORS OF LUNG 793

alveoli. The tumor presented alveoli and spaces lined by cylindrical cells
in papillary outgrowths and solid masses of polygonal cells. The papillary
structure persisted in lymph-nodes. The author suggested an origin from
both bronchioles and alveoli.

The exact mode of origin of the solid diffuse carcinomas is somewhat
obscure. In many cases the air vesicles are filled with solid masses of cubical
or cylindrical cells suggesting an origin from altered alveolar epithelium or
from the bronchioles. Ramon and Boidin, among others, found all transitions
from flat to cubical to neoplastic epithelium. The secondary changes of
atelectasis seem to precede the advance of the tumor.

In other cases the history and the minute structure indicate that the
neoplasm has arisen as a sequel or incident of croupous, productive, or tuber-
culous pneumonia. In a case of supposed croupous pneumonia Loser was
unable to decide whether he had an inflammatory proliferation of endothelial
or epithelial cells, or a true carcinoma. Yet there were subpleural nodules
of alveolar carcinoma.

Pepere's small contracted lung resembled interstitial pneumonia but
was the seat of alveolar carcinoma. Cahen found a structure which he
likened to desquamative pneumonia. Diffuse or miliary tuberculous lesions
in or about the tumor have suggested that the neoplasm may arise from exag-
gerated proliferation connected with this infection (Wolf, Domeny). Many
of the diffuse carcinomas arising from the alveolar epithelium contain pave-
ment or distinctly squamous-cells (Fuchs, Grunewald, Edlavitch, Domeny).
Menetrier could not demonstrate eleidin granules in these flat-cells, while
pearls and spine-cells appear to be limited to the bronchial tumors. A bulky
colloid acanthoma in the lung of a dog was referred by Rievel to the alveolar
epithelium.

Symptomatology. — The symptoms and course of pulmonary carcinoma
vary extremely according to the type of the tumor and the conditions which
have led to its development.

A large number of cases have been regarded clinically as acute or chronic
phthisis, and since tuberculosis is often present with bacilli in the sputum a
differential diagnosis may be impossible. Other cases appear as sequels of
prolonged pneumonia. An apparently sudden onset is often due to acute
changes in a long existant tumor. A long history of bronchitis with or
without hemoptysis has preceded the discovery of bronchial tumors. The
uncomplicated bronchial tumor usually gives physical signs of a progressive
intrathoracic growth, with cough, hemoptysis, pain, recurring pleural effusion,
serous or bloody, dyspnea, and cyanosis. According to Herrmann about half
the cases are of the pleuritic type. Extensive infiltration of the pleura
with adhesions may prevent effusion. Fever must be referred to complica-
tions. The diagnosis of a neoplasm has repeatedly been made from tumor
fragments in sputum or pleural effusion (Betschart, Rondeau), by axray
photography (Muser) , and by the bronchoscope (Karrenstein) . The duration
has varied from 4 years (Adler), to 10 days (Jaccoud). A fatal hemoptysis
may be the only symptom (Beveridge, Degen).

Cachexia is slight in uncomplicated cases but terminal stages are often
marked by suppuration, pneumonia, and gangrene. Immediate causes of
death also include rupture of large veins, thrombosis, pulmonary edema and
asphyxia.

In not a few cases the effects of metastatic growths have attracted chief
attention, and have centered chiefly in the central nervous system (Coats,
Domeny, Wolf). Finally pulmonary tumors have occasionally appeared
as wholly unsuspected conditions at autopsy.

794 N EOF LA STIC DISEASES

Operative interference with pulmonary tumors has been attempted by
Lenhaftz, and in one case the excision of the affected lobe was survived for
1 8 months.

SARCOMA OF LUNG

. From both clinical and pathological standpoints sarcoma of the lung is
a very ill-defined group of processes of varied origin and course. While
Adler was able to select 90 cases from the literature, only a minority of the
reports present sufficient evidence to justify their separation from diffuse
carcinoma.

In not a few cases the sarcoma has been associated with extensive chronic
exudative necrotic or productive inflammation, with abscesses, gangrene,
empyema, or fistulous tracts, which in a reactive tissue like the lung may
readily lead to overgrowth of reparative tissue simulating round- and spindle-
cell sarcoma. In another group active tuberculous lesions have been present
and so intimately associated with the whole process as to render a distinction
between tumor and inflammatory product somewhat hazardous. Thus
Pater and Rivet found tubercle bacilli in multiple nodules of large round-cell
sarcoma at both bases and in the liver, while Schnick describes as spindle-cell
sarcoma a large excavated tumor mass, partly calcified, in an actively tuber-
culous lung. Sangalli's round-cell fibrosarcoma, irregularly distributed
throughout an old tuberculous lung, does not accord with the usual behavior
of sarcoma.

Old syphilis is strongly suggested in a curious cystic tumor filled with
mucus and pus described by Milian and Mante. The precocious develop-
ment of pulmonary tumors secondary to growths in other organs, especially
in the bones, stands in the way of accepting certain bulky spindle- and giant-
cell tumors as primary in the lung. Before sarcoma or carcinoma can be
regarded as primary in the lung a very thorough search for primary tumors
in other organs must be made. There are possibly on record less thoroughly
studied cases than that of Lesieur and Rome, who found a massive apparently
primary carcinoma of the lung, but in the rectum a carcinomatous ulcer.
Of the lymphosarcomas very few, if any, can be regarded as primary in the
lung, while in many instances it is clear from the anatomical descriptions
that the tumor arose in the bronchial or mediastinal nodes or the thymus.
It also appears that many authors describe as lymphosarcoma any tumor in
which the cells are small and round. Nearly all the primary large and small
round-cell sarcomas of the lung, as of many other organs, are under suspicion
because of the fact that atypical carcinoma may yield exactly similar pictures
in rapidly growing areas. Adler among others has pointed out the necessity
of extensive study of all portions of such tumors and their metastases before
the mesoblastic origin can be assumed. I can support Fuchs' statement
that areas of spindle-cells may be found in pulmonary carcinoma. Hodenpyl
found spindle-cells in the hepatic and lymphatic metastases of a carcinoma.
The carcinosarcomas of the lung are probably thus explained.

Finally no one has succeeded in tracing the origin of any of the malig-
nant sarcomas of the lung, and the general field of pathological changes
in this organ does not point clearly to specific conditions under which meso-
blastic tumors may arise. The very marked overgrowth of endothelium in
some organizing pneumonias may perhaps have some significance.

Nevertheless these uncertainties hardly warrant the conclusion, once
drawn by Hertz, that primary sarcoma of the lung does not exist, for the
literature offers not a few reports indicating that mesoblastic tumors occa-
sionally arise in this organ.

TUMORS OF LUXG 7-95

A provisional classification of pulmonary sarcoma based on anatomical
features may be employed as follows:

(1) Diffuse spindle-cell sarcoma

(2) Peribronchial sarcoma

(3) Large round-cell sarcoma

(4) Lymphosarcoma.

(1) Diffuse spindle -cell sarcoma produces a characteristic gross and
microscopical picture and is the best defined type of pulmonary sarcoma.
The tumors are usually bulky, exceeding in size the largest carcinomas.
Bock's tumor in a child filled the entire left thorax, obliterating all pulmonary
structures. The ribs may be eroded (Elkan), and chest wall perforated
(Koblynski). Cavities may form from central necrosis and hemorrhage
(Ranglaret), or the whole tumor may be very soft and hemorrhagic (Rolles-
ton, Trevor). In several cases the tumor while large has been well encap-
sulated (Fuchs).

Smaller firm tumors are usually fibrous. In Chiari's case there was
extensive calcification. Blumental describes a large myxosarcoma. Metas-
tases are usually absent but there are extensions through lung and pleura
and to the neighboring nodes.

The structure presents large and small spindle-cells, or occasionally
giant-cells, writh varying proportions of stroma. This structure suggests
an origin from the pulmonary connective tissue, as mentioned by Mironescu.
The bronchi may be normal (Rutimeyer).

(2) Peribronchial sarcoma presents a specific anatomical distribution
which indicates an origin from the bronchial wall, with extension along the
bronchus. The infiltration follows the bronchi from the root of the lung or
trachea throughout the parenchyma and into the septa (Peritz, Pollak).
The bronchial walls may be ulcerated and weakened with ectasiae (Anderson,
Levitt) or compressed.

Nearly all the peribronchial tumors are composed of small round-cells
and some are often designated as lymphosarcoma. Their origin is obscure.
Since the bronchial nodes are constantly involved, the condition may repre-
sent a pulmonary invasion from these nodes. In Hildebrand's case the tumor
arose in a phthisical lung and tubercle bacilli were numerous. Small-cell
carcinoma of the bronchi may be difficult to distinguish from the round-cell
tumors of this class.

(3) Round-cell Sarcoma. — This highly indefinite term may be applied
to a group of tumors which do not appear to belong to the lymphosarcomas
and which cannot be positively identified with small cell diffuse carcinomas.
They differ from lymphosarcoma by their limitation chiefly to the lung.
Several cases have been reported in children or young subjects, Bjornsten
observing the disease at 2 years, Lehndorff at 3 years, Box at 5 years, Davies at
1 8 years, and Poore and Pitot at 20 years. They are usually bulky, involving
the whole of one lung with pleura, in a solid opaque tumor which obliterates
most pulmonary structures. In some cases the tumor is smaller and encapsul-
ated (Lehndorf, Roth). Areas of necrosis and large cavities may form.
Metastases are local or absent, but there may be extensions to hilus,
nodes, ribs and vertebrae. In the case of Millian and Bernard, of 4 months'
duration, the left lung was represented by a large cavity with sarcomatous
walls.

The structure presents small or large round-cells in diffuse, perivascular,
or alveolar arrangement. The alveolar structure described by Roth, Meyer,
Adami and McDonnell strongly suggests a carcinomatous nature.

796 NEOPLASTIC DISEASES

(4) Lymphosarcoma. — Although a large proportion of the round-cell
tumors of the lung have been described as lymphosarcoma, there is no satis-
factory evidence that true lymphosarcoma arises in the pulmonary paren-
chyma. It seems much more probable that the lymphosarcomas arise in
the bronchial or mediastinal nodes or elsewhere and invade the lung along
the bronchi. Such tumors present bulky masses about the hilus and more
or less extensive invasion of the parenchyma. Cases of this type are de-
scribed by Powell, Cohen and Kirkbride, Coats and others.

CHAPTER XLII

EPIDERMOID CARCINOMA
EPIDERMOID CARCINOMA OF SKIN

Carcinoma of the skin is remarkable for diversity of origin and course
and variety of histological structure.

Two main histological types of the tumor occur; (i) Hornifying cancroid,
acanthoma, (2) basal-cell carcinoma.

Of each of these there are several subvarieties which are distinguished
by structural, etiological, or clinical features.

(i) Acanthoma. — This tumor is distinguished by the presence of adult
squamous-cells, hornification, and pearl formation. The tumors are single
or multiple. The multiple tumors may be very numerous and widely dis-
tributed over face, trunk and limbs, and their early stages may be marked
by erythema, seborrhea, eczema, or pruritus.

The early lesion of acanthoma of the skin appears in two main types which
it is highly important to distinguish.

(a) Many acanthomas pass through a preliminary papillomatous stage,
in which they appear as definite elevated warty outgrowths movable on the
superficial fascia. Histologically these lesions are malignant but they long
remain localized and tend to spread laterally. In this phase they offer a good
prognosis, which is lost when the lesion becomes fixed, ulcerated, and
depressed.

(b) Other acanthomas are flat, depressed, indurated, and infiltrating
from a very early period. They are less impressive externally, but early
ulcerate and invade the deeper tissues and lymph-nodes, usually with a
tendency to assume the structure of tubular carcinoma, in which squamous
characters are lost.

In the more advanced stages of both types there is erosion and ulceration,
and the lesion gradually extends in the form of a broad ulcer with raised
nodular indurated edges and granulating base. Acanthoma of the skin
differs from rodent ulcer chiefly in its early papillary appearance, more rapid
lateral extension, and more destructive course. Yet both types of carcinoma
may occur in the same lesion. Occurring in tissues previously altered by
syphilis, tuberculosis, etc., its progress is facilitated by this association. The
local aggressive tendencies of acanthoma tend to produce deep ulceration
with extensions along blood-vessels and nerves with pain and hemorrhage,
and invasion of lymphatics with metastases in lymph-nodes and occasionally
in internal organs. Bulky internal metastases however are rare. The
largest I have observed were in the inguinal nodes and liver, from epithelioma
of prepuce. Secondary infection by streptococcus is nearly constant with
deep ulcers, may accompany the metastases, greatly influences the course and
termination, or may even dominate the clinical picture.

•The seats of single acanthoma of the skin are chiefly the mucocutaneous
junctions, the face, scalp, chest, breast, back of hands, shins, and toes. The
location varies with the numerous peculiar etiological factors. Thus chim-
ney-sweep's and paraffin cancers occur on scrotum and thighs. Kangri
cancer on the abdominal wall, while the scars of burns, chronic ulcers, #-ray

797

798 N EOF LA STIC DISEASES

dermatitis, and various forms of trauma are followed by tumors in many
regions. Acanthoma occurs chiefly in advanced life but has been observed
as early as the i4th year (Borrmann). Selberg has collected a series of cases
occurring in infants and children.

Structure.— Acanthoma of the skin presents the most typical form of
adult epithelioma and tends to maintain this structure rather rigidly. Hence
flat squamous epithelial cells, intercellular fibrils and pearl formation are
often observed, both in the primary tumor and in local or distant metastases.
Thus one finds in metastatic nodules in liver or bone-marrow extensive
hornification, spine-cells, and small cysts filled with exfoliated scales, and
these adult features may be more pronounced than in the primary tumor.
On the other hand many acanthomas lose their adult characters in the
growing edges of the primary tumor, where the cells appear in narrow cords

FIG. 370. — A hornified pearl in acanthoma. (Photo by B. H. Buxton.)

of opaque granular cells with hyperchromatic nuclei. This structure may
be called " tubular acanthoma." It is usually associated with a high grade
of malignancy. In certain acanthomas the coherent masses of epithelial
cells are replaced by a diffuse growth of rounded-cells each of pavement
character. Giant-cells may be very numerous in such tumors and may even
predominate over other forms. The cause of such marked variations in struc-
ture is not clear, but edema seems to play a part. Many peculiarities of cell
structure appear in acanthoma, which Unna has made an effort to classify.
These include many of the bodies once regarded as parasites and elaborately
pictured by Pianese. Unna has called attention to a peculiar X-cell seen in
condyloma and acanthoma. Its cytoplasm is homogeneous and basophilic,
and its microchemical reactions have been studied by Pansini.

In the metastases there may be great anaplasia, and after repeated recur-

EPIDERMOID CARCINOMA 799

rences there may be entire loss of adult epithelial characters and the tumor
may appear as an indifferent round- or spindle-cell growth. Unless the
history of such changes has been followed an erroneous diagnosis may be
made.

Secondary changes in acanthoma are numerous and frequent. Polynu-
clear leukocytic infiltration follows from infection. Round-cells, lympho-
cytes, and plasma-cells may gather in large numbers about early lesions, but
diminish as the tissue resistance fails and the rate of growth increases. Ex-
tensive calcification appears in some tumors without greatly influencing the
course. Giant-cells form from fusion of tumor-cells, or from phagocytic
tissue cells which gather about the tumor masses. Fibrosis is prominent
in most cases but seems to have little effect in limiting growth. Extensive

FIG. 371. — Prickle cell in acanthoma. (Photo by B. H. Buxton.)

hornification, and calcification of tumor-cells with overgrowth of hyaline
connective tissue, Orth regards as evidence of spontaneous healing.

In an interesting group of cases fatty degeneration, necrosis and calcifica-
tion may become very extensive, so as to destroy many or all of the epithelial
cells. Growth may then be very slow but in time the tumor may reach a
large size. In Landau's case it weighed 250 gm. Walkhoff reports a case of
50 years' duration. Strassberg observed extensive bone formation. The
exact nature of these " petrified epitheliomas " has remained in doubt.
Barlow regards them as forms of adenoma sebaceum, but Ribbert and most
authors consider that all of them are acanthomas.

Etiology. — Acanthoma of the skin is almost exclusively the result of
chronic traumatism, but the forms of the irritation are extremely varied, and
the relation to the tumor is indirect. Yet from the practical standpoint
irritation is the important factor, and all other influences such as heredity, or
local predisposition, are secondary. This tumor arises from previously nor-

800

NEOPLASTIC DISEASES

mal epithelium after a period of overnutrition and overgrowth, during which
the subepithelial tissues become altered and less resistant. Lymphocytic
infiltration, swelling with mucoid or other forms of degeneration, followed by
atrophy of elastic tissue, and chronic edema or fibrosis, usually but not
always precede the downward growth of epithelium. Yet the controlling
influence must, I believe, be regarded as inherent in the epithelial cell. All
cutaneous epithelium must be considered capable of developing acanthoma,
for which it is only necessary to supply the proper conditions. These con-
clusions seem to be justified especially by study of the conditions under which
acanthoma occurs. Thus the peculiar irritation to which chimney sweepers
and paraffin workers are sometimes exposed determines a peculiar localization

FIG. 372. — Giant-cell forming about an epithelial pearl in acanthoma. (Photo by B. H.

Buxton.)

of the disease. The observations on Kangri cancer of African natives, which
develops on the abdominal wall at the point of irritation of a hot earthen
oven, is a very direct demonstration of the rule. X-ray dermatitis appears
to occur indifferently in any region where the rays may have been applied.
Yet there is some evidence of a personal predisposition to o;-ray dermatitis
and its sequelae. Chronic ulceration, eczema, lupus, and the scars of burns,
present somewhat more complex but essentially the same conditions in which
acanthoma develops. In the localization about mucocutaneous junctions
there is an added factor in the anatomy of these regions, as well as increased
exposure to trauma. Cheatle believes that cutaneous cancer develops
mainly at the points where nerve-trunks reach the skin, and tend to spread
chiefly in such areas of nerve distribution. Warts, both simple and venereal,
may be the starting points of acanthoma.

Some very malignant acanthomas have developed after the bites of ani-
mals, especially the horse, and of insects.

EPIDERMOID CARCINOMA

801

In a series of cases of acanthoma, chiefly of the face, Borrel has found a
parasitic insect, Demodex folliculorum, which he regards as the direct exciting
cause of the tumor. He finds that about 50 per cent, of all subjects show an
invasion of the skin by this insect. I have observed the structures he depicts
in acanthoma, but find it difficult to draw any conclusions concerning their
significance.

B. Fischer, by injections of Sudan III in olive oil produced hyperplasia
of epithelium and downward growth resembling epithelioma, but the proc-
ess ceases when the oil is extruded. Specific "attraxines" of this and other
types may well exist, including derivatives of insect bodies, but the scope of
their activity in human acanthoma remains to be determined.

Certain deep acanthomas arising from particular conditions require
mention. The sebaceous cyst sometimes develops a somewhat malignant
deep epithelioma, in which the char-
acters of the duct-cells are promi-
nent. The true congenital epider-
moid cyst of the skin is another
source of deep epithelioma. The
branchiogenic cyst is a frequent
source of deep and often very malig-
nant acanthoma of the neck. This
tumor may appear anywhere from
the mastoid to the clavicle and often
reaches considerable development
before its true nature is recognized.

Many other congenital dermoid
cysts have given rise to deep epithe-
lioma. These occur chiefly in the
neck, head, buttock, navel, and
wherever embryonal fissures form
(Krische, Mertens, Linser). In the
breast, Kaufmann found a deep der-
moid with epitheliomatous changes,
associated with carcinoma of the
breast. The frontal dermoid ap-
pears beneath the skin of the fore-
head, or within the tables of the
skull, or within the cranial cavity,
where it may present the changes of
acanthoma, usually with bulky lamel-
lated concretions of horny scales (Hartley). Occasionally it shows an open-
ing through the scalp. Embryomas of ovary or testis may be the seat of
epitheliomatous change of the skin. I have studied an ovarian dermoid
which ruptured into the colon, and presented a papillary acanthoma at one
point invading the rest of the complex tumor.

Xeroderma pigmentosum is a condition regarded by many as an aggravated
form and sequel of the common lentigines (freckles). It is marked by over-
growth of pigmented epithelium, scaling, even ulceration, and eventually
by atrophy of the affected skin (Crocker). Several tumor-like processes in
the derma have been described as secondary to the disease, as angioma,
myoma, pigmented sarcoma, and especially epithelioma. The epitheliomas
may be of the type of acanthoma or of rodent ulcer (Kreibich, Fernet, Halle).
They are often pigmented as in sailor's carcinoma (Unna). Hutchinson
described as lentigo maligna juvenilis, v. senilis, cases of progressive freckles

FIG. 373. — Xeroderma pigmentosum with
multiple epidermoid carcinomas.

802 N EOF LA STIC DISEASES

of cheek and eyelid which become the seat of epithelioma. It occurs chiefly
between the seventh and ninth years (juvenile) or in old age. It appeared
in seven of eight boys in one family in which five girls were unaffected (Ruder) .
The exciting cause is exposure to sunlight, acting on the skin of constitution-
ally and congenitally predisposed subjects (Councilman, Magrath). Accord-
ing to Dalous and Constantin the most marked feature of xeroderma is
atrophy and scarring of the derma, with secondary carcinoma, while Unna's
pigmented epithelioma is a primary miniature carcinoma.

That the prolonged use of arsenic has an influence upon the development
of epithelioma of the skin has been urged especially by Hutchinson, who
reported two cases. The first effects are a hardening and pigmentation,
the appearance of palmar or plantar psoriasis, followed later by epithelioma.
Darier observed multiple carcinoma following xeroderma pigmentosum which
resulted from excessive use of arsenic. Fordyce described characteristic
cell changes in the epidermis.

Lupus Carcinoma. — Epithelioma develops in a considerable proportion
of cases of lupus vulgaris and much less frequently with 1. erythematodes
(Ashihara, Lit.). It arises both in the- active regions of the tuberculous
process in skin or mucous membranes and in about 30 per cent, of cases in
the lupus scar tissue (Steinhauser), and as early as the fourth or as late as the
fifty-fifth year of the original disease, the average period being about the
thirtieth year. In many cases but not in all the course is relatively rapid for
cutaneous carcinoma, with invasion of lymph-nodes and internal growths.
The prognosis is very grave, only nine cases of Ashihara's list of 122
recovering.

The initial stages of lupus carcinoma may be somewhat difficult to
separate from the usual hyperplasia and displacement of epithelium in the
lupus process. As a rule the tumor appears in multiple foci with the usual
local signs and increased destruction of tissue. The structure is that of
acanthoma, becoming tubular and atypical in advanced stages and metastatic
areas. Lupus erythematodes has been followed by carcinoma in seven
reported cases collected by Ashihara. Hartzell reports one case after tub.
cutis verrucosa, and Blaschko observed a case with leprosy. Several cases
developing in luetic scars are mentioned by Ashihara, and Rabaioye reported
a case following blastomycosis. Senger reports a case of malignant recurring
sarcoma following lupus.

X-ray Dermatitis and Carcinoma. — A single severe exposure to .T-ray,
or repeated slight exposures, lead to a peculiar form of dermatitis which in
many instances has been followed by multiple acanthoma of the skin, .and in
not a few cases by fatal extension of the tumor process to internal organs.
The growth of knowledge in this field has been coincident with the develop-
ment of the lesions in the unfortunate early workers with :v-ray, who watched
the appearance first of the acute dermatitis, then of the thickened skin,
alopecia, telangiectases, ribbed nails, and keratosis, and later of the warty
outgrowths, ulceration, and finally malignant carcinoma. Since the first
formal report of these lesions (Marcuse, 1896) observations have multiplied
rapidly. In 1900 Kienbock gave a very full description of the dermatitis
and its immediate sequelae and pointed out methods of avoiding the
"soft" or burning rays. The development of fatal carcinoma began to be
reported in 1904 (Porter), and at the time the urgent interest in the subject
brought out the careful histological study of Unna and the experimental
work of Gassmann and of Linser.

Clinical Course. — 'X-ray dermatitis appears in the form of an erythema
which follows a few hours after the application and varies in intensity and

EPIDERMOID CARCIXOMA

803

character with that of the energy employed. The immediate effects have
been compared with heat burns of various degrees. Many of these lesions
soon run into ulceration which long remains painful and indolent.

After repeated slight exposures a period of incubation is commonly ob-
served, lasting from 3 to n years and marked by, thickening of the skin, dry-
ness, scaling, fissures, keratosis, alopecia, and cyanosis. At any time
in this period local warty areas of keratosis may form or painful ulceration
develops. The deeper tissues being involved whole phalanges or limbs may
be destroyed by a dry gangrenous process. Carcinoma develops either on a
severe acute burn after prolonged ulceration (Porter) or after the more
chronic changes which have not been preceded by any severe acute dermatitis,
and it has frequently arisen as a combined result of a lupus or other lesion
treated by A'-ray. Da Costa found that 18 per cent, of lupus cases develop
carcinoma after .r-ray treatment, but carcinoma is by no means uncommon
in untreated lupus. The carcinoma occurs in the bases and edges of ulcers,
or beneath multiple foci of keratosis, and both because of its initial malignancy

FIG. 374. — Epidermoid carcinoma following rv-ray dermatitis.

and from the progressive development of new foci it is extremely clifricult
to combat. Involvement of lymph-nodes and internal metastases follow,
with death, as recorded in at least nine cases (Porter).

Structure. — -The early lesions are those of a subacute exudative inflamma-
tion in which vascular lesions are prominent. Linser who excised pieces
of skin at intervals during treatment for lupus, found thrombi in the vessels
in four days, which with swelling and desquamation of endothelium reached an
acme in eight days, and was followed by obliterating endarteritis. Unna
emphasizes the telangiectasis, which he refers to deep obliterating endo-
phlebitis. In a severe burn of 30 days1 standing I find hyaline necrosis of
endothelium and entire wall of venules, wide subepithelial telangiectases,
extensive edema, general infiltration with lymphocytes, swelling of collagen
fibrils, hydrops of the epithelium and beginning keratosis.

In more chronic lesions fibrosis and atrophy are predominant, so that the
condition resembles premature senescence (Lindhorn). Wolbach, who finds
foci of necrosis in the corium after many months, interprets the lesions as
the result of progressive degeneration from vascular changes and imperfect

804

NEOPLASTIC DISEASES

efforts at repair. The lymphatics are obliterated by endothelial proliferation
(Gassmann). The muscle-tissue, at first swollen and vacuolated, atrophies
and disappears. The connective-tissue cells are swollen and multiplied
and their nuclei may be hyperchromatic. Exaggeration of this feature has
led^to conditions interpreted by some as sarcoma (Schumann, Lit.). 1 have
seen one case of this type but the conditions were too obscure for positive
diagnosis. The structure resembled that of Clunet's experimental #-ray
sarcoma in a rat. The epithelium is altered from the first, showing hydropic
degeneration, keratosis or scaling, and erosion and overnutrition of the

. ! i

FIG. 375. — Chronic *-ray dermatitis. Precancerous stage. Showing keratosis, telan-
giectasis, destruction of collagen fibrils, lymphocytic infiltration, hypertrophy and hyper-
chromatism of epithelial cells, and beginning heterotopia of epithelium.

deeper layers of cells. Proliferation of these cells, usually under a thick cover-
ing of keratin, gradually leads to downward growth into the edematous co-
rium, or into dilated thrombosed vessels (Wolbach). In this stage the struc-
ture is usually that of acanthoma or tubular epithelioma.

Much use has been made of this experimental cancer, especially by Wyss,
for its bearing on the genesis of epithelioma, but it does not appear that the
factors concerned in #-ray cancer are simpler than in other conditions. A
specific change in the blood rendering it injurious to vessels and cells (Unna),
repeated efforts at regeneration (Wolbach), disturbed relations of tissue

EPIDERMOID CARCINOMA

805

tension from dermal fibrosis (Wyss), and acceleration of autolytic processes,
all deserve consideration. Those who assume that the dense fibrosis of the
deeper corium is the essential factor have perhaps underestimated the
importance of the changes in the epithelium which are constantly present.

Paget's Disease. — Paget's disease is a specific chronic progressive disease
of the epithelium of the mammary nipple and adjoining skin which is closely
related to and almost invariably followed by carcinoma. The exact nature
of the process is not yet fully determined, some cases appearing to represent
an extension of duct- or sweat-gland carcinoma into the epidermis,
others a primary precancerous affection limited chiefly or exclusively to the
epidermis.

It first appears as a keratosis of the nipple, soon followed by an itching
eczematoid condition of the nipple and surrounding skin which extends in

FIG. 376. — Diffuse carcinoma of breast (Paget's disease).

continuous concentric areas over most of the breast, producing a moist,
slightly indurated, glazed, partly eroded or scaling surface that shows no
tendency to heal. Extensions over the axilla and much of the thorax have
been observed (Kaufmann, Vignoli-Lutati), and the disease may occur in the
skin of penis, scrotum, vulva, navel, abdominal wall, or axilla (Zieler, Lit.).
It begins usually between the ages of 40 and 60 years and commonly runs a
very chronic course of 10 or even 20 years before death from the asso-
ciated carcinoma or from intercurrent diseases. The nipple is usually
retracted and a definite carcinoma of this portion of the breast may be present
from the first, or develop later. These tumors may run a rapidly fatal course
(Krogius) but more often their progress is relatively slow.

Structure. — The earliest changes have been located in the squamous

806

NEOPLASTIC DISEASES

epithelium of the nipple, or in the milk-ducts below the nipple (De Page),
or in the parenchyma of the gland (Kyrle, Elbogen), but it is doubtful if the
very earliest stages of the process have been observed. Usually both epider-
mis and milk ducts are found to be affected and the fact that the lesion is not
always continuous from one to the other is referred by Jacobeus to a sphincter
action of the tissues at the mouths of ducts. In the epidermis characteristic
"Paget's cells" appear as swollen, rounded, clear staining hydropic cells, single
or in small groups, with hyperchromatic nuclei often in mitosis. Many
observers have traced their derivation from the normal prickle cells, by a
process of hydropic degeneration with loss of fibrils (cellules dyskeratosiques,
Darier). Sekiguchi regards them as wandering carcinoma cells. The
marked isolation of some of these cells, especially when small, rounded and
pigmented, led Darier to regard them as psorosperms. The Malpighian

FIG. 377. — Mammary cancer.

Carcinoma simplex.
Paget's disease.

Duct carcinoma associated with.

layer containing these cells is usually thickened and the papillae elongated.
The corium is usually rich in plasma-cells. In advanced stages much of the
epidermis is replaced by Paget's cells, which appear in alveolar groups or
sheets or extend along the basal portions and into sweat-glands. The basal
layer alone may exhibit the characteristic changes (Zieler). In the milk-
ducts a similar process is usually present, but Unna and Karg both found
lesions limited to the epidermis, with milk-ducts intact. A notable feature
is the long integrity of the corium but eventually there may be invasion of
the connective tissue from the enlarged rete pegs. Many have noted the
long delay in the appearance of the usual structure of carcinoma, which takes
the form" of an adenoid growth. Pearl formation was observed by Darier.

EPIDERMOID CARCINOMA

807

In Krogius' case the secondary carcinoma was thought to be derived from
the sweat-glands.

The exact nature and origin of Paget's disease remain a subject of active
discussion and it seems probable that the disease in its various stages is
not always one and the same. The long duration of the disease, the very
wide and superficial extent of the lesion, the occurrence in several regions
besides the breast, and the long absence of any definite tumor render it
unlikely that the condition can be dismissed as a peculiar form of skin
invasion by duct carcinoma. There are many cases of epidermal invasion
by mammary and other cancers but they rarely take the form of Paget's
disease. Hence, Darier, Unna, and many others regard the condition as a
disease sui generis, and a type of precancerous condition. Zieler draws

Wfef*JWrC -A* -"f^Br^+x
fc§ ***3* «M£*J r'JE^I v*i

'»vi*.'<***'j*** *i^ »<y

•• $*<&?. • **<

FIG. 378. — Paget's disease of the buttock, showing edema and vacuolization of cells.
(From collection of Dr. J. A . Fordyce.)

an apt parallel between Paget's disease and xeroderma pigmentosum; both of
which represent primary disturbances of the epidermis which tend to result
in cancer. For many very extensive lesions without definite localized car-
cinoma this interpretation is probably correct. Such a case is that of
Fox and McLeod who were unable to find any definite primary tumor asso-
ciated with Paget's disease of the navel of n years' duration. Others,
finding a definite tumor of the breast or nipple regard the disease as nothing
more than an early and extensive intra-epidermal growth of a primary cancer
of the mamma (Jacobaeus, Ribbert, Schambacher, Hirschel, Sekiguchi).

Hannemuller and Landois, while accepting the origin from a primary
carcinoma of the breast, interpret the Paget cells as swollen overactive
edematous epidermal cells. Others again, and among them some of the

808

N EOF LA STIC DISEASES

earlier observers, regard the process as a peculiar form of primary cancer of
the skin (Thin, Duhring and Wile, Ehrhardt). Thus the three main theories
cover a precancerous condition, a definite carcinoma of the skin, and a
growth, sometimes early, more often terminal, of the breast, so that the
composite picture of Paget's disease presents prolonged stages of the evo-
lution of carcinoma.

Whatever the histogenesis may be, remarkable clinical and anatomical
characters are quite sufficient ground for recognizing the condition as a
specific malady. According to Fabry and Trautmann there is also a
specific etiological factor in the presence of a yeast which they were able to
cultivate but which is probably a secondary invader.

FIG. 379. — Paget's disease. Lesion of the buttock showing epidermal hyperplasia,
edema, vacuolation, loss of prickles and multinuclear cells. (Photograph from collection of
Dr. J. A. Fordyce.)

(2) Basal-cell Epithelioma. — -Two somewhat distinct but related histo-
logical types of tumors develop chiefly or exclusively from the basal cells of the
Malpighian layer of the skin, viz., (a) Reticulated epithelioma, and (b)
adenoid epithelioma.

(a) Reticulated Epithelioma. Rodent Ulcer. — The characteristic clinical
history of this disease is associated with a specific histological structure.
It occurs chiefly on the face, neck, and scalp, at mucocutaneous junctions,
especially about eye, nares, or ear, and is notably limited to adult or advanced
ages. Williams finds the average age 42 to 44 years but records a case in a
girl at 14 years fatal at 56 years.

It first appears as a flat papule or smooth wart which long remains without
marked change, or what is mistaken for a pimple maintains a persistent

EPIDERMOID CARCINOMA 809

ulceration which resists efforts at cure. The early lesions may appear as
broader flat elevations or as multiple small thickenings which coalesce.
Occasionally in cases of multiple tumors there is a history of local erythema,
eczema, or seborrhea (Janeway). After a period wThich may cover several
years and often marked by inadequate therapeutic procedures and other
forms of trauma the lesion ulcerates. The characteristic rodent ulcer shows
a remarkable tendency to remain superficial. It destroys the skin down to
superficial fascia where its progress is long restrained. Later it strips the
tissues down to bone or muscle where again it makes slow progress. Thus the
base varies in depth but is usually covered by granulation tissue and warty
islands of tumor. Extensive fibrosis of the base may limit the downward
growth and at the same time obstruct any natural or artificial efforts at
cure. The secretion is first thin and serous, later purulent, and with frequent

FIG. 380. — Basal-cell carcinoma of scalp.

small '.bleedings. The edges are raised, nodular, indurated, pearly and
constantly hyperemic. The vicinity may be glazed and hyperemic over a
wide margin or the indurated border may be sharply marked. Extension
being through the superficial lymphatics, new areas when involved first show
subepithelial nodules which later break through the epidermis. As the
ulcer widens there may be a distinct tendency toward healing in the older
areas.

In advanced stages the dimensions of the rodent ulcer become very
wide, involving much of the face, neck or scalp. The destruction of tissue
becomes deeper, especially with the aid of incomplete excision. The eye, ear
and nose are often completely destroyed. The periosteum is invaded with
destruction of bone, with penetration of bony sinuses, cranium and middle ear
or bone-marrow. Erosion of large vessels may lead to fatal hemorrhage.
Cachexia results chiefly from chronic suppuration, hemorrhages and mental
depression.

810 N EOF LA STIC DISEASES

Rodent ulcer seldom involves the lymph-nodes even after many years
of' 'growth, but in a few cases the regional nodes become invaded and the
progress is more rapid with certain changes in structure (Dubreuilh, Auche,
Fordyce).

Crateriform ulcer is a special variety of rodent ulcer which appears
on the face in the form of a conical induration which resembles a furuncle.
In a few months it ulcerates deeply, involves lymph-nodes and proves fatal
in one to two years, but early excision is usually successful (Hutchinson).

Many of the clinical features of rodent ulcer may be simulated by a less
malignant low papillary acanthoma of wide extent.

FIG. 381. — Structure of a basal-cell carcinoma of skin. Widely infiltrating under

normal epidermis.

The structure of rodent ulcer is usually characteristic and uniform.
Section shows relatively bulky compact masses of darkly staining cells
connected by narrow strands of similar cells, all lying in dilated lymph-
channels or artificial spaces from which they readily shrink on hardening
(reticulated epithelioma) . Or the cells appear in narrower columns separated
by hyaline connective tissue after the manner of cylindroma. Or large cell
masses may exhibit numerous small clear areas resulting from mucous degen-
eration, and these spaces may reach the size of small cysts. In cases with
a certain adenoid character the cystic structure may approach that of adenoid
cystic epithelioma.

The whole tumor-mass usually appears well circumscribed and sepa-
rated from the overlying epithelium, and in all ordinary forms of the disease

EPIDERMOID CARCINOMA

811

a derivation from the overlying epithelium cannot be demonstrated. This
rule is, however, not invariable and is quite inapplicable to the earliest
stages. In advancing lesions long slender strands of tumor-cells may be
traced for some distance through the lymphatics and eventually connecting
with what may appear to be multiple foci of origin. This histological
feature explains the persistent recurrence of these tumors after apparently
thorough extirpation.

The tumor-cells resemble the basal-cells of the epidermis and are small,
polyhedral or spindle, with relatively large vesicular nuclei, minute nucleoli,
and scanty cytoplasm. Flat pavement characters, spines, hornification,
and pearl formation are regularly absent, but in rare cases may appear in
traces. Definite combinations of acanthoma and reticulated epithelioma
have been observed. In certain cases which clinically and anatomically
resemble rodent ulcer the structure presents convoluted or lenticular rows

i?f(e*PP^El^f^

FIG. 382. — A basal-cell carcinoma of skin, showing origin from rete pegs.

of columnar cells which suggest an approach to the type of adenoid epithe-
lioma. In a few cases all the cells are of spindle form and closely re-
semble spindle-cell sarcoma. Thus the cells of rodent ulcer tend to main-
tain their original and partly embryonal character throughout, but the
varying origin of these tumors gives opportunity for the exhibition of
many cell forms.

The histogenesis of reticulated epithelioma and rodent ulcer has been
the subject of much careful study. Krompecher, 1900, first adequately
emphasized the specific structure of the group of epidermal tumors wrhich
maintain the characters of basal-cells and introduced the term basal-cell
carcinoma. He traced the origin to the basal-cells of the Malpighian layer
and of the ducts of sweat, hair and sebaceous follicles. He described in
detail the clinical and histological characters of many tumors of this class
occurring in various situations. Many such tumors had previously been
regarded as endothelioma of skin, mucous membranes, and salivary glands

812

N EOF LA STIC DISEASES

(Coenen, Lit.). Hansemann argues against the use of the term "basal
cell," urging that all epidermal tumors arise from basal cells. Yet this
view is probably not entirely correct even for rodent ulcer, and Krompecher's
choice of terms may be justified on the ground that the tumors maintain the
characters of the basal-cells from which, also, they probably arise.

Borrmann, in an elaborate study of epidermal carcinoma, also derives
the reticulated epithelioma from basal epithelium. He concludes that the
origin is not from the normal epidermis, but from misplaced superfluous and
embryonal cell groups derived from the skin and appendages (corium carci-
noma). The apparently complete isolation from the epidermis of many
early tumors, their occurrence chiefly along embryonal fissures, on the face,

FIG. 383. — Epidermoid carcinoma of skin arising from hair follicles and reproducing small

hair shafts.

and in salivary glands, as well as their partly embryonal character are
considerations which favor this view. Some basal-cell tumors with compact
groups of small elongated cells, or occasionally with adenoid characters, arise
from the hair follicles. Mallory finds that these tumors differ from the others
in producing long fibrils recalling the formation of the hair shaft. Janeway
has clearly shown that epithelioma of basal-cell type may arise either from
isolated epithelial structures in the corium or from areas of basal cells
which are normally incorporated in the epidermis. The two origins impress
somewhat different characters on the resulting tumors. Preceding the neo-
plastic change in the basal cells he observed transient erythema and a
dilatation of subepithelial lymphatics, about which the epithelial cells first
showed hypertrophy and hyperchromatism and into which the first downward

EPIDERMOID CARCINOMA 813

growth occurs. Ribbert accepts the origin from multiple foci of normal
basal-cells and emphasizes the changes in the connective tissue which fre-
quently precede the downward growth of epithelium. Whether these changes
are constant it is difficult to determine. Bonney who analyzed the connec-
tive-tissue changes in detail found them of very constant occurrence. Wyss
in a series of early carcinomas of skin and other regions found extensive
infiltration of the connective tissue in 77 per cent, of 36 cases, and some form
of alteration in 91 per cent. In some cases the changes are so slight as to
escape demonstration by the usual methods of detection. They appear to
be more constant with acanthoma than with reticulated epithelioma.

(b) Adenoid Epithelioma of Skin. — Many epithelial tumors of the skin
show a tendency more or less pronounced to reproduce the dermal glands and
are therefore designated as adenoid. They differ from the rarer true adeno-
mas of the dermal glands in the predominance of squamous or basal epithe-
lial cell characters. Several varieties of these tumors are observed.

(i) Adenoid Cystic Epithelioma (Brooke). — 'This tumor was long grouped
with the adenomas of sebaceous glands and confused with many other con-
ditions, from which it was separated by the careful clinical and histological
studies of Brooke, Fordyce, Unna, Walters, and others. It differs from
adenoma sebaceum in its occurrence in much smaller numbers and in the
absence of the definite histological characters of sebaceous gland tumors and
prominence of squamous-cells.

It occurs in the form of a limited number of small, firm, nodular, painless,
circumscribed tumors in the skin of forehead, eyelids, nose, cheek or scalp,
notably about the age of puberty. They are also seen on back, chest
and limbs but not below the pelvis (Brooke). Fordyce observed them in
mother and daughter and Brooke in three members of a family. The early
lesions may resemble milium and they slowly reach but do not exceed the size
of a pea or bean, continuing to enlarge slightly for some years. While no
serious grade of malignancy has been reported there is no tendency toward
regression. The color differs little from that of the skin, with a tendency
to become darker, yellowish, shiny and occasionally translucent.

The structure varies but is dominated by the presence of embryonal
epithelial cells arranged in cords, masses, and alveoli, and of groups of
concentric hornifying epithelium inclosing homogeneous material. Brooke
found more of the adenomatous structure than is usual. Unna emphasizes
the squamous-cell elements in his designation, " acanthoma adenoides cysti-
cum," and he regards the tumor as a pure embryonal acanthoma with marked
tendency to cyst formation.

The adenoid structures appear as finger-like projections from the basal
epithelium or ducts of glands, and they commonly contain minute or large
cystic areas of hyaline, colloid, or mucoid material. The cells inclosing these
foci are often cylindrical. The squamous-cells in concentric form undergo
extensive hornification or calcification, and these structures may compose
the bulk of the tumor (Schapper). Or the structure of reticulated epithe-
lioma, resembling rodent ulcer with many thin-cell strands, may be prominent
(Czillag, Walters).

The origin of the tumor is referred by Brooke to the normal cells or to embry-
onal cell groups derived from the hair follicles (lanugo) and from the basal-
cells of the epidermis. While this view is supported by most recent observers,
Torok and Darier derived their tumors from the sweat-glands and W. Pick
from the sebaceous glands. The identity of these cases with Brooke's tumor
is doubtful, but it seems probable that in different cases the origin may in-
volve different elements with corresponding variations in structure. Thus

814

N EOF LA STIC DISEASES

Dorst and Delbanco observed multiple tumors of the scalp in the same
patient, some of which had the structure of adenoma sebaceum, others that
of adenoid cystic epithelioma.

In addition to the relatively small and multiple tumors of the above
type, the structure of adenoid and cystic epithelioma occurs in larger and even
bulky single tumors of the skin and subcutaneous tissue about the face and
neck. Such a tumor has been described by Buxton as arising at the orifice of
Steno's duct. It ran a slow course for 20 years, producing a growth as large as
a hen's egg, and finally involved the sub maxillary lymph-nodes. The struc-
ture presented many cystic cavities lined by convoluted layers of basal cells,
among which in turn were many small spaces filled with mucoid material.

(2) Simple Adenoid Epithelioma. — At the usual seats of rodent ulcer larger
and usually more active tumors often arise in which there are large alveoli
lined and filled with cylindrical or cuboidal epithelial cells of a type inter-
mediate between squamous epithelium and the duct cells of dermal glands.
These tumors are not cystic, they are usually sharply circumscribed and

FIG. 384. — Low magnification of epithelioma adenoides cysticum.

relatively large, and their course is progressive, with occasional involvement
of lymph-nodes or ulceration.

The structure often suggests a large alveolar carcinoma, but certain areas
may usually be found containing flat squamous epithelium without spines
or hornification, and in many cases the derivation from the rete pegs and
especially from the basal cells is revealed with striking clearness. In one
group of cases clinically resembling rodent ulcer, I found alveoli composed
of low cylindrical epithelium which was probably derived from hair follicles.
In another, large alveoli are lined by low columnar cells and filled with
cuboidal granular epithelium and occasional squamous cells. In a third
type, all the rete pegs over a large area, i-i ^ cm., are hypertrophied and con-
tinuous with broad cellular columns of cuboidal cells which compose a rather
bulky tumor of the derma.

Tumors of Sweat-glands. — -The sweat-glands have been assigned as the
source of a variety of tumors which have figured extensively in dermatological
literature under many different terms (Petersen, Lit.). The tumors vary in

EPIDERMOID CA RCIXOMA

815

FIG. 38 v — Topography of sweat-gland tumor of skin. (Photo by B. H. Buxton.}

FIG. 386. — Adenocarcinoma of sweat-glands.

816

NEOPLASTIC DISEASES

structure and form according to their exact point of origin and the conditions
under which they arise. From the alveoli arise the somewhat specific
spiradenomas, with many well-formed alveoli surrounded by membrana
propria and filled with small cuboidal cells. They appear as pearly white
tumors beneath the epidermis, and they may be small and multiple. Carci-
nomas of this type are occasionally encountered. Dilated alveoli of spirade-
noma probably constituted the tumor described by Jarisch as lymphangioma
tuberosum multiplex. The ducts of the glands may be dilated forming
cysts, and into these papillary outgrowths occur, which have been described
as papillary adenomas (Elliott). Neither rodent ulcer nor epithelioma
adenoides cysticum have been positively traced to the ducts of sweat-glands,
but it appears probable that the ducts give origin to a certain proportion
of the adenoid epitheliomas of the skin. The adenomas are regularly benign,

while the adenocarcinomas and car-
II cinomas are relatively slow in invad-

ing lymph-nodes.

EPITHELIOMA OF THE LIP

Epithelioma of the lip is chiefly
a disease of elderly men, 50 to 70
years, but occurs in women and in
young adults. Among 73 cases
collected by Warren four were in
women, three of whom were smokers.

^_PIIPI_ Of 1338 cases Fricke found 91 per

•N*^ jOB^jiigrf^ v cent, in men, four of which were mul-

kfi- .<_*£• tiple. A definite group of cases fol-

lows seborrheic keratosis (Mont-
gomery, Sutton). Many cases are
clearly traceable to the irritation
of pipe or cigar. Hence it appears
usually on the side of the lower lip,
rarely on the upper. Dugue be-
lieves that tobacco causes a leuko-
plakia of the lip as on the tongue,
which is followed by epithelioma.
Many forms of trauma have pre-
ceded the disease, as simple scratches,
bee stings, erosion by teeth. One
patient, syphilitic in youth, a smoker until 45 years, developed a minute
chronic fissure of the lip at 50, which remained indolent and indurated for
three years, when ulceration supervened and gradually extended over 1^2
cm. for one year longer before it was recognized as epithelioma. Contact
infection has been held responsible for the appearance of epithelioma on the
upper, opposite a [lesion on the lower lip, but lymphatic connections offer
an alternative explanation, since both blood- and lymph-vessels encircle the
lips.

Two main forms of the lesion occur, (i) papillary and (2) ulcer ative
infiltrating types. The papillary form appears as a wart-like thickening
which long remains elevated, at times with much elongated papillae. It
extends slowly in all diameters, as a flat thickening in the epidermis, is slow to
invade the deeper tissues or lymph-nodes, and the underlying tissues remain
soft. Later it may ulcerate and follow the usual course of infiltrating epithe-

FIG. 387. — Epidermoid carcinoma of lip.

EPIDERMOID CARCINOMA 817

lioma. This type of epithelioma is of long duration and of somewhat charac-
teristic gross appearance, and since it yields to conservative operation it
should be carefully distinguished from the more malignant variety.

The early infiltrating process may appear as a flat thickening of the
epithelium, or as a nodular growth invading from the first the submucosa,
and. lying beneath rather than in the epithelial layer. Early ulceration pro-
duces a broad deep ulcer with pearly indurated edges, or a more bulky
excavated tumor which may become fungating. With these lesions there is
often much inflammatory reaction, extension along the floor of the mouth,
involvement of periosteum, and early invasion of submental, lingual, and
maxillary nodes.

The structure is usually that of typical acanthoma with many variations
in details. A preliminary softening and cellular infiltration of the submucosa
usually precedes the overgrowth of epithelium. Ribbert insists that down-

FIG. 388. — Early carcinoma of lip.

ward growth of epithelium never occurs into normal connective tissue but
only after infiltration by round-cells. In the papillary form the outgrowth
produces long papillae with or without hyperkeratosis. Some downward
growth of altered papillae is nearly constant but may long be held in check by
round-cell exudate and fibrosis of deeper tissues. In the ulcerating tumors
the invasion of tissues is preceded by edema and perivascular infiltration
by leukocytes. After the tumor has become established there is no evidence
of lateral extension over normal epithelium, but the papillae over a wider
area may be much hypertrophied.

The tumor-cells may retain the type of adult squamous epithelium (acan-
thoma) or they may lose these characters and appear in anastomosing
columns of opaque granular polyhedral cells. "Infiltration of perivascular
sheaths, nerve-trunks and areolar tissue is attended by much growth of firm
connective tissue. This infiltration tends to follow preexisting lymph paths
but is by no means limited thereto.

818

N EOF LA STIC DISEASES

4H6rV v AJ *•'- -V >• ?%?*

i> !;»?» ; ;iW •»— •- '-• • "

"^ , "V •\,'*r» * * " *„ ," " *"**[Tt~ • — *•

\:S?i ^ i^^» *"^£tr>s'^^"-
^^'^^•^W, ^sb

FIG. 389. — Infiltrating epidermoid carcinoma of lip.

. :;\: 'j\... >. f ».-' • x.:,--5^Tv« ^" v -^ "f >- ^' v

•vliS SSi

,1 ">«

FIG. 390. — Invasion of labial artery by recurrent epidermoid carcinoma of lip. Note the

evidences of growth restraint.

EPIDERMOID CARCIXOMA 819

While the lymph-nodes may be involved early they seldom reach a large
size, and visceral metastases are occasionally observed. Yet I have seen the
right submental nodes as large as an orange, while the left were uninvaded
from a left-sided tubular epithelioma of lip. Secondary infection usually by
streptococcus pyogenes plays a prominent part in the progress of the disease,
and leads to extensive local suppuration, erysipelas, septicemia, thrombosis
of vessels, edema of glottis, and pneumonia.

The operative treatment of carcinoma of the lip is comparatively favor-
able. Fricke placed the cures at 60 per cent, and Steiner (1908) reported 35
definite cures after a 5-year limit out of 43 cases (70 per cent.). The decisive
influence of the character and extent of the disease appears in the fact that
three-fourths of the fatal results occurred within a year after operation.
Surgical experience emphasizes the necessity of removing the lymph-nodes
of both sides, even with comparatively early lesions. Of 32 cases in which
only the tumor but not the lymph-nodes were removed Bloodgood found
only two cured. After invasion of the maxillary bone he could find no record
of recovery. The more favorable statistics probably include many compara-
tively benign lesions. Fully developed carcinoma of the lip is a very fatal
disease, and only when the lesion is early and limited can a favorable result
be assured by operation. Such lesions also respond well to radium.

EPIDERMOID CARCINOMA OF TONGUE AND MOUTH

Several general peculiarities distinguish this form of cancer. In fre-
quency it is placed by Jessett second only to uterine cancer, by Jacobsen third,
and by Wini waiter fourth. While among the most accessible of cancers and
readily recognizable in its early stages, it is yet one of the most fatal of
malignant diseases, with a mortality of 75 to 90 per cent. (W7arren, Butlin,
Meller). Although its microscopical anatomy is rather uniform the gross
features and clinical course vary extensively, so that a very detailed acquain-
tance with the disease is demanded of one who hopes to deal with it suc-
cessfully. The failure to recognize the significance of early or precancerous
conditions, temporizing with small but fully developed lesions, and extrava-
gant sacrifice of tissue in mild cases, are common errors committed in the
case of these patients, and are largely responsible for the ultimate mortality
and for that dread of the disease which leads many to conceal its existence
as long as possible.

Etiology, — The disease occurs chiefly in the 4th to 6th decades. Sigel
observed a case in a boy of six years. Piquantin estimated that 17 per cent,
of the cases occur in women.

The important factors in the causation of buccal cancer are syphilis,
tobacco, and defects of the teeth. In a large group of cases all three factors
are combined, while one or more are nearly constantly present.

The frequency of syphilis is variously estimated, Meller finding signs
of lues in only 7 of 207 cases of buccal cancer, while Fournier found the
disease in 155 of 184 cases. The action of syphilis is indirect and the epithe-
lioma is always preceded by a definite and usually prolonged luetic lesion.
The pearly white thickening of the epithelium in leukoplakia is a character-
istic picture which must always be regarded with suspicion as furnishing the
beginning of cancer. According to Fournier leukoplakia is followed by cancer
in 30 per cent, of the cases, but many authors hold all such lesions under
suspicion, and there is no doubt that the disease has a definite tendency to
become malignant and should be treated in every case as a specific pre-
cancerous condition. Of 159 cases of cancer of tongue v. Bergmann found

820 NEOPLASTIC DISEASES

leukoplakia in 34.6 per cent. Other syphilitic lesions which lead to cancer are
localized wart-like epithelial hypertrophies, fissures, gummas with or without
ulceration, and chronic glossitis with atrophy of papillae (Jacobson). The
epithelial overgrowth, submucous edema, lymphocytic infiltration, and
eventual scarring with loss of elastic tissue are microscopical features explain-
ing the remarkable relation between lues and cancer of this organ. It is a
notable fact that the syphilitic process may subside or even completely heal
under treatment while a coexistent cancer may continue or develop later in
the scar, or appear in the lymph-nodes under a smooth epidermis (Landau,
Sachs, Warren, Lang, Lydston).

Tobacco has a predominant influence in the development of cancer
of the buccal mucosa. Its action is not fully understood, but the irritant
effects stimulate the epithelium, produce chronic hyperemia, local erosions,
lymphocytic infiltration, edema, and ulceration. The effects of heat must
also be considered, while mechanical irritation appears in the cancers of
the tip of tongue in pipe smokers. Tobacco chewers often develop cancer at
the point where the quid is held. Many of the tobacco cancers arise at

FIG. 391. — Leukoplakia of tongue.

the base of the tongue, on palate, tonsil or pharynx, while the relation
to laryngeal cancer is well known.

An imperfect condition of the teeth is directly responsible for many
buccal cancers. The most obvious cases are those in which a projecting or
ragged tooth continually abrades the edge of the organ, along the sides, or
at the frenum. It is often difficult to detect the exact source of the effective
dental irritation and it is often overlooked. An imperfect alignment of the
teeth, a sharp although smooth edge, or chronic caries especially of the roots,
pyorrhea, chronic alveolar abscesses, or the traumatismof extraction, maybe
sufficient to incite a cancerous growth, especially in luetic smokers.

Many other forms of irritation resulting in chronic inflammatory changes
have been observed to precede buccal cancer, and they were early designated
by Hutchinson as precancerous states. They are thus enumerated by
Jacobson: (i) Chronic glossitis with hypertrophy and fissuring, (2) leuko-
plakia, especially when warts appear, (3) ichthyosis, or late stage of leuko-

EPIDERMOID CARCINOMA 821

plakia, (4) chronic atrophic glossitis, "Bald tongue," (5) papillomas of
various types, (6) fissures, (7) ulcers of any type.

Structural abnormalities or other forms of tissue predisposition are not
commonly considered in the genesis of buccal cancer, and probably have
little relation to the superficial acanthomatous forms, but for many tumors
located in the floor of mouth, tonsil, or pharynx, which exhibit the structure
of adenoid or embryonal epithelioma, such factors cannot be ignored and
indeed demand more attention than they have received. This entire region
is beset with mucous glands and their ducts, and with tortuous ducts of large
salivary glands, while the remnants of branchial clefts and other embryonal
fissures must also be considered as contributing to certain forms of epithe-
lioma, especially the deeper lying tumors. The thyroglossal duct is a source
of cysts at the base of the tongue, and it seems probable that remnants of the
endodermal portions of the upper branchial clefts may also be included in the
sources of buccal cancer. A characteristic lingual cancer develops in the
middle line of the organ, often appearing first as a slowly growing papilloma.

Gross Anatomy. — The usual form of buccal epithelioma is an indurated
ulcer, which extends with considerable activity and much pain and discharge,
over a widening area. The indurated base and edges are characteristic.
This lesion arises from fissures, abrasions, and erosions, and is ulcerated and
superficial from the first.

Beginning as a deeper submucous nodule another type of the lesion
remains for a time as a solid tumor of moderate dimensions but eventually
breaks down, producing a deep ragged excavation.

After leukoplakia epithelioma appears as a broad, flat, pearly white
induration which may long escape necrosis, but infiltrates the tissues over
a wide area and finally ulcerates. Multiple points of origin may exist in
this type, and after excision the disease may recur in new areas.

A diffuse infiltration of one or both sides of the tongue occurs in rare cases
and leads to extensive increase in the size of the entire organ, interfering
with deglutition and preventing extrusion. Simple papilloma of the tongue
may become malignant, the enlarged papillae invading the submucosa.
Steiner observed malignant changes in a lingual wart of six years' duration.
The change is indicated by an increase in the dimensions of the lesion, but
ulceration may long be delayed. Sachs describes an extensive papillary
epithelioma of the tongue, with very slight structural indications of malig-
nancy but with invasion of lymph-nodes.

Diffuse papillomatosis of any part of the lingual or buccal mucosa
presents a most noteworthy lesion, from one or many points of which carci-
noma, usually of moderate malignancy, may develop.

I have seen cases of very extensive lingual cancer without invasion
of lymph-nodes, in which the lesion consisted of plexiform infolding of the
entire epithelial layer without invasion by loose cell groups.

The location of the lesion may be in any part of the lingual or buccal
mucosa. The edges of the tongue, the under surface near frenum, the
tip or base, are most frequently affected. The dorsum is relatively immune.
Equally frequent is a primary location in the floor of the mouth. Tonsillar
lesions constitute about 10 per cent, of the cases, while a still smaller propor-
tion occur in pharyngeal wall, gums, and palate (Meller, Warren).

Local extensions of buccal cancer are usually early and wide. In the
tongue the arrangement of blood-vessels and lymphatics may somewhat
restrict the growth to one lateral half or to the base, but advanced lesions
invade both sides, extend from the base in all directions, and from the tip
and edges to the floor of the mouth. Lesions of the cheek remain relatively

822

NEOPLASTIC DISEASES

localized; those of the tonsil invade pharyngeal wall, larynx, nares and
soft and hard palate; those of the buccal floor extend actively to tongue
gums, hps, and deeper tissues.

Lymph-node involvement occurs early in the course of buccal cancer
and may be the first symptom to attract notice, but there is great variation
in the period of its occurrence, depending on the very variable structure
Meller describes extensive carcinoma of tongue, tonsil and buccal floor
without invasion of nodes, while Sachs' superficial papilloma of indistinct
cancerous structure had already invaded the nodes. Most observers urge
that it is impossible to establish anyfrule regarding the occurrence of metas-
tases. Yet I venture to think that
this impression is due largely to lack
of acquaintance with the anatomical
varieties of the disease. Papillary, plexi-
form, superficially diffuse, and leuko-
plakic lesions are of relatively slow

course.

Metastases are unquestionably
favored by a malignant atypical struc-
ture, by an origin from deep rather than
superficial structures, by deep ulcera-
tion, by long duration of the disease,
and by the presence of inflammatory
complications. Reclus mentions the
later occurrence of metastases in cases
following leukoplakia. Tumors of ton-
sil, cheek, and especially of antrum, are
often slow in involving lymph-nodes.

The affected nodes are usually those
directly draining the diseased focus, but
in many cases the extension seems to
violate anatomical rules. Thus both
sides of the neck may early be involved,
and in a notable group of cases there is
extensive involvement of one or both
sides from a primary lesion which it is
difficult to locate even at autopsy.

The mode of extension of buccal
and lingual cancer to the lymph-nodes,
I have been led to conclude, is chiefly
by embolism. This conclusion is based on the very early invasion of nodes
in some cases, the appearance of infected nodes at anomalous points while
intervening nodes escape, and the failure to find permeated lymphatics in
sections of tissue leading from the original lesion. The great vascularity of
the tissues and the active muscular movements of the parts seem to be a
sufficient explanation of the events observed.

Metastases in the organs are rare but have been observed in liver, heart,
adrenal and mesentery. Extensions to lungs and pleura are even rarer.
The total number of cases with internal metastases is small (i per cent. Crile)
and bulky internal growths are rare. In 148 autopsies at the Middlesex
hospital there were metastases in the liver (8), lungs (7), pleura (4), adrenal
(3), heart (2).

The distribution of metastases is determined by the course of the cervical
lymphatics, which has formed the subject of careful study by many observers

FIG. 392. — Vertical view of lym-
phatics of tongue in relation to tonsil.
(After Kuttner.}

EPIDERMOID CARCINOMA

823

(Poirier, Kuttner, Crile). The main groups are defined by Warren. The
submaxillary group drains the border of the tongue as far back as the fauces,
the middle section of the anterior half of tongue, and under surface of tip and
floor of mouth. The superior deep cervical group, lying on internal jugular
vein and carotid, drains all parts of mouth, tongue, fauces, and upper part of
pharynx. Nodes at the lower end of the parotid drain the anterior surface
of palate. The inferior deep cervical nodes, lying on the jugular vein and
extending down behind the clavicle, receive branches directly from apex and
base of tongue, and anterior portion of floor of mouth. The submental
nodes drain the lips, and anterior portions of the buccal floor. The submaxil-
lary gland, often extirpated, is rarely invaded.

FIG. 393. — Diagram of lymphatics of tongue. (After Kuttner.) Note chain leading
directly from tip of tongue to supraclavicular node.

Structure. — The great majority of buccal epitheliomas are of the simple
acanthomatous type. Their early stages illustrate many phases of the
development of epidermoid carcinoma from chronically inflamed, hyper-
trophied papillae. Lymphocytic infiltration and edema of submucosa and
hyperkeratosis nearly always precede the downward growth of epithelium.
The adult characters of the epithelial cells may long be preserved, or they may
assume the type of indifferent polyhedral cells as in tubular epithelioma. An
original papillary structure may persist, even after metastases have occurred.
Rarely the structure is that of basal-cell epithelioma. Berkeley saw both
types in the same tumor. An alveolar arrangement of polygonal cells devoid
of squamous characters suggests an origin of some tumors from ducts of
mucous glands (Steiner, Hulsmeyer, Kaufmann).

824

N EOF LA STIC DISEASES

Embryonal forms of epithelioma arise in the base of tongue, tonsil, and
pharynx, but their exact source is undetermined. The cells lack squamous
characters and they grow in columns or indistinct alveoli.

In all types of structure the cells infiltrate surrounding tissues, following
chiefly the lymph-vessels and nerve-trunks. Goldmann observed the inva-
sion of a vein, but the blood-vessels are usually occluded by the extensive
new connective tissue which follows the process. Secondary infection by
the streptococcus complicates or dominates the later stages and gives rise to
suppuration and necrosis.

The clinical course of buccal cancer is usually progressive and terminates
fatally in an average period of two years. More rapid courses are commonly
observed in lingual cases (6 to 12 months) and in tonsillar (6 to 10 months),

FIG. 394. — Spindle-cell epidermoid carcinoma of tonsil.

and pharyngeal tumors (4 to 10 months) (Meller). In a large series in all
locations Meller found that operation prolonged life on the average 13.4
months and cured 14.6 per cent., while the operative mortality was 13 per
cent. While the duration and extent of the disease chiefly determined the
result, the cured list includes several with large ulcers, extensions to lymph-
nodes, and some with local recurrences.

The chief causes of death are pneumonia, septicaemia, edema of glottis,
and hemorrhage.

It seems probable that the prognosis of buccal cancer will be influenced
in the future by the introduction of radium. This agent, either alone or in
combination with surgery, has produced encouraging results, especially in

EPIDERMOID CARCINOMA

825

localized cases or lingual, tonsillar, and pharyngeal cancers in inaccessible
positions.

TUMORS OF THE LARYNX

Papilloma of Larynx. — Of benign tumors of the larynx epithelial papilloma
constitutes 39 per cent. (Juracz) but the proportion varies with different
histological criteria from 59 to 8 per cent. (Janeway, Schech). The chief
location is the anterior and middle portion of the under surface of the true
vocal cords, but the epiglottis and various mucous folds may be involved.
All ages are found to develop papillomas, especially in the fourth decade
and in males far more than in females. An hereditary influence is rare, but

FIG. 395. — Atypical epidermoid carcinoma of tonsil.

more papillomas appear in infants and children, indicating a congenital
predisposition (Casnit, Gerhardt). Overuse of the voice, irritant inhalations,
the sequelae of exanthems, alcohol, and tobacco, have been recognized as
etiological factors, and all probably act by producing some form of chronic
laryngitis. Yet some cases develop without a demonstrable trace of previous
inflammation. L. Browne attributes many laryngeal polyps to the influence
of nasal and pharyngeal adenoids.

The tumors appear as (i) a single smooth red to gray, firm, pea-sized
nodule, or as (2) a group of elongated papillae resembling a cock's-comb, or
(3) a more bulky cauliflower tumor. The base may include a small circum-
scribed area, or much of the mucosa may be the seat of papillary outgrowth
and lead to suffocation, or stenosis after extirpation. Laryngologists generally

826

NEOPLASTIC DISEASES

agree that while most benign papillomas may be recognized through the
laryngoscope, yet in some cases a full microscopical study is necessary.

The early stages have been traced by Werner to a condition first of
hyperemia and round-cell infiltration of submucosa, which is followed by
nodular overgrowth of epithelium. The area affected by these changes may
be considerable and a basis is thus furnished for the appearance of multiple
tumors at once or at intervals. In the condition called "singer's nodes"
the epithelial hypertrophies become chronic, more or less keratinized,
associated with dilatations of blood-vessels, and sometimes give origin to
papilloma.

FIG. 396. — Bulky papillary epidermoid carcinoma filling larynx.

nodes.

Xo invasion of lymph-

The structure shows an active overgrowth of normal or slightly altered
epithelium, in many projecting folds and with some downward elongation
of papillae, but with an intact basement membrane. The stroma consists of
branching strands of vascular connective tissue which may be very scanty or
so abundant as to resemble papillary fibroma.

The epithelium is of squamous type with much or little hornification.
Small concentric cell groups and mitotic figures may be found in benign
growths, but when these features are prominent they should be regarded with
suspicion, especially when combined with irregularity in the form and arrange-

EPIDERMOID CARCINOMA 827

ment of the cells. Papillomas removed shortly after cauterization or imper-
fect curettage may show great disorder of the epithelium.

In the diagnosis of malignancy in early papillary tumors of the larynx
chief attention should be given to atypical cells in the epithelial layer. I
have seen a fatal course in so many apparently simple laryngeal papillomas
in which the sole sign of malignancy consisted in atypical hypertrophic
hyperchromatic cells in a uniformly thickened layer, that 1 am compelled to
regard this appearance as of grave significance. Reliance on this criterion
leads to the conclusion that most epithelial papillomas of the larynx tend to
become malignant, especially in adults, and this conclusion is strengthened
by the frequent occurrence of long existing bulky papillary growths which
have eventually invaded the lymph-nodes.

While most papillomas are completely eradicable, not a few recur locally,
either immediately or after an interval which may be as long as 9 (Curtis)
or even 22 years (Lincoln). Partial extirpation of a broad base is responsible
for some recurrences which appear immediately with apparent acceleration of
growth. Or a new tumor may slowly develop in a predisposed mucosa.
There are no sufficient grounds for assuming a local infectiousness of these
tumors.

Rapid and .extensive recurrence in histologically benign form is observed
especially in children, and illustrates the remarkable regenerative powers of
the laryngeal epithelium. Laryngotomy and excision or cauterization has
been performed, three, four, and even seven times in a relatively short
period before the disease could be arrested (Wilkinson, Lendon, Clubbe).
In this group of cases radium treatment has given excellent results.

The question of the transformation of a benign papillomatous into a
malignant process has been extensively discussed. Semon could find only
45 definite reports of this event, 12 spontaneous, 33 after operation, and of
these he discards all but 12. It is difficult for the laryngologist to secure
satisfactory material for histological study, which must include a considerable
portion and especially the deeper parts of the growth. Tissue from the edges
of a carcinoma may show the structure of simple papilloma. Even with
these sources of error histological data have often proved more reliable than
laryngoscopic appearance. When the microscopical study can be made of
satisfactory material its evidence must be regarded as final and on such evi-
dence it seems probable that laryngeal disease not infrequently appears first
as simple papilloma, later as carcinoma. I have examined the whole of an
excised papilloma in a case which developed carcinoma three years later,
possibly at another point.

In cases in which such a transformation appears to occur there are several
possible explanations: (i) The original disease is a simple papilloma which
really changes its clinical character and develops infiltrative growth. (2)
The original disease is carcinoma but the examination of tissue is incompetent
or inadequate. (3) An original papilloma is removed but the disease recurs
elsewrhere as carcinoma. Such events are observed in other mucous mem-
branes. (4) An original papilloma is imperfectly removed and the remnant
is stimulated to atypical growth.

Miscellaneous Benign Tumors of the Larynx. — Fibroma is a frequent, with some authors
the most frequent, tumor of the larynx. It appears on the true or false cords, near the
anterior commissure, or on the epiglottis, rarely elsewhere. Fibromas are usually single,
small and pedunculated, but may be multiple, and present a broad base and reach a large
size. Solis-Cohen observed six in one case. The structure varies with the consistence.
Hard tumors are composed of adult connective tissue, while the soft growths are edematous
or mucoid or contain an excess of vessels. The surface lining of squamous epithelium may
be quite smooth or convoluted. Very small fibromas constitute a portion of the so-called

828

NEOPLASTIC DISEASES

singers' nodes (A. Chiari). In some cases the structure shows hornification of epithelium,
dilated lymph-spaces, dilated gland ducts, and collections of lymphocytes, all of which
indicate an inflammatory origin. When the mucoid element is prominent the tumors have
been called myxomas (Fauvel, Bruns).

Chondroma. — Bruns collected 14 reports of chondroma of the larynx. The largest
reached the size of a walnut. The chief location was in the cricoid cartilage, and the
structure showed hyaline cartilage often with calcification.

Lipoma has been reported in and about the larynx in nine cases (Jurasz). They were
usually small and single, but Seyfert's tumor was lobulated and of considerable bulk.

Bruns described a rather large adenoma arising from the vocal cord and consisting of
alveoli lined by cylindrical cells. A few other cases are mentioned by Jurasz.

Angioma has been observed by many authors. Phillips and Ruh collected 26 cases from
the literature and report one case in a child following measles, in which there was extensive
dilatation of vessels below the cords and evidences of chronic laryngitis. The structure
indicates a close relation to fibroma, both in histogenesis and in etiology. Many of these
tumors consist of simple varices, capillary or cavernous, and are not neoplastic. Others

FIG. 397. — Pachydermia laryngis. A form of beginning carcinoma of the larynx.

reach considerable size, and show a definite overgrowth of new vessels. In Loomis' case
there were also angiomas of tongue, pharynx, and neck.

A large cavernous lymphangioma is described by Koschier.

A primary lymphoma of the sinus pyriformis is recorded by J. Mackenzie, and lympho-
sarcoma of pharynx and larynx by Stoerk. Generalized lymphosarcoma may occlude the
larynx. Aberrant thyroid tissue in the wall of the larynx may be the source of submucous
tumors (Ziemssen, Heise).
^

Carcinoma of Larynx. — -Carcinoma and sarcoma of the larynx form i
to 5 per cent, of all malignant tumors and about 16 per cent, of all laryngeal
tumors (Jurasz).

The chief age of incidence is the fifth decade, but many cases occur between
60 and go years, and several cases have been observed in children of 3 to 6
years (Rehn, Steiner). The evidence suggesting an hereditary influence
in cancer of the larynx is probably not more definite than with other forms

EPIDERMOID CARCINOMA

829

FIG. 398. — Bulky hornifying papillary carcinoma of larynx, with invasion of cervical

lymph-nodes.

FlG. 399. — A flat papillary subglottic carcinoma which g

cervical lymph nodes.

>rigin to bulky metastases in

830

N EOF LA STIC DISEASES

of cancer in the adult (Semon, Lit.). Syphilis and tuberculosis seem to
have no definite relation to the disease, although a few cases have arisen
in tuberculous or syphilitic lesions (Schmidt, Wolfenden, Crone). Baum-
garten has observed tubercle diffused throughout a laryngeal carcinoma.
Males are much more often affected than females (400 to '68, Sendziak). The
special factors concerned in the etiology of carcinoma are very similar to
those of papilloma. Chronic laryngitis and the misuse of alcohol and tobacco
probably determine the great predominance of the disease in men.

Molinie emphasizes the combined influence of syphilis, alcoholism, and
tobacco.

Pachydermia laryngis or leukoplakia is a condition of epithelial hyper-
trophy and hyperkeratosis affecting the posterior portions of the vocal

FIG. 400. — -Epidermoid carcinoma involving tonsil and pyriform sinus of larynx.

cords. The mucosa appears smooth or warty and scaly. The papillae
are elongated and the submucosa is infiltrated with round-cells, while the
glands are hyperplastic (Virchow, Fraenkel). It is not known to precede
cancer in the larynx but its relation to cancer in other tissues renders it
suspicious in all situations. With C. Jackson 1 have seen one characteristic
case in which the downward growth of papillae and atypical qualities of the
cells were very prominent.

Anatomy. — -The earliest stages of carcinoma present to the laryngoscope
(a) a broad but circumscribed thickening of the mucosa, or (b) a projecting
whitish nodule, (c) a broad warty excrescence. Only four cases of carcinoma
with a definite pedicle have been reported (Schmidt). These lesions are

EPIDERMOID CARCINOMA

831

commonly associated with signs of laryngitis which precedes or accompanies
the growth. A characteristic light opaque color may or may not be
prominent. The early carcinomas may not differ in any gross feature from
benign papilloma, but usually they are broader, more dense and opaque, and
more firmly incorporated in the submucosa.

The anterior portion and commissure of vocal cords and vicinity are the
chief seat of carcinoma, but it may develop in any part of the organ and its
various folds and sinuses. Immobility of the vocal cord occurs with tumors
of the posterior segment. In frequency the various locations stand in the
following order, true vocal cords, false cords, posterior surface of cricoid,
epiglottis, and the lateral plicae and sinuses. These locations suggest the
division of laryngeal carcinoma into intrinsic and extrinsic forms (Krishaber).
The former are much the more numerous, except in females (Molinie).

FIG. 401. — Malignant papillary carcinoma of larynx.

The established disease takes the form of a circumscribed papillary growth,
or a more diffuse infiltration. The cordal tumors long remain localized to
one side, but diffuse growths spread backward and to the opposite side (cir-
cular carcinoma), and many extrinsic tumors early involve both sides.
Ulceration supervenes in the second year in nearly all cases, greatly altering
the gross appearance and giving rise to many complications.

Arising in the submucous tissues of the ventricle of Morgagni the tumor
reaches a moderate size, displacing the false cord and causing a 'protrusion
of the overlying mucosa. Later it perforates the mucosa and reveals itself
unexpectedly as an extensive ulcerating carcinoma (Sendziak).

Larval Carcinoma.—^. Schmidt described a form of deep-seated carcin-
oma of the larynx associated with superficial benign papillomas. It may

832

N EOF LA STIC DISEASES

cause considerable destruction of the cartilages before it appears on the sur-
face and discloses its malignant nature.

The advanced disease varies considerably in its form and mode of exten-
sion. Many reach a large bulk while retaining a papillary form. Others
infiltrate early and cause only minor laryngeal symptoms. Intrinsic cancer
long remains confined to the larynx and is slow to infiltrate the lymph-nodes,
but the outlying or extrinsic tumors extend to esophagus, tongue, pharynx
and trachea, and to the neighboring lymph-nodes. Quite bulky tumors may
develop in the late stages, and the extensions may be remarkably wide.
Thiersch observed invasion of the cervical vertebrae, Moure saw extension
to the submaxillary tissues, and Gougenheim and Gaston reported a large
secondary thyroid tumor.

J;Contact implantation from one vocal cord to the other has several times
been observed (Butlin, Newmann, Semon, Jurasz). With the invasion of

FIG. 402. — Epidermoid carcinoma of larynx. Extensive hornification and calcification in

cervical lymph-node.

the soft tissues above the glottis there is soon involvement of the submaxillary
and cervical nodes which may reach large dimensions even with small laryngeal
growths. In some cases the cervical tumors long precede definite laryngeal
symptoms. Intralaryngeal tumors may first affect the prelaryngeal nodes.

The structure is usually that of adult acanthoma with abundant kerato-
sis and pearl formation. These tumors are locally destructive but of slow
growth. Many laryngeal cancers exhibit transitional epithelial characters
with cylindrical or cuboidal cells, free from keratosis. They arise from the
folds and sinuses of the larynx and are the source of extensive tumors in the
lymph-nodes (Kosinski, Maydl). Glandular carcinoma arising from the
alveoli and ducts of mucous glands is rare (Schmidt, Schmiegelow, B. Fraen-
kel, Krieg). Its chief location is in the ventricle of Morgagni.

In some tumors, probably arising from the stratified cells lining the crypts,
the cells rapidly become changed to an indifferent rounded or polyhedral

EPIDERMOID CARCINOMA

833

form and grow in very small groups or diffusely. Such a structure may
readily be mistaken for sarcoma.

Lymphatic Extension. — Based on Cuneo's studies of the laryngeal lym-
phatics, Molinie shows that: (i) Supraglottic cancer early invades the supe-
rior nodes of the external jugular chain; (2) cancer limited to the vocal
cords rarely invades any nodes; (3) subglottic cancer invades the deep
nodes about larynx and trachea, subcricoid, and peritracheal, as well as in-
accessible posterior groups along the recurrent nerves and behind the
esophagus.

The course of laryngeal carcinoma is much influenced by the type and
location of the tumor. Acanthoma of the vocal cords is of relatively slow

FIG. 403. — Epidermoid carcinoma of larynx invading the lymphatics of the thyroid.

development, long remains confined to the larynx, but in the ulcerative
stage extends widely and involves neighboring tissues and nodes. Periodic
remissions are often observed and two or three years may elapse before a
small carcinoma begins to grow rapidly. Extensive perichondritis may be-
come established, in which the carcinomatous process combined with second-
ary infection perforates and sequestrates the cartilage. Diffuse carcinoma
of the cords may cause asphyxia. The usual termination is by cachexia,
from dysphagia, suppuration, and hemorrhage with terminal pneumonia.
The extrinsic carcinomas usually progress more rapidly, early invade lymph-
nodes, and are very subject to ulceration and extensive suppuration. Many
of these are composed of cylindrical or cuboidal cells without hornification.
Glandular carcinoma is usually less malignant. In advanced stages second-

834 NEOPLASTIC DISEASES

ary deposits may occasionally appear in distant organs, as the lungs, liver,
kidney, humerus, dura mater (Snappers, Desnos, Sands, Virchow).

Secondary carcinoma of the stomach, probably from extension through the
lymph-vessels, is recorded by Gougenheim.

Sarcoma of Larynx. — -Sarcomas form 1 1 per cent, of malignant laryngeal
growths (Molinie). The series of 117 cases analyzed by Bergeat, 50 by
Sendziak, and 23 by Butlin, show that sarcoma arises in much the same
situations and in its early stages closely resembles the epithelial tumor.
Thus they are extrinsic or intrinsic in location and polypoid or diffuse in
form. Some develop a long pedicle (McWhinnie).

Many histological varieties are described, most frequently spindle-cell,
mucoid, round-cell and giant-cell types. Lymphosarcoma is described by
Koschier and Stoerk. Spindle-cell sarcoma is practically limited to the
vocal cords and epiglottis, while the so-called alveolar types (carcinoma ?)
appear in the folds and sinuses (Sendziak). The surface of the early sarcoma
is usually smooth. In late stages ulceration occurs but less frequently than
with carcinoma, the lymph-nodes may be invaded (15 per cent.), and the
conditions resemble the advanced carcinomas. It is probable that many
cases recorded as sarcoma are of epithelial origin.

CHAPTER XLIII

EPIDERMOID CARCINOMA (Continued)
CARCINOMA OF ESOPHAGUS

Carcinoma of the esophagus is characterized by the variety and often
by the obscurity of its symptoms, the peculiarities of its structure, and by
its high mortality.

Etiology. — Males are affected in 75 per cent, of the cases (Kraus), and
while the disease occurs chiefly about the fiftieth year, Kaufmann saw a
small lesion in a woman of 90 and Heiman reports a case in a girl of 19 years.

Alcohol, irritating hot foods, tobacco, and wounds of various kinds
stand as contributing factors. Leukoplakia and tuberculous ulcers have
also furnished the basis of the disease.

The anatomy of the organ has a prominent bearing on the location
and incidence of esophageal cancer. The three points of predilection,
(i) upper, (2) middle, and (3) lower thirds, are also points of normal con-
striction, the narrowest being at the level of the cricoid. Mehnert holds
that there are 13 natural constrictions at the vertebrae. Others enumerate
narrowings and points of election as at .cricoid, aorta, tracheal bifurcation,
left bronchus, and cardia. At these points also diverticula form and these
abnormalities either on their edges or in the depth may be the seat
of carcinoma (Heller-Arndt, Ritter).

Anomalies of structure of the esophageal mucosa seem to be an important
predisposing factor in carcinoma but their exact importance has not been
determined. The great majority of subjects exhibit interruptions in the
squamous lining of the mucosa by islands of mucous glands resembling
those of the stomach (Schaffer). The most notable of these islands appear
at the level of the cricoid to fifth tracheal cartilage, as bilateral spots 2-10 mm.
in diameter, resembling gastric mucosa, or they are much smaller, irregularly
distributed, and require microscopic identification. The cardiac end of the
esophagus is also regularly beset with similar glands. The glands are of
branched tubular type, lined by cylindrical cells, containing mucus and
often becoming cystic. Mucus and parietal cells are often to be dis-
tinguished. Much has been written on the origin and significance of these
glands and their relation to carcinoma (Hewlett, Lit.). They doubtless give
origin to the mucoid and adenoid varieties of carcinoma, and the sudden
transition of epithelial types which they present offers a predisposing factor
for epithelioma. They are probably not to be regarded as misplaced islands
of gastric mucosa, but as a type of normal development of the embryonal
esophageal epithelium (Eberth, Neumann). The general incidence of
carcinoma does not seem definitely related to these structures, Kraus finding
158 cases in the upper third to 699 in the middle and lower thirds.

Another series of abnormalities of importance in the origin of esophageal
cancer is described by GKnski, Ciechanowski and Mosher, and consists of

(1) canals lined by cubical or squamous-cells lying in the submucosa, or

(2) deeper canals perforating the muscular coat, and (3) of complete tracheo-
esophageal fistulae. Many of these canals open on the mucous surface of the

835

836

NEOPLASTIC DISEASES

esophagus and always on the anterior surface in the middle line. Stoeber,
Kern and others describe cysts of this origin. Kathe found in a case of
esophageal cancer an opening in the esophagus in the above position, 18 cm.
below the laryngeal orifice, leading into a canal which passed in the sub-
mucosa downward 5 . 5 cm. where it again opened in the middle line. All these
structures may be referred to incomplete separation of trachea and esophagus
at an early embryonal period. That epidermoid carcinoma may arise from
such structures is indicated by Grabowski's case, in which a tumor protruded
into esophagus and also to a less extent into the trachea. An origin from such
deep structures may also explain the common failure to find early superficial
lesions of the lining epithelium, the early onset of deep ulcerations, the wide

vertical extensions of the disease, and prob-
^ ably also, the embryonal character of certain

very malignant cases.

Gross Anatomy. — The tumor appears as
(i) a flat infiltrating ulcer, or (2) a more
bulky polypoid or globular mass, or (3) a diffuse
infiltration.

(i) The ulcer may encircle the tube
causing constriction and invading surround-
ing tissues. Above, it invades larynx, below,
gastric wall and externally it permeates lymph-
nodes and ruptures into trachea, bronchus,
lung, aorta (Stadelmann, Kaufmann), and me-
diastinum. Fatal hemorrhage results also from
erosion of pulmonary vessels, or carotid and
thyroid arteries. Infection and suppuration con-
stantly supervene. In many cases of this type
the initial lesion is small and resembles a peptic
ulcer, while the invasion of nodes and tissues is
extensive. Thus there may be bulky tumors in
the neck, or extending down the mediastinum, or
involving pleura and pericardium, and these
tumors may cause secondary stenosis or per-
forations. A second ulcer of the mucosa may
appear, probably formed in this manner
(Seelig).

Pressure on the recurrent laryngeal nerve
is a frequent and early symptom recalling
aneurysm. It occurred in 18 of 236 cases
(Sakata). Ehret once noted hoarseness as the
initial symptom.

(2) Globular or polypoid tumors are usually of the adenocarcinomatous
type (Coplin, Lit.). They form circumscribed growths within lumen, wall,
or lying externally.

(3) A diffuse infiltration of much of the esophagus occurs, of which
Caesar describes a typical case. The organ from larynx to cardia, as well
as a portion of lesser gastric curvature, was uniformly % cm. in thickness,
stenosed, but free from ulceration, and the mediastinal nodes were much
enlarged.

The early and extensive metastases of esophageal carcinoma are favored
by the abundant blood and lymphatic supply and by the movements of the
organ. The influence of the latter element is only less prominent than in
the stomach. Of the lymphatics Sakata describes a rich plexus in the mucosa

FIG. 404. — Congenital fistulous
tracts in esophagus. Probable
sources of carcinoma. (After
Glinski, V. A., 199.)

EPIDERMOID CARCINOMA

837

which is chiefly longitudinal and a plexus of much finer vessels in muscularis
and outer coats. Hence growth along the tube is readily accomplished and
this mode of extension probably accounts for the multiple growths and sup-
posed implantations in lower esophagus and stomach (Borrmann). Once
beyond the fibrous coat extension through lymph-vessels occurs with unusual
rapidity, giving secondary tumors in
neck, thyroid, pleura, lung, and liver.
The blood-vessels appear to be pen-
etrated in rare cases. Diirr found a
large metastasis in the muscles over
the pubic bone. Francke sectioned
a case supposed to be a brain tumor,
finding an adenocarcinoma of eso-
phagus with metastases in lymph-
nodes, pericardium, pleura, spleen,
ovaries, pancreas, and brain.

The structure is usually that of
acanthoma, but pearls, hornification,
and prickle cells are often missing
and the tumor has an embryonal
type. The adenocarcinomatous va-
rieties resemble similar tumors of
the stomach and may exhibit an
alveolar or a more diffuse structure.
Mucous production may be abund-
ant. The structure may vary in
different portions of the same tumor
and Kaufmann mentions mucous pro-
duction in the secondary deposits
from an acanthoma.

Among atypical varieties may be
mentioned a highly embryonal
growth described by Norris. In this
case with an ulcer of the usual gross
appearance in the upper esophagus,
there were enormous tumors in the
liver. In both, the cells were of in-
different large polyhedral, or spindle,
or round type.

Extensive involvement of cervical
lymph-nodes with comparatively
small tumors of the esophagus oc-
curs in an important group of cases.
Large tumors of one or both sides of
the neck may form when esophageal
symptoms are indefinite or absent.
The structure of the tumors in the
nodes may be typical acanthoma or more embryonal and atypical.

Carcino sarcoma of the esophagus is an atypical growth of uncertain
significance, of which several cases have been reported. In some of them
there was adult acanthoma in sarcomatous stroma (Herxheimer, Lit.
Donath).

The very early stages of esophageal carcinoma are rarely encountered.
Janeway examined in this laboratory an early epithelioma i cm. in diameter.

FIG. 405. — Carcinoma of esophagus.

838

X EOF LA STIC DISEASES

It had not yet broken the line of basal-cells, but the cells were hypertrophic,
nuclei very hyperchromatic, the focus was rather sharply demarcated and
the whole area resembled a very early basal-cell carcinoma. Probably many
tumors arise from embryonal submucous or the deeper structures previously
described.

EPITHELIAL TUMORS OF BLADDER

The natural history of epithelial tumors of the bladder is determined
by the structure of its mucosa, and the physical conditions to which it is

exposed. The transitional character of the
vesical epithelium, which exhibits both pave-
ment and glandular properties, accounts for
the histological varieties of tumors arising
from it. Thus the superficial cells are chiefly
of the squamous type, while the deeper
cells rapidly become polygonal and in many
cases deep lying crypts, often called Brunn's
follicles, are present and exhibit a lining of
polygonal or cylindrical cells. Muscular
activity and a constant bathing in fluid ex-
plain the villous form of the tumors. The
villous form probably determines the long
confinement of the tumors to the site of
origin, which was once wrongly attributed
to absence of lymphatics. Multiplicity may
be referred to ready diffusion of the irritants
which cause inflammatory and then neoplastic
overgrowth.

There are two common varieties of these
tumors: (i) Papilloma, which is fibrous,
benign, or malignant; and (2) Carcinoma,
which may be of adenoid or diffuse type.
Adenoma is very rare. Several subvarieties
are mentioned by various authors, as
Albarran and Fenwick. The bladder fur-
nishes between 0.96 per cent, of all carcinomas
(Hadda) and 0.25 per cent. (Albarran). Rau-
enbusch finds the disease three times as
common in men as in women. Yet Stein
observed 16 simple papillomas in women to
1 4 in men. Sarcomas are much more frequent
in women and children.

Papilloma. — -This common tumor occurs
usually as a coarse villous growth with narrow
pedicle, or the papillae may be feathery or fleecy,
or the growth may be rather flat and lobu-
lated, or the tumor has a broad flat base and is sessile. Rarely long cylin-
drical papillomas are observed (Albarran). The surface of some papillomas
may be of low warty character or nearly smooth, and it may vary in different
portions of the same tumor. Half the tumors are multiple; as many as twenty
different growths may be scattered over a wide area; and in some cases much
of the bladder wall is the seat of very numerous villous outgrowths. Hence
the discovery of one papilloma indicates a search for others at once or later.

FIG. 406. — Double ulcerating
epitheliomas of esophagus. (After
Seelig, A. S., 46.)

EPIDERMOID CARCIXOMA 839

The multiple villous tumors must be distinguished from a form of diffuse
low papillary inflammatory hypertrophy of epithelium, which has been
known to cover almost the entire mucosa, producing a velvety surface. This
condition is a curious exhibition of the regenerative tendencies of the irri-
tated mucosa, is seen in exstrophy of the bladder, with calculus, and about
other tumors, and may be arrested by curettage (Keyes, Fenwick).

The size of the papillomas varies extremely. Some long remain small,
not exceeding 2 cm. in length. Others while pedunculated attain the size of
a small orange. The more solid and malignant tumors may also attain con-
siderable bulk. A very large pedunculated myoepithelioma is described by

FIG. 407. — Advanced carcinoma of eso.phagus with rupture into bronchus.

Albarran. The chief location is about the ureteral orifices and along the
edges of the trigone. Fenwick notes a relative immunity of the trigone
itself, where the mucosa is less mobile.

The course of the tumors is generally prolonged. Hadda refers to cases
lasting 1 8 years. Guyon observed a case of 30 years' duration, and Fenwick
attributed to one case a duration of 60 years. They arise at any period
of life from 21-? to yg years (Albarran, Frisch), but are most common after
middle life, especially in the sixth decade. The life of most papillomas
remains confined chiefly to the bladder. Some remain benign for many
years, and rarely spontaneous expulsion occurs. Others (25 per cent.)
become malignant after a variable period. Some are malignant from the
first (Albarran). Almost 75 per cent, reach an urgent condition or are

840 NEOPLASTIC DISEASES

fatal in 3 years. Albarran found 68 malignant cases to 13 benign papillomas.
There is to be considered in addition the tendency of the benign disease
to become malignant. Most authors are agreed that the macroscopic ap-
pearance is no safe criterion of clinical course, while the microscopic structure
usually indicates considerable growth capacity which in other situations
would always prove malignant. The clinical malignancy is also influenced
by the tendency of new tumors to progressively develop in a predisposed
mucosa.

In many cases the removal of the original tumor is followed by recurrence
at another site. It is probable that the recurrence usually represents a

FIG. 408. — Bulky papillary carcinoma of bladder.

development of a new tumor from preexisting lesions but not a recrudescence
or implantation of the old growth. Frankly malignant cases however,
doubtless exhibit a growth of retained cell groups in the submucosa. Of
103 simple papillomas Frisch, after suprapubic cystotomy, saw 21 recurrences
in 53 cases which he could follow. Of 49 papillomas which gave microscopical
signs of malignancy 29 recurred, 3 in the form of flat carcinomas. Of 95
definite cancers 62 recurred and the others were not traced. In three cases
a simple papilloma recurred as single or multiple carcinoma.

Extensions occur through the wall of the bladder to the pelvic tissues,
up the ureters toward the kidneys, along the pelvic lymphatics to the pre-

EPIDERMOID CARCINOMA

841

vertebral lymph-nodes. Rarely there is a superficial extension of a papillary
cancer of the urethra into the bladder (Fluss, Lit.), or vice versa (Adenot).
Metastases are not common but have been observed in liver, lung, pleura,
kidney and inguinal and axillary lymph-nodes.

Albarran saw a pulmonary metastasis two years after removal of a
solitary papilloma, the bladder remaining free. He accepts frequent propa-
gation by contact but does not insist on the actual implantation of tumor-
cells. The bulky widespread metastases of prostatic cancer are regularly
wanting.

The complications of malignant papillomas and of other cancers are
hemorrhage with anemia, infection with cystitis and pericystitis, hydrone-
phrosis, renal suppuration, and septicemia. Extension occurs late and true
cancerous cachexia from generalization is rare.

The structure of the vesical papilloma is rather simple and uniform.

FIG. 409. — Spindle-cell epidermoid carcinoma of bladder.

It consists of a series of branching tufts of stroma covered by multiple
layers of epithelium resembling that of the bladder. The variable element
is the stroma, which may consist of a single delicate capillary sometimes in
immediate contact with the epithelium, more often supported by delicate
strands of connective tissue, occasionally accompanied by smooth muscle-
fibers. The muscular stroma may be quite abundant and in Albarran's
myo-epithelioma it composed the bulk of a large malignant tumor. Fibrous
polyps are described, consisting chiefly of localized overgrowth of submucous
tissue. They are of inflammatory nature. Stein found mucous polyps
almost as common as papilloma. True fibromyxomas are rare but may
reach large dimensions (Stein, Albarran). The epithelium is usually over-
nourished, with hyperchromatic nuclei, but mitoses are rare. The cell
form may exactly reproduce that of the bladder, or the cells may be elongated,
or rounded or extensively vacuolated. Albarran describes as the "allantoid

842 N EOF LA STIC DISEASES

type" a simple papilloma of which the villi are capped with cylindrical
cells as in the intestine. Venulet described a structure resembling chorioma.
The papillae are closely packed together in the more solid tumors, so that
the section may resemble alveolar carcinoma.

Signs of malignancy in papillomas include much variation in the size
and type of the cells and extensive and irregular overgrowth, but the most
important indications may be found only in the pedicle which is seldom
accessible in operative material. Downward growth of the convoluted
epithelium invading the pedicle and subjacent tissue is the chief factor in
local recurrence and malignancy. There is reason to believe that chronic
inflammation with edema and round-cell infiltration facilitates this down-
ward growth and renders it possible without any great change in the growth
capacities or morphology of the cells. Yet in some papillomas the invasive
tendency is present from the first. That a slowly growing and originally
benign papilloma may become malignant is abundantly attested (Albarran,
Fenwick, Frisch). Frankly malignant papillomas exhibit throughout the
atypical and lawless growth of carcinoma.

Buerger places the proportion of carcinomas preceded by papilloma
at 30 to 36 per cent. While it is impossible to determine from the structure
which papillomas will become malignant the actual presence of malignant
characters, he finds, may be determined from examination of portions ac-
cessible to the cystoscope. The changes, as usual, consist in atypical
qualities of the cells and nuclear hyperchromatism.

Degenerative changes in papillomas include fragmentation, infection,
and ulceration, edema, necrosis, cellular infiltration, and calcine incrustation.

Adenoma. — The literature contains isolated reports of adenoma and
adenocarcinoma of the bladder (Albarran, Fenwick). These tumors are
usually small, single or multiple, located on trigone or other portion of wall,
and they may be flat or pedunculated. They are composed of large alveoli
lined by multiple layers of cells some of which are usually cylindrical. They
show a tendency to mucous degeneration, as in Kaltenbach's case. Some of
the large glandular cysts of the bladder are probably related to adenoma.

The occurrence of cylindrical cell and mucoid adenoma and carcinoma
in the bladder suggests an origin from mucous glands, which are not always
attributed to the structure of this organ. Yet short tubular glands are
regularly found in the bladder mucosa, especially in the trigone and about
the urethral orifice '(Albarran, Aschoff). They have been variously inter-
preted as aberrant prostatic glands (Virchow), or urethral glands (Aschoff),
or as the result of snaring off of papillae of epithelium by thickened con-
nective-tissue septa (v. Brunn's follicles). In cystitis cystica many of the
invaginated epithelial tubules are lined by cylindrical cells and the modified
epithelium develops secretory tendencies. Albarran describes in the trigone
tubular glands in the submucosa lined by cylindrical and cuboidal cells
and simpler tubular crypts scattered over the bladder wall. No true secre-
tory processes have been established in these glands, but the lumina are
filled with desquamated cells. It is probable that such glandular structures
increase in number with increasing age and in cases of chronic cystitis
(Prezwosky).

Glandular Carcinoma. — A rare type of carcinoma of the bladder takes
the form of a diffuse infiltration of the wall, with extensive mucoid degenera-
tion. Rauenbusch has collected 10 cases of this type and offers a de-
scription which indicates that such tumors may result from an extensive
malignant growth of the same type as the mucoid adenomas. Yet the well-
known difficulty of distinguishing secondary and primary carcinoma of the

EPIDERMOID CARCIXOMA 843

bladder, and the occurrence of somewhat similar conditions from secondary
invasion by intestinal cancer, leaves a reasonable doubt as to the exact
origin of some of the colloid carcinomas. Montfort, for example, was able
to find only four primary glandular cancers of the bladder in 83 cases fully
examined. The observations of many authors indicate the importance of
this point of view.

Secondary invasion of the bladder by carcinoma may closely simulate
primary tumors. Carcinoma of the prostate frequently invades the bladder
at the trigone, and Klebs once thought that all carcinomas of the bladder
arose in the prostate. The differential diagnosis is often difficult and at
times impossible. Many observers have found that only a small proportion
of true carcinomas involving the bladder are primary in that organ. Besides
the prostate, the uterus and rectum furnish a considerable proportion of
the invading tumors (Fere). The invasion of the trigone from the prostate
may take the form of a fungating mass or a flat ulceration; or the urethral
orifice, trigone, and prostatic urethra may be the seat of hard projecting
nodules; or the growth originating in the anterior portion of the prostate
may invade and thicken the anterior wall of the bladder (Fenwick). Sar-
comas of the prostate or vagina, especially in children, may grow extensively
in the bladder. From the seminal vesicle a carcinoma, described by Fenwick,
invaded prostate and bladder-wall, forming a hard cup-shaped ulcer involving
one-half of the trigone and ureteral opening.

Primary ureteral carcinoma has occurred in rare cases (Yoelcker, Rundle\
and downward growth of this tumor may yield a tumor mass at the urethral
orifice (Drew). Yet it is difficult to exclude a primary growrth at the ure-
teral orifice, as in Fen wick's case (/. c., p. 18). The cases in which the renal
pelvic mucosa, ureter, and ureteral orifice are involved by nodular or villous
carcinoma probably signify the development of multiple primary tumors
over a wide area. The possible extent of this predisposed territory is in-
dicated by various cases of pyelitis, ureteritis, and cystitis cystica (Stow,
Lit.). A similar explanation probably applies to the alleged cases of im-
plantation of renal carcinoma along ureter and in bladder. This view is
strengthened by the occurrence of benign papillomas in the bladder in cases
of malignant renal or ureteral growths (Fenwick, Lit.). Several observers
have noted that the invasion of the bladder by malignant tumors of other
organs may excite the growth of villous papillomas in the adjacent mucosa.

Etiology. — The great majority of bladder cancers can be traced to a
previous or coexistent cystitis. In one group the cystitis long antedates
the tumor and may be forgotten. Vesical calculus is associated with car-
cinoma in a rather small proportion of cases, varying greatly with different
authors. It is especially common when stones form in Bilharzia cystitis
(Goebel).

Stoerk has traced a definite relation between cystitis cystica and its
forerunners with multiple papilloma, and he and Cohen report cases of cystitis
cystica developing into carcinoma. I have observed one case in wrhich a
large portion of the bladder was the seat of low, nodular and cystic outgrowths,
from many points of which carcinoma had developed. The multiple tend-
ency of villous carcinoma and the heterotopic recurrences indicate the
existence of widespread lesions in the mucosa from which tumors may develop.

In Bilharzia disease there is a series of changes, including venous and
lymph stasis, catarrhal cystitis, irritation by ova, and lithiasis, which have
been shown by Goebel and others to lead in many instances to epithelial
and other tumors. The frequency of chronic cystitis, papilloma, carcinoma,
and even sarcoma among anilin workers has been pointed out by Rehn,

844

NEOPLASTIC DISEASES

Wendel, and Leichtenstern. Here the cystitis and the tumors are often
located at the ureteral orifices. A large proportion (50 per cent., Seyberth)
of these tumors are malignant.

Miscellaneous Tumors of Bladder. — Among the rare tumors sarcoma
of the bladder is of chief interest. Albarran collected 51 cases. They occur
chiefly in young subjects. They produce a large globular or polypoid
intravesical growth or diffusely invade the wall. The structure varies,
round, spindle, and mixed cells predominating. Vascular myxosarcomas of
large size are reported by Kaufmann. Osteochondrosarcoma is reported

FIG. 410. — Cystitis cystica. A lesion often followed by carcinoma of bladder.

by Beneke and W. Fischer. Secondary invasion of the bladder by the
myxosarcoma of the vagina in children is a well-recognized condition.

Rhabdomyoma has been described in a few cases (Monckberg). Leio-
myomas appear as polypoid tumors, sometimes of large dimensions (Terrier,
Hartmann). Various mixed tumors of the bladder occurring chiefly in
children are described by Husler and R. F. Miiller. Probable sources of
these tumors and their interpretations are discussed under Teratology.

TUMORS OF PENIS

Epithelioma of the penis forms from i to 3 per cent, of all cancers in
males (Paget, Billroth) and occurs most frequently in the sixth, fifth, and

EPIDERMOID CARCINOMA 845

seventh decades of life (C. Kaufmann). Curtis refers to a case of epithe-
lioma at 1 8 years, and Demarquay saw nine cases between 20 and 30 years.
Creite describes an atypical embryonal carcinoma of the corpora cavernosa
of undetermined origin in a child of two years.

The disease arises chiefly on the glans (69 per cent., Barney), and on the
dorsal aspect near the corona (Thomson). Kaufmann found it more fre-
quently on the prepuce. Cancer arises from the normal or chronically
inflamed urethral mucosa. Hottinger collected 20 cases of this type, which
took the form of epithelioma or carcinoma with mucoid degeneration and
occasionally with alveoli lined by cylindrical cells. Cowper's glands were
the source of carcinoma in three cases described by Kaufmann. Contrib-
uting factors are chiefly phimosis and syphilis. Demarquay and Barney
noted phimosis in 80-85 per cent, of their cases, and Kaufmann found a
chronic balanitis with warty vegetations, the result of irritating secretions, in
29 of 33 cases. Hebrews are practically free from the disease. Thomson
describes as a precancerous condition of the penis a catarrhal balanitis
with desquamation or, later, epithelial hypertrophy with overgrowth of sub-
epithelial connective tissue. Schuchardt calls this condition "psoriasis
preputialis. "

Syphilitic scars and venereal warts are not infrequently the starting
points of epithelioma, and the trauma of circumcision is occasionally men-
tioned. Buday reports a urethral carcinoma following elephantiasis of the
penis.

Implantation by contact with a cancerous cervix has been maintained
as a source of penile carcinoma by Demarquay, Martin, and others, but
without satisfactory data.

The initial lesion is usually regarded as a simple wart, or it appears as
an eroded papule, more dense and pearly than a chancre, or as a smooth
lump or thickening of the epithelium, or finally, as a definite ulcer. Many
cases are not recognized until an irritating purulent discharge calls for the
relief of phimosis and discloses an established lesion, and most cases have
progressed for months or years before recognition.

The established disease regularly takes the form of a papillary epithelioma
and may long remain a relatively warty tumor of considerable dimensions,
but ulceration commonly supervenes, excavates the central portions and
leads to infection and suppuration. Early ulceration and infiltration of
the base may obscure the papillary character from the first and lead to a
more rapid and malignant course. C. Kaufmann speaks of bulky non-
papillary lobulated tumors arising from the glans. Papillary tumors of
the glans are nearly always malignant.

Local extensions of. the disease occur late, but eventually the glans is
destroyed, the corpora cavernosa are invaded, and the whole penis may
be infiltrated, especially in the ulcerative form. In most cases, however,
the corpora cavernosa long resist invasion and the corpus spongiosum
remains free, so that urination through the urethra or a fistulous tract is
maintained.

Lymphatic extension occurs through the superficial vessels to the inguinal
nodes and through the deep lymphatics of the urethra and along the dorsal
vein to the pelvic nodes. The inguinal nodes are commonly involved and
often on both sides. Kaufmann found the inguinal nodes free in only 8 of
48 cases. Martin found 30 out of 40 invasions bilateral. Kuttner proved
that many swollen nodes were free from cancer. He records invasion of
pelvic nodes and in prevesical region in two cases without the affection of
inguinal nodes and emphasizes the connections of the deep urethral and dorsal

846

N EOF LA STIC DISEASES

vein lymphatics with the iliac vessels. A notable case is that of Taylor
who amputated the penis without removing the nodes in the sixth year of
the disease, the patient remaining well for ten years. Permeation along the
dorsal lymphatics is the rule, and continuous cords have been traced up to
groin, pubes, and even to umbilicus. Localized nodules may develop in the
course of the lymphatics and break through the skin. Highly infected
cancerous ulcers develop in this way and hasten cachexia. In advanced
cases there may be widespread ulceration and extensions with metastases
in pelvic and abdominal nodes and internal organs. The liver is a favorite
seat of metastases from carcinoma of penis, which may occur early in the

FIG. 411. — Carcinoma of penis. Suppurating carcinomatous inguinal lymph-node.

disease. The lungs, heart, stomach, and central nervous system have also
been invaded. Rarely the disease appears to become implanted by contact
from glans to prepuce or scrotum.

The course of penile carcinoma is relatively slow, especially in cases
which remain papillary and escape ulceration. Barney shows that most
cases run i to 3 years before reaching a critical condition, but he reports n
cases of over five years' duration and one case living n years without
operation. The gross mortality was 32 per cent., while 15 per cent, devel-
oped visceral metastases, the others succumbed to local and pelvic lesions,
and of all types of cases 38 per cent, were cured. Recurrences are usually
observed in the first year, but often develop after five years. Ten of Barney's
26 recurrent cases died of cancer after an average duration from the begin-
ning of the disease of about eight years.

EPIDERMOID CARCINOMA

847

The structure of epithelioma of the penis is uniformly that of adult
acanthoma of papillary type and with abundant development of pearls and
hornification. This structure is usually maintained in the secondary growths
and may be very prominent even in hepatic metastases.

Urethral carcinoma presents the structure of epithelioma of the bladder
(Hall, Lit.). It is quite possible that the endothelioma intravasculare of the
corpora cavernosa is a urethral carcinoma (cf. Borrmann). The malig-
nant tumors arising from Cowper's glands show the structure of glandular
carcinoma (Beck).

Melanoma of the glans penis is described by Payr (Lit.).

Scrotal cancer is interesting, especially because of the variety of specific
exciting factors to which it has been attributed. Chimney-sweeps' cancer

FIG. 412. — Beginning epidermoid carcinoma of female urethra inv

of 2 sq. cm.

superficial area

figured frequently in the literature from 1820 to 1870, but has now largely
disappeared from observation. It was attributed to the irritation of carbon
and oils derived from the soot. It was first recognized by Pott and fully
described by Curling. It first appears as a "soot- wart" which may long
remain innocent and may long grow as a harmless process, or with ulcera-
tion may develop malignant features. The lesion may develop in the cuta-
neous glands and produce a subcutaneous nodule. Creighton states that
the epitheliomatous nature of chimney-sweeps' cancer, although always
assumed, is far from clear in the recorded cases. He notes that the lesions
appear first as subcutaneous nodules, that there are visceral metastases
in fatal cases, that the structure is not that of adult acanthoma, and he traces
the origin to the sweat-glands of the skin. Many parts of the body have

848 NEOPLASTIC DISEASES

been affected. Curling relates several histories indicating that the disease
may develop long after exposure. It has been observed chiefly in England.

Paraffin cancer of the scrotum has occupied a somewhat less definite po-
sition. V. Volkmann was chiefly responsible for the view that irritation by
products occurring in the manufacture of paraffin gives rise to scrotal cancer.
He described the chronic irritation of the skin of the genitals in paraffin
workers and stated that the lesions had a notable tendency (90 per cent.)
to run into epithelioma.

J. K. Mitchell, andLewin, studied the cutaneous eruptions among workers
in petroleum but found no cases of carcinoma. Lewin describes a form of
chronic acne which in advanced cases leads to diffuse chronic inflammation
with crusting. It was observed especially among the handlers of the by-
products of petroleum refining.

That cancer of the scrotum often develops in subjects that are free from
exposure to bituminous products is generally recognized. Exposure to
trauma, and irritating secretions, are probably an important factor in its
genesis. While many of the cases are of slow progress, very active and
malignant forms occurring at an early age (8 to 15 years) are reported by
Curling and Heath.

CHAPTER XLIV
MELANOMA

Melanoma is a pigmentiferous tumor arising from a specific mesoblastic
cell, the chromatophore, and possibly also from epithelial cells which have
been modified by pigment production. It arises chiefly in the skin, and the
choroid coat of the eye, less frequently in the meninges, rectum, and other
organs. In the skin its origin is connected with a congenital abnormality
consisting of overgrowth and pigmentation of epidermis and often of the
cutaneous glands, occasionally with angiomatous processes, and especially
by the presence of many peculiar abnormal cells in the derma, forming a
lesion known as the congenital nevus. In many cases the process terminates
in widespread extension of the proliferating cells, giving a highly malignant
tumor process. The peculiar and obscure conditions of its origin, the re-
markable physiological properties of the chromatophores in the animal
kingdom, the eccentricities of its clinical course, and its interesting history
as a field of debate, render this tumor one of the most notable topics in oncology.

History. — The congenital character, the origin from various forms of
pigmented moles, and the numerous clinical peculiarities were fully recog-
nized by the early writers before Virchow (1864, Lit.), while their views
concerning the exact position of the process were about equally divided.
Virchow recognized both a sarcomatous and a carcinomatous melanoma,
the former exhibiting a diffuse structure of spindle-cells, the latter an alveolar
structure, and he employed the term melanoma for the entire group. Dem-
ieville in 1880, traced the origin of nevus cells to the perithelium and endothe-
lium of blood-vessels, and in 1882 Recklinghausen discussed the origin of
melanoma in connection with multiple fibroma of the skin. He accepted
by exclusion the endothelial origin, but could not trace any transitions of
capillary endothelium into nevus cell masses. He dealt especially with the
older fibrous nevi which may resemble fibroma.

In 1893 Unna presented in substantial form the evidence in favor of the
epithelial origin of nevus cells, and while at first his views received little
support (Delbanco, Hodara, Scheuber, Gilchrist), or were actively combated
(Bauer, Jadassohn, Lubarsch, Hansemann, Borst), they have been actively
supported by many later writers up to the present time (Favera, Lit.).

According to Unna "All pigmented and nonpigmented flat- or wart-like
nevi of newborn infants and children exhibit a direct connection between
the cutaneous epithelium or hair follicles or ducts of sweat-glands and the
cell cords of the nevus. In these structures there is a progressive trans-
formation of prickle cells into clumps of pliable ameboid cells without
spines or fibrils, whose epithelial origin and nature is still attested by their
clear oval vesicular nuclei and their immediate contact with each other
and with the neighboring epithelium without the intervention of intercel-
lular substance. This metaplastic process shows a constant tendency to-
ward the complete isolation of groups of altered epithelial cells which are
completely surrounded by the connective tissue of the derma."

Definite limitations to this explicit doctrine were soon encountered,

54 849

850 N EOF LA STIC DISEASES

concerning especially the relation of the nevus cells to the abundant con-
nective tissue in older nevi, and their behavior toward the lymph- and
blood-vessels of the cutis.

The rather definite indications that the nevus cells actively participate
in the formation of the cellular and fibrous tissue which surrounds them
have been interpreted by Kromayer as evidence of the desmoplastic property
of epithelium and this phase of the subject has been pursued by Kromayer
in a series of studies 1898-1905 and by others, with interesting results. Jud-
alewitsch especially has confirmed Kromayer's views and depicts the gradual
loss of fibrils, pigmentation followed by depigmentation, and isolation of
epithelial cells and their transformation into fusiform cells with fibrillar
prolongations. Yet there is a strong probability favoring the conclusion
of Favera and others that this fibrous tissue is a product derived from the
preexisting tissue of the derma. Riecke and Pini, however consider the
nevus cells to be modified fibroblasts. The relation of the nevus cells to
the endothelium of vessels has remained a difficult question and a few more
recent observers have clung to theory of endothelial origin of certain nevi,
while admitting that many are derived from epithelium (Lowenbach, Walsch,
Herxheimer, Borrmann, Moller, Fox, Johnston). The particular form which
this compromise takes, and the grounds for it, vary considerably with the
authors, and specific features distinguishing the two types of tumors have
not been demonstrated. According to Soldan the endothelium of the nerve
sheaths gives origin to nevus cells.

The presence of many large polygonal or multipolar heavily pigmented
cells in nevi and melanomas and certain considerations bearing on the ques-
tion of pigment production in general, as well as observations on melanoma
of the uveal tract, have led Ehrmann and Ribbert to maintain the origin
from the highly specialized mesodermal cell, the melanoblast or chromato-
phore, and to attribute the nevus and its tumors to aberrations of this cell
(Ribbert's chromatophoroma) .

The evidence accumulating in recent years from the comparative study
of the physiology of the color function in the animal kingdom is a very
formidable argument in favor of the specific mesoblastic nature of the
chromatophore. It is much less cogent evidence that all melanomas are
derived from mesoblastic chromatophores. Melanoma undoubtedly arises
from nevus cells and the histologkal signs point very strongly toward the
origin of nevus cells from the epidermis. The relation of chromatophores
to the nevomelanoma is not yet clear. The theoretical considerations
favor the origin of all melanomas from the mesoblastic chromatophore,
while the histology of human tumors favors the origin from epithelial cells
which have taken on pigmentary functions. The established tumors
exhibit either carcinomatous or sarcomatous structure or both.

Under these circumstances the writer confesses his inability to reach a
conclusion regarding the nature of melanomas, and he will therefore present
the data regarding them as impartially as possible, awaiting further elucida-
tion of the many subjects involved.

Although the chromatophore is a mesoblastic cell, it arises very early
in the formation of this germ layer and exhibits many specific properties
some of which resemble those of epithelium, so that the identification
of this tumor with carcinoma or sarcoma seems undesirable. The term
melanoma should be employed to emphasize the specific character of the
tumor and its cells of origin. The possible origin from epidermal cells may
be indicated by the term melanocarcinoma, and the sarcomatous character
of other tumors is indicated as melanosarcoma.

MELANOMA 851

Clinical Characters. Modes of Origin. — The pigmented mole or nevus
which is the source ol cutaneous melanomas occurs chiefly on face, neck,
and back, but may be found on any portion of the body. It may even
appear on the sole of the foot and in this and other exposed positions is
more liable to malignant change. A relation to nerve-trunks has sometimes
been noted, as well as a unilateral or symmetrical distribution. It appears
as a minute pigmented spot (n. spilus), or soft, flat elevation, and often
grows to a warty excrescence (n. verrucosus), or papillary tumor (n. papil-
laris). Many exhibit a growth of soft or coarse hairs, pointing to the impli-
cation of hair follicles (n. pilosus), and larger tumors may contain much
loose connective tissue and fat tissue suggesting a complex disturbance
of dermal structure (n. lipomatodes).

Remarkably wide extension over much of the body occurs in rare cases
of " bathing trunk" type, of which Fox has collected 25 cases. The color
varies from a light brown to black, but not a few notable cases of pigment-
free moles have been described (Moullin). The consistence is usually
soft, in older fibrous lesions firm, and the vascularity slight. Eventually
they may become hard and pedunculated (molluscoid degeneration). The
clinical distinction from capillary nevi, port-wine stains, and lentigines

FIG. 413. — Extensive hairy nevus. Bathing trunk type. (After Fox, J. A. M. A., 58.)

(freckles) is usually obvious, but other pigmented tumors and processes
in the skin may require microscopical study.

Pigmented moles are sometimes associated with vascular nevi, and
with molluscum fibrosum. These various lesions may be wholly distinct in
the same region, or so intimately combined as to greatly complicate the
question of their essential relations.

Melanotic whitlow (Hutchinson) is a heavily pigmented malignant epi-
thelioma which begins as a swelling of the lateral nail fold of finger or toe.
The lesion soon ulcerates and early involves the regional lymph-nodes. The
disease has all the essential features of melanoma (Faguet, Plantier, Galloway).
The process may take origin in the flat pigmented lesions called lentigo, which
may or may not show irritation or ulceration (Bayet).

Finally in rare cases no local point of origin of the disease can be demon-
strated clinically or at autopsy.

In the lower animals moles and melanomas are relatively frequent.
Their occurrence in white horses was noted by Virchow as evidence of a
constitutional dyscrasia.

Course. — The natural history of the vast majority of pigmented nevi
includes a long period of slow growth, a stage of inertia, followed by a process
of regression. A congenital disturbance of the structure of the derma
must be assumed for all cases, and some moles are visible at birth. Many

850 N EOF LA STIC DISEASES

concerning especially the relation of the nevus cells to the abundant con-
nective tissue in older nevi, and their behavior toward the lymph- and
blood-vessels of the cutis.

The evidence accumulating in recent years from the comparative study
of the physiology of the color function in the animal kingdom is a very
formidable argument in favor of the specific mesoblastic nature of the
chromatophore. It is much less cogent evidence that all melanomas are
derived from mesoblastic chromatophores. Melanoma undoubtedly arises
from nevus cells and the histological signs point very strongly toward the
origin of nevus cells from the epidermis. The relation of chromatophores
to the nevomelanoma is not yet clear. The theoretical considerations
favor the origin of all melanomas from the mesoblastic chromatophore,
while the histology of human tumors favors the origin from epithelial cells
which have taken on pigmentary functions. The established tumors
exhibit either carcinomatous or sarcomatous structure or both.

MELANOMA 851

Remarkably wide extension over much of the body occurs in rare cases
of "bathing trunk" type, of which Fox has collected 25 cases. The color
varies from a light brown to black, but not a few notable cases of pigment-
free moles have been described (Moullin). The consistence is usually
soft, in older fibrous lesions firm, and the vascularity slight. Eventually
they may become hard and pedunculated (molluscoid degeneration). The
clinical distinction from capillary nevi, port-wine stains, and lentigines

FIG. 413. — Extensive hairy nevus. Bathing trunk type. (After Fox, J. A. M. A., 58.)

(freckles) is usually obvious, but other pigmented tumors and processes
in the skin may require microscopical study.

Finally in rare cases no local point of origin of the disease can be demon-
strated clinically or at autopsy.

In the lower animals moles and melanomas are relatively frequent.
Their occurrence in white horses was noted by Virchow as evidence of a
constitutional dyscrasia.

854

N EOF LA STIC DISEASES

but progressive growth. The structure then fails to show the clear cells
of the quiescent nevus but presents small groups or alveoli or a diffuse
growth of larger opaque polygonal cells with hyperchromatic vesicular
nuclei. Pigmented cells are scanty in the quiescent adult mole and appear

FIG. 415. — A quiescent papillary pigmented nevus. (After Johnston.)

FIG. 416. — Cells in a resting congenital nevus.

chiefly in the outskirts of the cell masses. The basal cells of the epidermis
may, however, be deeply pigmented and swollen.

In rare cases the mole may be entirely free from pigment.

(3) Fibromatous and molluscoid regression overtakes many moles in
their late history. Much new fibrous tissue replaces the cellular areas and

MELANOMA 855

surrounds sweat, sebaceous and hair glands, and this tissue may be cellular
and mucinous. The nevus cells become atrophic, compressed and disappear.
Pigmentation is scanty or absent. The included fat lobules may be enlarged.
The mole may be much elongated, pedunculated or extruded.

(4) Malignant changes supervene spontaneously or after trauma or
incomplete extirpation. The apparently innocent histological character of
certain moles which have given rise to secondary tumors is one of the mysteri-
ous features of this disease, but as a rule the dangerous lesions give gross
and microscopical evidence of active growth and especially of increased
vascularity. The vigorous preparation of the skin is perhaps responsible for
some unsuccessful operations on these vascular growths. Deep pigmentation
is commonly observed to belong to dangerous moles.

The histological signs of malignant tendencies are readily detected and
consist of increased vascularity, hypertrophy of cells, with nuclear hyper-
chromatism and occasional mi to tic figures. An alveolar grouping of poly-

FIG. 417. — Section of a flat heavily pigmented mole on skin of forearm, which had given
rise to metastases in axillary lymph-nodes.

hedral cells with prominence of epithelioid characters are observed in many
moles \vhich prove malignant. Fibrous lesions containing only cords of
clear cells are seldom dangerous. Pigmentation usually increases with the
advent of newgrowth but this rule has shown exceptions. The local growth
of nevi is usually the result of multiplication of -the cells originally isolated.
In _ some cases, however, there is evidence of a progressive involvement
of previously normal rete pegs. The histological appearances indicate that
this secondary process begins in the basal epithelium, is often accompanied
by pigmentation of these cells, but is not associated with the presence of
specific chromatophores.

The extensions of melanoma pass through either lymph- or blood- vessels.
In -the former case the regional nodes are involved, the generalization is
relatively slow and repeated local extirpation may accomplish a cure or
long delay the fatal termination. Preceding the invasion of the nodes there
may be pVonounced hyperplastic lymphadenitis. Through the blood-vessels

856 NEOPLASTIC DISEASES

dissemination is usually general. There is little histological indication of
the factors which determine the mode of extension, but the accumulation
of tumor-cells about blood-vessels often reveals an imminent danger of
rupture into the vessels. Numerous dilated blood sinuses are occasionally
present and offer a ready access to the general blood-stream. In some malig-
nant moles I have found great variations in the size and grade of anaplasia
of the cells, some reassuming their epithelioid characters, others multiplying
in the form of small indifferent round- cells.

The structure of metastatic tumors presents the same wide variations.
The tumor may appear as an alveolar or diffuse carcinoma, as a large spindle-
cell sarcoma, often as perithelioma, and even as lymphosarcoma. Well
circumscribed groups of characteristic large round or polyhedral clear cells
are often seen in cutaneous metastases, pigmented or not, and at once

FIG. 418. — Melanoma of pseudoperitheliomatous type.

suggest their true origin. The appearance of such tumors may be the first
indication of the existence of an offending mole. Metastatic nodules may at
first be surrounded by hemorrhage from dilated blood-vessels and the ab-
sorption of the blood may be followed by cicatrization and marked regres-
sion of the tumor. In some cases there are very numerous pigmented points
and spots in skin and mucous and serous membranes. These lesions may
contain so much pigment and so few traces of tumor-cells as to suggest that
pigment emboli have formed. The assumption that such pigment may
incite tumor growth of normal cells is without definite support, but there is
no satisfactory explanation of the great number of small metastatic tumors
arising from some very small primary tumors.

In the organs the metastatic tumor may contain the common large poly-

MELANOMA

857

hedral cells, or smaller round-cells of highly anaplastic type. In a large
hepatic tumor I founci the cells all of spindle form resembling sarcoma. In
another case all the numerous visceral metastases contained small polyhedral
cells whose desmoplastic properties yielded the structure of alveolar carci-
noma. In two cases I have found adenomatoid hypertrophy and hyperplasia
of polyhedral nonpigmented cells in the medulla of the adrenal.

The pigmentation of metastatic tumors varies greatly, being excessive
in some tumors or parts of tumors, entirely absent or scanty in others.
When excessive it may lead to destruction of tissue and the formation of
cysts containing black fluid. There is no constant relation between the
degree of pigmentation of primary and metastatic tumors. Heavily pig-
mented primary tumors may give origin to pigment-free metastases.
The absence of pigment is observed in some of the most rapid and malig-
nant cases. Not infrequently the pigment is limited to the large fusiform

f >' , v

.,r^-<-

FIG. 419. — Structure of metastatic melanoma in lymph-node. Note the limitation of
pigment to invaded stroma cells.

cells in the connective tissue about tumor nodules. In large areas of non-
pigmented cells small foci may contain swollen, apparently hydropic and
heavily pigmented cells. The conditions of pigment formation appear to
be very delicately balanced.

The Pigmentation of Melanoma. — The origin and nature of the pigment
in melanoma have been the subjects of long and elaborate investigation
Furth (Lit.). Special interest attaches to this study since variations in this
substance offer a very delicate indicator of the functional activity of the
cells and a unique opportunity to trace the relation between a functional
activity and the growth capacity of tumor-cells. In fact it is not unlikely
that a complete elucidation of the pigment problems may reveal at the same
time the secret of the excessive nutrition and overgrowth of this particular
tumor-cell.

Morphology.— The earliest indications of pigment deposit in nevi appear

858 NEOPLASTIC DISEASES

in the form of fine yellowish granules in the swollen basal-cells of the mole,
and these appearances are nearly identical with those of normal pigmentation.
As the epithelial proliferation progresses the foci of new cells continue to
exhibit increasing pigmentation and single cells in the groups may develop
excessive deposits of pigment, increase in size, and become elongated or mul-
tipolar. Multipolar chromatophores are usually present in pigmented moles,
lying beneath the epidermis, passing between the basal-cells and occa-
sionally lying within the Malpighian layer. When absent it is permissible
to assume that they have yielded their pigment to the epithelium and then
disappeared.

With the further progress of the cell-growth the pigment may appear in
very large quantities, and in these cases evidences of intranuclear forma-
tion of pigment appear and it becomes scattered widely in neighboring cells
and tissues. The intranuclear formation has been described by several
authors (Ritter, Mertsching, Kromayer, Jarisch), and is frequently observed.
A parallel formation of pigment from the chromidia of protozoa has been
described by Hertwig. The nuclear origin led Bohn to assume that the
pigment granule is a biological entity with nuclear properties. Rossle
noted an excess of nucleolar material in pigmented tumor-cells and traced
its escape into the cytoplasm in the form of pigment grains. He concluded
that the production of pigment reduced the regenerative capacity of the
cell. This relation of the nucleoli to pigment production has been elaborated
by Staffel and by Meirowsky.

The dissemination of pigment to neighboring cells may be very exten-
sive and in metastatic nodules it may be almost exclusively present in the
stroma of invaded tissues while scanty or absent in the tumor-cells. This
condition may be attributed to the phagocytosis of free pigment, to the
assumption of pigment production by normal cells (Fuchs), or to absorption
of extravasated blood. Pigment streaks leading from cutaneous tumors,
patches of pigment in serous membranes, extensive deposits in lymph-
nodes and bone-marrow, and englobed granules in the vascular endothelium
of many organs, melanemia, and melanuria, mark the advanced stages of
the process. Invaded organs may show much diffuse pigmentation. Kat-
surada observed diffuse pigmentation of cerebral capillaries without cere-
bral tumor. The extensive pigmentation of lymph-nodes led Gierke to con-
clude that the tissue cells must be induced to elaborate pigment by some agent
derived from the tumor-cells. Berdez and Nencki have calculated that
as much as 500 gr. of pigment may be produced in one case.

That the pigment of melanoma is the product of a special metabolic
function of the cell, is the conclusion of the great majority of observers.
Virchow regarded the local deposits as the expression of a general dyscrasia.
Many find a close parallel between the physiological formation of pigments,
that occurring in Addison's and other metabolic diseases, and that of melan-
oma. Lubarsch concludes that melanomas, contrary to the rule with many
tumors, contain no glycogen and that from a specific disturbance of metabo-
lism they convert protein material into pigment. Nevertheless many
facts have been interpreted in favor of the direct hematogenous origin of
the pigment. Langhans has described the englobement of red cells by tumor-
cells, but this event must be rare. The perivascular position of many chroma-
tophores may be explained as an adaptation in the interests of nutrition
and appears in a wide variety of nonpigmented tumors. The view that
ameboid chromatophores carry the pigment to the nevus cells is in conflict
with some definite histological appearances in early nevi. Their movement
is probably in the opposite direction.

MELANOMA 859

The evidence of microchemical reactions favors the view that the pig-
ment is essentially of metabolic origin, but that secondary pigmentation
from the absorption of extravasated blood is of frequent occurrence. In
the early mole pigment almost constantly fails to give Perls reaction for
free iron, but in more advanced cases this reaction may often be obtained
(Vossius, Hamburger, Walter) although not always (Perls, Rindfleisch,
Lubarsch, Ravenna). Melanin stains with some basic dyes, as polychrome
methylene blue, after which careful treatment by tannic acid leaves melanin
colorless, hemosiderin greenish-blue (Unna). Barlow finds that the pigment
granules blacken with osmic acid. The comparative study of pigment
production in lower animals points to its metabolic nature (Furth, Lit.).

Chemical studies have thrown much light on the nature and origin of
tumor pigments, while leaving many questions still unsettled. The black
pigment of the hair, choroid, melanotic tumors, and sepia pigment, known
as melanin, usually contains C, H, N, while S is by no means constant.
The elements C, H, N, occur in the general proportions of i, 5, 5 (Hoff-
meister). The presence of Fe also appears to be variable and inconstant
(Berdez, Nencki), so that one may conclude that melanin is essentially free
from S and Fe but possesses a strong tendency to unite with these elements.
It may be dissolved slowly by strong alkalis, and bleached by H20o, chlorin,
and by Whitefield's method, wrhich includes laying sections some hours in
potassium permanganate 10 per cent., followed by dilute sulphurous acid.

Heated with strong alkali melanin from tumors yields indol, skatol,
volatile fatty acids, and an ether soluble acid which gives a dark blue color
with ferric chloride. The chief product is the melanic acid of Nencki.
Under dry heat melanin gives off pyrrhol.

Thormahlen found that the urine of advanced cases of melanoma gives
a characteristic reaction with sodium nitroprusside. When this reagent is
added with KOH a deep reddish violet color appears, which on acidification
becomes blue. The reaction occurs in other diseases and is given by indol,
and probably depends on the presence of the pyrrhol ring in the reacting
substance (Eppinger). Melanin appears in the urine of advanced cases
either constantly or periodically. Stiller observed it only during febrile
periods, and Ganghofner noted an increase during regression of cutaneous
tumors. The urine may be very dark on passage but usually darkens
only on standing. Hence the pigment is chiefly in the form of dissolved
melanogen which oxidizes to melanin on exposure to the air. Various
oxidizing agents hasten the reaction.

Many investigators have attempted to determine the construction of
melanin and its relation to the protein molecule. Nencki concluded that the
protein molecule contains a heterocyclic chromogenic radicle which is the
source of both melanin and hemoglobin, and may be split off by pancreatic
digestion. Hopkins and Cole isolated from pancreatic digestive products a
crystalline tryptophan which they regarded as the mother substance of the
chromogen. The demonstration that the ferment tyrosinase is concerned in
the remarkable pigments of many insects and in the cuttle fish (Furth)
led to the search for this ferment in melanoma. Gessard first demonstrated
the presence of tyrosin and tyrosinase in melanoma of the horse, and he
concluded that the pigment of tumors and that of the cuttle fish are produced
in the same way, by the action of tyrosinase on tyrosin and other aromatic
compounds. Eppinger isolated from the urine of a case of melanoma of the
liver a crystalline melanogen which he regards as a derivative of tryptophan.
On dry distillation it yielded pyrrhol, treated with strong alkali it gave
indol and skatol, blackened with oxidizing agents, and gave a blue color

860 N EOF LAST 1C DISEASES

with sodium nitroprusside (Thormahlen's reaction). He concluded that the
disturbance of metabolism in melanoma consists essentially in the inability
to split the pyrrhol ring and thus destroy the excessive pigment produced
by the tumor-cells. He would regard the excess of pigment and its products,
especially indol and skatol, as the cause of the overgrowth of the cells. Stoe-
ber and Wacker observed that indol and skatol cause marked proliferation
of epithelial cells. In a melanoma, regarded by Orth as originating in the
adrenal, Neuberg demonstrated a ferment which failed to act on tyrosin
but split adrenalin. Alsberg in a melanoma of liver found a ferment which
acted on pyrocatechin and hydrochinon but not on tyrosin. In all of these
fields, as Furth remarks, the various hypotheses require further substantiation.

0. Adler by treating tryptophan or tyrosin with strong H2SO4 secures
black pigments which he regards as very similar to those occurring in mela-
noma. He devised a color test which seemed to be specific of melanoma.

That the pigment or its derivatives exert a toxic action in the disease,
while probable, is without definite proof. Rosenfeld increased the excre-
tion of pigment by administering iodide of potash, without causing any
toxic symptoms. Most of the pigments artificially produced or extracted
from tumors or urine are toxic for animals, but it is difficult to trace these
effects in the cachexia of the disease. The antigenic properties of choroid
pigments have been studied by Elschnig.

Orbital Melanoma. — Pigmented nevi and melanomas occur in the con-
junctiva, iris, choroid, and in the sheath of the optic nerve and surrounding
tissue. In each of these situations they present characteristic features of
origin and course, and variations in the aspect of the problem of histogenesis,
all of which have been very fully studied by ophthalmopathologists (Winter-
steiner, Lit.).

In the eye there occur processes which correspond to the cutaneous
nevus and to the malignant tumors derived from them, as well as pigment-
free tumors which are difficult to separate from the pigmented forms.

In the conjunctiva pigment spots appear at birth or later and may re-
main unchanged throughout life or become the source of malignant tumors.
Parsons describes them as of epithelial origin reproducing the picture of
cutaneous pigmented moles. There is epithelial hyperplasia, shallow ex-
tensions into the deeper tissues, and appearance of chromatophores. The
lesions may gradually extend over conjunctiva and eyelid and when incom-
pletely removed may be followed by the usual widespread dissemination
through blood-vessels. I have followed one congenital case for ten years
which gradually extended, was twice excised, and eventually became
disseminated.

In the iris Fuchs and Parsons describe brownish nodules which appear
on the pupillary margin, in the horse nearly constantly, and are said to be
derived from the pigmented epithelium. They also describe brownish
tumors of the iris which grow into the anterior chamber, and are derived
from the chromatophores of the iris. Both begin as slow benign tumors
which may become malignant.

The ciliary body is a frequent seat of melanomas, of which Groenouw
has collected 50 cases. The tumor first appears as a protuberance on the
ciliary body and extends in various characteristic forms as a flat tumor
involving a segment of the ciliary body and contiguous choroid, as a pro-
jecting mass displacing the lens, or as a diffuse growth of entire ciliary
body, the so-called ring sarcoma of Evetsky. It may infiltrate the iris
in various ways (Verhoeff), extend over the choroid throughout most of the
eyeball, or appear as discontinuous multiple foci in the choroid (Meyerhoff),

MELANOMA 861

or perforate the cornea along the ciliary vessels. The variety of histological
structure is considerable, spindle, rounded, and polyhedral cells appearing
diffusely or in alveoli, or in perithelial form, while pigment may be scanty
or absent (Rogman). An alveolar structure with pronounced epithelial
character is described by Groenouw, and appears in one of my cases. In a
very early case Derby claims to have traced the origin to the pigmented
cells of the intermuscular connective tissue.

The choroid is the most frequent site of ocular melanoma, yet the disease
is relatively rare, occurring in .58 per cent, of ophthalmic patients (Winter-
steiner). About one- third of all melanomas originate in the choroid (John-
ston). The earliest stages of the growth have seldom been observed. Fuchs
encountered several isolated elongated pigmented spots near the macula.
On section these consisted of groups of proliferating cells between the large

FIG. 420. — Flat infiltrating melanoma of choroid, with epibulbar nodule. (A. Knapp.)

vessels of the choroid and apparently from cells lining the elastic lamella.
The pigmented epithelium of retina and the choriocapillaris were normal.
Very similar tumors are described by Wintersteiner and by Purtscher.

In more developed stages the tumor takes various forms. Usually a
globular mass forms in the choroid, which displaces the basal lamella (Bauch)
and retina into the vitreous. Perforation of the basal lamella is followed by
extension along the retina. A flat growth long confined by the basal mem-
brane, on perforating this structure, grows more rapidly, producing a globular
tumor connected by a narrow pedicle with the flat base. Rarely the flat
growth in choroid is maintained until almost the entire eyeball is encircled by
a diffuse tumor (Evetsky). About the entrance of the optic nerve the tumor
may encircle the nerve, in which position early extension along the nerve must
be feared (Fehr). The intrabulbar extensions are usually by continuity.
The retina is detached, infiltrated, split up by layers of tumor-cells and de-
stroyed. Reaching the anterior chamber free cells or pigment may become
loosened and deposited on the iris or cornea or choke the canal of Schlemm
(Kamocki, Michel). The ciliary body and iris are invaded and the ciliary

862

NEOPLASTIC DISEASES

vessels may be penetrated by tumor-cells (Gutman), thus opening the way to
intravascular dissemination. The sclerotic may be perforated by the same
channels or along the optic nerve, producing a retrobulbar tumor which
extends even to the chiasm. Focal or extensive necrosis of the tumor may
result from occlusion of blood-vessels, or complete phthisis bulbi may result.
In such cases extensive arteritis has usually been found, which Evetsky
refers to toxic products derived from the disintegrating tumor. The com-
plicating sympathetic ophthalmia has been referred to the same factor.

Fuchs divides the natural history of the tumor into four stages, including
the periods before and after the onset of glaucoma, the stage of extra-ocular
growth, and that of general dissemination. Excision in the first stage has

been followed by cure in 60 to 80 per cent, of '
the cases (Stock, Hirschberg), after which the
prognosis becomes rapidly worse. Local re-
currence is rare after removal of intra-ocular
tumors. Virchow observed a local " carcino-
matous" recurrence after removal of a "sar-
comatous" primary tumor. In all stages,
especially after extension through the capsule,
metastases through the blood-vessels develop
in liver, brain, stomach, lungs, skin, lymph-
nodes, bones, and other tissues, frequency in
the order named. The dissemination may be
extremely widespread or limited to one organ,
as the liver. As with cutaneous melanoma,
the appearance of metastases may be long
delayed, and generalization may occur with
apparently insignificant primary lesions.

The structure of melanoma of the choroid
is somewhat varied, a fact which complicates
the problem of histogenesis but hardly justifies
the present confusion in nomenclature. The
tumors may be pigmented or non-pig-
mented, in the same patient, or in different
tumors of the same organ, or in different
metastases. Among the pigmented growths
Kerschbaumer has made a notable attempt
to distinguish true primary melanomas from
those with secondary hematogenous pig-
mentation. Focal accumulation of coarse
yellow pigment giving the reaction for
atrophic liver free iron, in cells of variable form dis-
tributed along blood-vessels, are characters
of hematogenous type, while diffuse dis-
tribution of fine brownish-black pigment, not yielding the hemosiderin
reaction and with cells chiefly of spindle form, belongs to the primary
pigmentation. Yet since hematogenous pigment may be diffuse and may
lose the reaction for free iron, and since hemorrhage may occur in true mela-
noma, these distinctions cannot be applied rigidly. They may perhaps serve
to eliminate certain pigmented tumors which have no relation to melanoma.
The arrangement of the tumor-cells varies. The majority of the tumors
in early stages appear superficially as large spindle-cell sarcomas, but on
careful study an alveolar arrangement of large polyhedral cells may often
be detected in small tumors. A concentric arrangement about vessels has

FIG. 422. — Metastatic melanoma
of choroid. Spindle tumor cells
growing among
cords.

MELANOMA 863

led many to employ the term perithelioma, and an extensive growth of blood-
vessels has received the designation angiosarcoma. Each of these struc-
tures has been called by some endothelioma. None of them offers any
definite indication of histogenesis. After penetrating the retina and after
passing the eyeball the tumors grow more rapidly, the cells enlarge,
pigment is less abundant and the structure soon duplicates that of melanoma
from other sources.

In the etiology of ocular melanoma, hereditary influence rarely appears,
but Silcock observed the disease in three generations. A frequent traumatic
origin has been claimed by Leber and Krahnstover, but on uncertain data.

FIG. 422. — Primary melanomatosis of cerebral pia. (After Schopper, Frank/., Z. P., 13.)

Sex is without influence. The age incidence is chiefly between 40-60 years,
but a few cases have occurred in infants (Wintersteiner).

Melanoma of Brain and Cord. — In a series of cases which now number at
least nine, primary melanoma of brain or cord has been observed (Boit, Lit.).
Beginning with the normal chromatophores which are sometimes found along
the vessels of pia and even in the brain tissue, a considerable increase of these
cells, producing definite pigment spots and streaks, has repeatedly been
observed (Obertsteiner, Rokitansky). In a notable case of Grahl's an exten-
sive skin nevus of the bathing trunk type was associated with profuse pig-
ment spots of pia mater, and Oberndorfer saw the same extensive cutaneous
nevus with symmetrical pigment spots and tumors of cerebral pia. Thorel
observed diffuse pigmentation of the pia of brain and upper cord, which

864 N EOF LA STIC DISEASES

merged into a tumor process only at the cauda. Some of the tumors have
been multiple (Virchow, Stoerk) others single (Minelli). Boit's tumor arose
from the outer side of the spinal dura, Hirschberg's developed in the sub-
stance of the lumbar cord, and Minelli's in the centrum ovale.

Although intracranial metastases of cutaneous or orbital melanoma are
frequent, in several of the above cases a careful autopsy eliminated the pos-
sibility of a primary tumor elsewhere. There is, therefore, no doubt that
primary melanoma of the central nervous system occurs and that it arises
from the pigmented cells often found along the cerebral vessels.

The origin of the cerebral chromatophores appears more difficult to
establish than in any other situation. The structure of the simple pigment
spots and areas has suggested to many that these cells are specialized peri-
thelial cells of mesodermal origin, and in this field Ribbert's views find their
best support. The structure of the tumors is that of a diffuse growth of
elongated or polyhedral heavily pigmented cells without intervening fibrils,
often sheathing blood-vessels as in perithelioma.

In a remarkable case described by Berblinger, in an infant of nine
months, multiple melanomas of the skin and neurofibromatosis were asso-
ciated with a melanotic tumor of the gyrus hippocampus, multiple pigmented
spots in various portions of the brain, glioma of pons, diffuse perithelial
sarcoma of cerebrospinal pia with secondary deposits of pigment and a
true accessory adrenal. The author's interpretation of the diffuse sarcoma
as an independent process may be questioned, since many observers have
regarded such perithelial growths as derived from perivascular chroma-
tophores. The chromatophores were very widely distributed throughout
the brain, sheathing the larger vessels, lining the endothelium of capillaries,
and forming rosettes resembling those of neuro-epithelium. The case pre-
sents a universal disease of the fetal pigment-producing function, and involv-
ing disturbances in skin, central nervous system and even the adrenal gland.

Melanoma of Intestine. — -Diffuse melanosis of the colon is not an uncom-
mon condition in elderly subjects and is generally referred to the elaboration
of blood extravasated in the mucosa. I have observed it in pernicious ane-
mia as well as in many other conditions. Its extent recalls the diffuse pig-
mentation by chromatophores in the intestinal tract of lower vertebrates.
Pigmented tumors of the rectum are relatively common in horses (Eiselt).

Melanoma of the intestine, occurring almost exclusively in the rectum,
was recognized by Virchow, has been described in isolated reports by various
observers, as Paneth, Dietrich, Tuffier, Wiener, while recently Chalier and
Bonnet have collected and fully analyzed 64 cases. They form about 2 to
3 per cent, of all melanomas.

The tumors occur chiefly in adults, but I have examined a cecal melanoma
from a child of 8 years. They arise from the anal orifice or from the rectal
ampulla, and produce circumscribed nodules or bulky masses as large as a
child's head. A polypoid form is very common, but Meurier found the
rectum encased in a cylindrical mass. I found the ileocecal orifice sur-
rounded by a lobulated tumor. The growth originates and expands within
the submucosa so that the mass is movable and only later do ulceration and
fixation supervene. Metastases in pelvic nodes, liver, and other organs are
extremely common. Only two of 64 cases were reported free after operation.

The structure presents the usual appearances of melanoma. Chalier
and Bonnet emphasize the resemblance to epidermoid carcinoma and they
derived their tumor from the anal epidermis. Yet most tumors occupy the
ampulla and some lie 5-6 cm. above the anus, necessitating an origin, if
epidermal, from a misplaced tissue rest. Most authors have been unable to

MELAXOMA 865

trace the origin, so that the observations on intestinal melanoma do not
strengthen the epithelial theory of the nature of chromatophoromas.

Melanoma of Uncertain Origin. — -In a series of fatal melanomas careful
search at autopsy has failed to demonstrate the origin of the tumor. In some
of these the presence of a large tumor of the adrenal has suggested a primary
melanoma of this organ. In Orth's case the structure of some metastases
resembled the adrenal cortex, and Neuberg, finding in them a ferment acting
on adrenalin with the production of a black pigment, suggested that disturb-
ance of adrenal function might be concerned in the pigmentation of mel-
anoma. In Davidsohn's case there were many tumors of brain and colon
and a large growth in the adrenal. Reiman found a large growth in adrenal
with small tumors elsewhere. Wieting and Hamdi described a supposed pri-
mary melanoma of gall-bladder. In Johnston's case Elser was quite unable
to fix any point of origin for a massive hepatic tumor. I have studied a large
melanoma of the spleen in which the structure presented very large poly-
hedral cells in perithelial and alveolar arrangement. There were no other
tumors in the body.

Histogenesis of Melanoma. — The extant theories of the origin of melan-
oma are as follows:

(1) Exclusively from mesoblastic chromatophores (Ribbert).

(2) Exclusively from epithelial cells and epithelial chromatophores (Post,
Wieting and Hamdi, Favera).

(3) From epithelial nevus cells in the skin, and mesoblastic chromato-
phores in choroid and meninges.

(4) From endothelial cells of blood- and lymph-vessels, or of nerve-trunks.
It is of first importance to determine the origin and function of chromato-
phores before considering their probable relation to tumors.

Origin and Function of Chromatophores. — A competent opinion regarding
the nature of chromatophores must be based on a knowledge of the color
function in the whole animal kingdom. This comprehensive point of view
will inevitably influence the interpretation of phenomena observed in man.
The comparative physiology and morphology of the color function, as pre-
sented by R. Fuchs, strongly supports the view that pigment production
belongs essentially to a specific mesoblastic cell, the chromatophore. Only
in the highly pigmented vertebrates, as the frogs and reptiles, in which the
ova are pigmented and pigment is required in unusual quantities, is there any
reasonable doubt of the mesoblastic origin of chromatophores and of the
exclusive relation of this cell to pigment production and transport. In these
animals, however, there is some evidence to show that pigment production
may overflow to epithelial cells. Yet the conditions here are not favorable
for a ready solution of the problem of pigment production by epithelium.
Even in the frog Ehrmann concluded that pigmentation is controlled exclu-
sively by the wandering chromatophores. In the higher vertebrates the
evidence swings distinctly in favor of the mesoblastic chromatophore.

In Fundulus embryos, 48 hours old without a circulation, Stockard has
watched with the binocular microscope the first appearance of pigment in
large mesoblastic wandering cells of such huge size that they can be traced
with great certainty. These cells have a notable tendency to gather along
blood-vessels and they can be readily followed in the act of depositing pig-
ment in the ectoderm. In cephalopods the migratory movements and
changes in form of the chromatophores are facilitated by muscular processes.
Many of them are provided with rich connections with sympathetic nerve
fibers (Hoffmann). In some species the chromatophores exhibit many prop-
erties of protozoa (Chun). In Amphioxus chromatophores exist only in the

866 NEOPLASTIC DISEASES

central nervous system, and in crustaceans intestinal chromatophores are the
rule. In man the prominence of the chromatophore was demonstrated by
Kolliker, and has been maintained by an unbroken line of subsequent observ-
ers. These observations establish the mesoblastic origin of the primitive
pigment cells, and they are especially significant in emphasizing certain char-
acters which reappear in human melanoma, viz., extreme motility, peculiar
relations to blood-vessels, and distribution throughout central nervous
system, choroid, and intestinal tract.

This extensive chapter of natural history must unquestionably incline the
student of tumors to regard all manifestations of melanoma in terms of the
chromatophore. If forms a strong theoretical basis for Ribbert's view of the
origin of melanoma exclusively from chromatophores.

On the other hand there has always been a considerable number of
observers, occupied chiefly with the direct study of pigment processes in man,
who have maintained the epithelial origin of the pigment. Post attributed
pigment production in mammals almost exclusively to the epithelium.
Pigmented connective-tissue cells he regarded as carrying off excess pigment
from the epithelium. Caspary and Kaposi maintained the epithelial origin
of pigments in skin and hair. It is generally agreed that chromatophores
cannot be traced in the hair follicles. The great majority of close histolog-
ical studies of nevi and early melanoma have led to the conclusion that
epidermal pigment arises in the epithelial cells (Abesser, Wieting and Hamdi,
Favera) . It must be admitted that the course of pigment production in man
is not as clearly defined as in lower mammals and that the doctrine of specific
chromatophores may not be rigidly applicable to man.

Results of the Studies of Nevi. — The minute studies of nevi by many observ-
ers have told strongly in favor of the epithelial origin of nevus cells and their
pigmented derivatives. Unna's derivation of the resting nevus cell from the
rete pegs has been verified in detail by Judalewitsch, Favera, and many
others, who have traced every stage of the passage of cell groups from the Mal-
pighian layer into the derma, where they lose their fibrils and become con-
verted into the glassy rounded nevus cells. Kromayer has further traced
these cells into fusiform cells with intercellular fibrils, a process which he
interprets as the transformation of basal epithelium into fibroblastic elements.
These intercellular fibrils Ribbert regards as an indication of a mesoblastic
origin of nevus cells which he identifies with depigmented chromatophores.
The sharp circumscription of the pigmented cells in the Malpighian layer he
interprets as the result of inwandering of superfluous chromatophores.

I believe that the histological data do nol permit a final decision between
these contending hypotheses. The histological data appear to me strongly
but not decisively in favor of the epithelial origin, while the theoretical con-
siderations are all against the epithelial theory.

Subordinating the evidence drawn from comparative morphology, the
following conception of the origin of moles and cutaneous melanoma might be
suggested. The deposit of excessive pigment by mesoblastic chromato-
phores in certain cells of the fetal epidermis excites these cells to prolifera-
tion and causes them to assume the function of pigment production, thus
producing the early congenital nevus. This process is favored by excess of
blood-vessels in the derma, and possibly by some abnormality in the innerva-
tion of the part. Chromatophores are attracted by blood-vessels and prob-
ably somewhat controlled by the nervous system, and some nevi are asso-
ciated with capillary angioma, and some appear to be in relation to peripheral
nerve-fibers.

The congenital nevus tends to regress or remain quiescent, the cells de-

MELANOMA 867

scending into the derma and losing their pigment as in the adult nevus.
Through irritation of simple traumatic, or nervous, or more complex origin,
the quiescent nevus cells may be incited to overgrowth and renewed pigment
production, developing a malignant localized tumor. The overlying epider-
mis soon participates in this tumor process, developing pigment, the presence
of which still further stimulates growth and often the extension of the tumor
process along the basal cells of previously normal rete pegs. From both
these sources actively proliferating epithelial cells/ bearing pigment and
devoid of fibrils, become disseminated by lymph- or blood-vessels. In this
scheme the part assigned to chromatophores, while initial and essential, is
subordinate. Histological appearances do not indicate that these cells are
more than camp followers during the advance of the tumor process. On the
other hand, assuming that the nevus cell is a mesoblastic chromatophore, the
tumor process becomes simply a neoplastic overgrowth of a specific cell,
while the appearances suggesting participation of rete pegs and hair follicles
must signify invasion of these structures by tumor-cells. In this dilemma
one may turn to evidence presented by melanoma in other situations.

In the eye much the same obscure histological pictures as in the skin
present themselves for interpretation. Although Wieting and Hamdi claim
that embryological studies indicate the epithelial origin of all ocular pig-
ments, yet the mesoblastic origin of the choroidal chromatophores must be
conceded. The origin of the tumors from these cells is somewhat less certain.
Leber found the retinal epithelium in active proliferation and from them he
derived the uveal melanoma. Very early melanomas have however been
traced by Fuchs, Winters teiner, and Purtscher, to the pigmented cells of
the choroid, while the retinal epithelium was intact. In the iris and ciliary
body exactly the same relations between pigment cells and epithelium are
encountered as in the skin, and here many authors have derived their
tumors from the epithelium (La Grange, Bard, Griffith, Mitrolsky, Wein-
baum, Kerschbaumer). In very early artificially depigmented ciliary
melanomas I find the usual indications of the splitting off of heavily pig-
mented basal epithelial cells.

In primary ocular melanoma spindle-cells are more prominent than
with cutaneous tumors, but in metastatic growths the structure of each type
shows identical variations. The occurrence of melanoma in the sheath of
the optic nerve is difficult to reconcile with an epithelial origin but is quite
consistent with the distribution of chromatophores.

The melanomas of the central nervous system arise from the wandering
chromatophores which are scattered over the meninges, about the vessels,
along nerve sheaths, and in the subependymal tissue. That these cells are
homologues of the mesoblastic chromatophores appearing abundantly in the
meninges of lower animals there can be no reasonable doubt. The associa-
tion of these tumors with extensive cutaneous nevi strongly indicates that in
both situations the process is identical in nature. While the melanomas of
the nervous system resemble sarcoma or perithelioma in structure, these
features are frequently seen in cutaneous tumors and their metastases. ^ »«

The series of intestinal melanomas may safely be referred to groups of
chromatophores located in the submucous tissue. Their presence recalls the
great abundance of intestinal chromatophores in crustaceans.

For the rare cases of melanoma occurring in the internal organs as in the
spleen, an origin from aberrant chromatophores is the most reasonable
assumption. Pigmented adrenal tumors belong in a special group which need
not be considered in this connection.

Thus the review of the different forms of melanoma reveals a direct con-

868 NEOPLASTIC DISEASES

flict between the histological data derived from cutaneous melanomas on the
one hand, and on the other the occurrence of melanoma in several situations
where an epithelial origin is a strained hypothesis, as well as the formidable
body of evidence presented by comparative morphology. If the epithelial
derivation of nevus cells were not so strongly supported by observation and
argument, there would no longer be any reason for delay in accepting Rib-
bert's theory, to which the author inclines. Until more light is thrown on the
nature of the supposed epithelial changes in congenital nevi, a final decision
may be withheld.

The endothelial origin of the nevus has received little new support in
recent years. The general behavior of malignant tumors arising from nevi
is strongly against their endothelial nature. No other known endothelioma
approaches melanoma in its cell forms, peculiar course, and malignancy. The
endothelial theory can best be pursued in old quiescent nevi, where it is quite
impossible to reach any conclusion regarding the origin of the cells which have
lost their original form, while their relations are disturbed by fibrosis and
atrophy. 'From the study of sections in which others have claimed to find
lymph and blood-vessels terminating in nests of nevus cells, I have been
impressed with the unsuitable nature of the material for such analysis. The
cell columns of epithelial tumors have been found canalized and filled with
blood. Where angioma is associated with nevi I find the two processes
invariably distinct.

Adrenal Melanoma. — Small brownish benign cortical tumors of the adrenal
are described by Lucksch. They occur in adults and are composed of corti-
cal cells containing pigment resembling melanin and they seem to form a
probable source of the malignant pigmented tumors of the adrenal. Not a
few of the typical adrenal carcinomas contain areas of pigmented cells of the
adrenal type.

Primary bilateral melanotic malignant tumors of the adrenal are de-
scribed by Davidsohn, Goldzieher, Tuczek, and MacLachlan. The tumors
occurred in adults, were of moderate size, and sometimes produced extensive
metastases, but primary sources in skin or choroid were missing.

The origin of the tumors it is difficult to determine. Davidsohn thought
he recognized the zona fasciculata in a mesenteric metastasis, claims to have
demonstrated adrenalin in this tissue, and derives the tumor from pigmented
adrenal cortex cells. Tuczek found the pigment a true melanin and not a
lipochrome as is found in the adrenal cortex. He derived the tumor from
the pigmented ganglion cells of the medulla, which contain melanin. Mac-
Lachlan concluded that the adrenal melanoma arises from the wandering
chromatophores which are said to exist in the loose tissue about the adrenal.
Yet the tumors seem to involve the whole organ, which long preserves its
form.

CHAPTER XLV
TUMORS OF THE THYROID

Epithelial overgrowth in the thyroid occurs in three main conditions:

(1) Simple goiter, and the benign tumors or tumor-like processes asso-
ciated with it.

(2) Graves' disease.

(3) True tumors.

These conditions are not sharply separated from each other, simple goi-
ter may assume the characters of the exophthalmic type, and true tumors
may develop in the course of either form.

The correct interpretation of hyperplastic processes in the thyroid
demands special standards dependent upon the development, structure, and
functions of this gland, and not applicable elsewhere.

In the development of the organ there is progressive centrifugal growth of
separate new vesicles from central embryonal foci which produce independent
lobules. Hence the central portions of lobules contain the older vesicles, a
relation which is specially apparent in certain fetal adenomas. The inde-
pendence of the vesicles and lobules is most clearly shown in the wide dis-
semination of thyroid acini in the fish (Gudernatsch), and of accessory thy-
roids in man. More striking evidence of unusual capacity of independent
growth is seen in the cases of structurally benign but metastasizing goiter.
Dissociated thyroid alveoli tend to grow rather than to regress, a fact demon-
strated more recently by the survival of thyroid tissue in transplants and
cultures.

A second important principle governing pathological processes in the
thyroid is the remarkable response to functional stimulus, and the wide
variations in the functional activity and structure of the gland in different
physiological states. Marked cellular hyperplasia may readily be induced
by changes in diet, and by drugs, and correspondingly reduced. The excessive
hyperplasia of severe Graves' disease, which is probably the result of func-
tional stimulus, equals that of some malignant tumors, but may promptly
regress under suitable treatment. No other gland, and only the lymphoid
tissues, exhibit such adaptations.

A third dominating factor is found in the structure of the gland. The
vascularity is enormous and subject to wide variations, owing to the great
capacity of the venous sinuses. Capillaries encircle the alveoli and the blood-
current is separated from the epithelium only by an endothelial barrier. A
basement membrane is absent in the thyroid gland, and the mobility of the
epithelium is thereby increased. The colloid secretion of the organ varies
rapidly in quantity and in composition and exerts a marked influence on the
structure of the diseased organ.

Simple Goiter. — Under this term are included self-limiting but often
bulky enlargements of the thyroid of congenital or spontaneous origin and
usually unattended by other than pressure symptoms. Two chief forms are
observed: (i) colloid and (2) parenchymatous.

(i) Colloid goiter is a very common disease of sporadic, endemic, and even
epidemic occurrence, and is commonly referred to some influence residing in

869

870

N EOF LA STIC DISEASES

drinking water. Reference to the extensive discussion of its etiology may
here be omitted (Bircher, Lit.).

The enlarged gland reaches considerable, sometimes enormous, dimen-
sions, the growth affecting single nodules, or one lobe, or the isthmus, or the

FIG. 423. — Cross-section through a simple goiter.

FIG. 424. — Cystic adenoma of thyroid. A form of encapsulated cystic goiter.

entire gland, or accessory glands in many situations. The chief accessory
goiters are substernal, intratracheal, retropharyngeal and esophageal, and
lingual (Payr, Martina, Lit. Meerwein).

TUMORS OF THE THYROID

871

On section the gland presents distended spaces filled with colloid to which
the enlargement is due, and which yields a translucent, shiny, brownish,
honeycomb appearance. Cysts of all sizes may form by fusion of adjoining
spaces, liquefaction, and hemorrhage (cystic goiter). The appearance is
greatly altered by hemorrhage, pigmentation, fatty degeneration, and by
late fibrosis and calcification. Smooth shiny areas may be produced by
hyaline changes in the stroma. Amyloid deposits in stroma and blood-
vessels may be very prominent (v. Eiselsberg). Bone deposits are often
observed in late stages (Sehrt, Heinziger, Pfister). The blood-vessels may
be overdeveloped, at times so much that the gland pulsates.

The structure of colloid goiter presents chiefly normal alveoli distended
with colloid. The lining cells are flattened, the walls of adjoining alveoli

FIG. 425. — Benign cystic adenoma of thyroid. Tissue from wall of cyst.

melt away and large spaces and cysts form. New alveoli are commonly
observed in small foci in the stroma and abundantly beneath the capsule.
Wolfler finds an increase of alveoli in all cases of colloid goiter and hence
speaks of the process as adenoma gelatinosum.

The colloid is of normal appearance, or more often soft or fluid. It may
infiltrate the stroma, collecting in lymphatics, vessels, and tissue spaces,
often in great abundance. Small capillary hemorrhages or bulky extra-
vasations are common, producing cysts and leaving pigment. Into these
hemorrhagic areas new alveoli sprout, and gradually fill with colloid as the
blood is absorbed. Fatty and hyaline degeneration, calcification and fibrosis,
regularly mark the advanced stages.

Notwithstanding the great size of colloid goiter the process lacks any

872

X EOF LAS TIC DISEASES

definite neoplastic character, and consists in a functional hyperplasia, reten-
tion of colloid, simple regenerative growth, and regressive and inflammatory
changes. Yet true tumors may arise in its course, as papillary adenomas
growing out into cysts, and the low grade interacinous adenomas. Malig-
nant tumors if they arise in colloid goiter usually develop early, but the great
majority of colloid strumas maintain their individual character for many
years. A few cases develop Graves' symptoms and structure.

Interacinous Adenoma. — In many cases of colloid goiter the overgrowth
of epithelium reaches considerable proportions, many alveoli are lined by
clusters of small round or cubical cells, many new alveoli form between the
older acini and the condition suggests a low grade of neoplastic process. Such
areas may occur in circumscribed portions of the gland and recur after
extirpation. In all cases they are of slow growth and after reaching variable
dimensions they remain stationary. The new alveoli thus formed tend to

FIG. 426. — Wall of a cystic adenoma of thyroid. Active growth of alveoli with very
small cells, and formation of cholesterin crystals in cyst contents.

develop into normal colloid-holding vesicles. Wolfler derives these focal and
diffuse overgrowths from the same superfluous cell groups which give origin
to the fetal adenoma. Interacinous adenoma is distinguished from fetal
adenoma chiefly by the more adult character of the cells, and by its occurrence
in colloid goiters.

(2) Parenchymatous goiter is less frequent but of wider significance than
the colloid form. It is congenital or acquired.

(a) Congenital Goiter.- — -In the newborn infant the thyroid may be much
enlarged, pressing upon the trachea and causing death by asphyxia. In
many instances there has been a history of chronic goiter or idiocy in the
parents (Demme). It is rather common in goitrous regions (Escherich).
The infants are often stillborn or survive only a few hours, but occasionally
there is a gradual regression and the goiter disappears after some years
(Kamann).

Wolfler divides the congenital strumas into parenchymatous, angio-

TUMORS OF THE THYROID 873

matous, cystic, and adenomatous. The anatomical condition is usually a
diffuse parenchymatous hypertrophy, with overgrowth of well-formed alveoli
lined with cells somewhat larger than in the normal fetus, and without any
collection of colloid (Demme, Fabre, Therenot). In a case of the writer's
this condition was remarkably uniform. Hewetson reports a very large goiter
in which parenchymatous hypertrophy with desquamation of cells was com-
bined with extensive development of blood-vessels. Cysts and nodular
hypertrophy are usually wanting. Simple distention of the blood-vessels in
face presentation may give a marked swelling of the fetal thyroid which
disappears in a few hours or days. The existence of a true angiomatous
condition is doubtful. Berry describes congenital circumscribed adenoma
and sarcoma, and Zahn a case of congenital osteochondrosarcoma. In a
few cases the congenital parenchymatous goiter has given origin to a very
early carcinoma (O. Ehrhardt, Lit.).

(b) Acquired parenchymatous goiter is less frequent than the colloid form,
from which it is distinguished by the prominence of new alveoli and the rela-

FIG. 427. — Circumscribed follicular adenoma of thyroid.

tive diminution of colloid. The newgrowth of alveoli is diffuse or nodular.
The diffuse type gives a uniform or focal distribution of alveoli containing
little or no colloid, intermingled with alveoli filled or distended with colloid.
The structure therefore may approach that of colloid goiter. The nodular
masses usually exhibit the structure of Wolfler's fetal adenoma.

Fetal Adenoma. — This condition appears in the form of small or large
opaque nodules in one or both lobes. They develop slowly, reach consider-
able dimensions, form nodular projections of the capsule, but eventually
become stationary. The larger tumors may reach the size of the fist, re-
placing nearly the entire lobe. They are often the seat of hemorrhage which
alters the gross appearance and structure. The structure presents numerous
small alveoli lined by low cubical epithelium, and without colloid. Or the
cells are small and round with densely staining nuclei, while a definite lumen
is wanting. The growth is centrifugal, so that the center of the nodules often
show alveoli with colloid and abundance of stroma, while on the periphery

874 NEOPLASTIC DISEASES

there are many small closely packed cell groups in scanty stroma. The
embryonal character of the cells is quite prominent, and when they become
closely packed the structure resembles sarcoma. When interstitial hemor-
rhage occurs the structure is disordered. The alveoli sprout with renewed
energy into the blood-mass, which undergoes hyaline transformation and
absorption, or it becomes mucoid and gradually replaced by newgrowth of
fetal alveoli (secondary adenoma). Small cysts may appear, into which the
epithelium grows in low papillary form (papillary fetal adenoma). The
circulation in the fetal adenoma is of the lacunar type with many pouched
blood sinuses, a structure which favors hemorrhage on moderate congestion.
Wolfler traces the fetal adenoma to somewhat ill-defined groups of
superfluous embryonal thyroid epithelium which he finds throughout the

FIG. 428. — Follicular adenoma of thyroid, with very small cells. Benign course.

organ. The existence of these cell groups is not easily demonstrated.
The diffuse colloid goiter he refers to the same sources, more diffusely dis-
tributed, and not to proliferation of adult follicles. In this latter view he is
not confirmed by the majority of observers. The fetal adenoma may give
origin to adenocarcinoma, carcinoma and, as I believe, to many so-called
sarcomas. It arises in early life, and appears as a definite tumor usually
before the twentieth year. Both colloid and parenchymatous goiter may
develop Graves' symptoms, in which case the structure assumes the peculi-
arities of exophthalmic goiter.

(c) Exophthalmic Goiter. — 'The relation of the symptoms of Graves'
disease to the structure of the thyroid gland is variable, complex and in many
respects obscure. These symptoms in mild form are rather frequently

TUMORS OF THE THYROID

875

observed in the course of simple colloid goiter, and less frequently a colloid
goiter precedes the development of progressive Graves' disease (Moebius).
In the course of relatively benign, as well as with certain malignant tumors,
Graves' symptoms may also appear (Koeber, Ehrhardt).

In the great majority of cases Graves' disease is associated with a series
of structural changes in the thyroid which signifies functional overgrowth.
While in the early stages these changes may occasionally be duplicated in
other conditions, yet in nearly all stages the changes are peculiar and taken
as a whole the series is distinctly characteristic of the disease (Greenfield,
Ewing).

•^^^••^^•b^J?- • -i2. •:• '^^^m^^^mmi^m^mmHmm
429. — Miliary adenoma of thyroid in exophthalmic goiter.

Several phases of the natural history of the exophthalmic goiter may be
traced. Not all cases pass through every stage of the disease. Some are
mild and early arrested; others are fatal at the height of cellular activity;
not a few pass a critical period and become chronic; while the remainder
pursue a very chronic course ending in glandular atrophy and myxedema.
The determining factor seems to be the intensity of the process.

Four somewhat distinct stages may be recognized in the exophthalmic
goiter.

(i) Hyperemia with increased secretion of colloid showing diminished
staining reaction with eosin. In these cases the disease is early and the
symptoms are mild.

876 NEOPLASTIC DISEASES

(2) Increased vascularity, abundance of abnormal colloid, and beginning
cellular hyperplasia. These changes are observed in established cases,
often of considerable duration and intensity. Some of them are long
preceded by simple goiter and the lesions differ from those of simple colloid
goiter in the greater vascularity, reduction of colloid, and greater cellular
activity.

(3) Varicosities of large vessels with diminished capillary circulation,
comparative or complete absence of colloid, extensive cellular hyperplasia,
and interstitial thyroiditis or fibrosis may be present.

(4) In chronic cases of long duration cellular hyperplasia is succeeded
by atrophy, arteriosclerosis, cyst formation, and calcification, and the
structure approaches that of myxedema. These cases are of long duration,
with urgent symptoms, and often fatal.

There is much variation in the structure of the gland in the advanced
disease, but the lesions regularly present the most pronounced types of
parenchymatous goiter. The follicles proliferate, forming many new alveoli
without colloid and almost diffuse cellular areas. The cells are hyper-
trophied, nuclei are hyperchromatic, and giant-cells may form. Or the out-
lines of follicles aie better preserved but the lining cells are enlarged and
appear in multiple layers often filling the lumen. Dilated spaces may appear
in which there are papillary projections of epithelium lying on thickened
septa. In a bulky thyroid of this type the cellular hyperplasia far exceeds
that of some true tumors, but the Graves' process is not neoplastic. The
chief histologicaJ distinction is the preservation of a more or less typical cell
form and orderly arrangement. The capsule, septa, lobules, and alveoli
remain intact, the course of the disease is prolonged, and the natural tend-
ency of the lesion is toward regression, atrophy, and fibrosis.

True tumors rarely develop in the Graves' thyroid. When miliary
adenomas appear their structure is at once distinguished from that of the
hyperplastic gland. When malignant tumors are associated with Graves'
symptoms it is possible that the initial hyperplasia belonging to the general
disease passes rapidly into a malignant overgrowth, which thereafter domi-
nates the clinical picture. In several cases marked Graves' symptoms
continued throughout the course of thyroid carcinoma (Ehrhardt, Lit.).
I have observed Graves' symptoms with a fetal adenoma of the thyroid
during a period in which the thyroid tumor was invaded by mammary
carcinoma.

Adenocarcinoma. Malignant Adenoma. — This tumor appears in the
form of a rather large, solid, well-encapsulated growth presenting a nodular
or lobulated texture. The lobules show a soft opaque periphery and a firmer
or fibrous central area. The red color indicates an abundant or excessive
blood-supply, and hemorrhage is frequent. Yellowish opaque or pigmented
areas represent fatty and cellular portions and the sites of hemorrhage.
On section the tumor may yield a mucinous exudate, and colloid portions may
resemble the normal thyroid. Papillary cystadenocarcinoma is a well-
defined subvariety, in which small cysts and a papillary structure may be
detected in the gross examination.

The appearance of the tumor is usually preceded by a period of slow
enlargement of the gland which may extend^ over several years.

The rate of growth is active but not often rapid, two to three years being re-
quired for the appearance of serious pressure symptoms. Local recurrence is
frequently observed, as a single tumor arising from remnants of the old, or in
the form of primary multiple nodules. Metastases are observed in some
cases but less frequently than with carcinoma.

TUMORS OF THE THYROID 877

The structure is much the same in each of the constituent lobules, which
present a peripheral cellular zone of small alveoli without definite lumina, or
cellular cords of secondary alveoli, and a central zone in which alveoli are
more adult and may contain colloid, while the stroma is more abundant. This
structure has often been interpreted as representing a centrifugal growth
from an original focus of embryonal thyroid tissue, passing through the natu-
ral course of development of the thyroid lobule. Hence the peripheral
alveoli are the youngest. There is much variation in the size of the cells,
the distinctness of alveoli and the presence of colloid, but there are always
signs of an alveolar tendency. The cells are sufficiently atypical to indicate
the presence of a true neoplasm. They are regularly larger and usually
more adult in type than the fetal adenoma, from which however, this tumor
may arise.

The stroma is usually very vascular, the vessels showing the characters
of sinusoids, a definite adventitia is often lacking, and in the usual absence
of membrana propria the tumor-cells lie on the vascular endothelium. Or
convoluted columns of tumor-cells surround thick-walled veins. A perithe-

FIG. 430. — Embryonal follicular adenocarcinoma of thyroid.

lial arrangement may be assumed and has led some observers to seek a specific
origin for these particular forms of adenocarcinoma.

In some of these very vascular tumois the alveolar structure is reduced
to a minimum or entirely lost and the tumor is composed of a network of
columns of round- or spindle-cells surrounding the blood-spaces and resem-
bling angiosarcoma. Many of these growths pulsate.

In different portions of the same tumor the structure of simple goiter, of
adenocarcinoma, and of solid carcinomatous cell masses may appear. In the
metastases the structure is usually of the more adult type and many alveoli
contain colloid. Hence this type of growth contributes some of the so-called
benign metastasizing strumas.

In rare cases the original tumors contain alveoli lined by cylindrical
cells. Some authors regard such growths as belonging in a separate class
and the very peculiar structures sometimes observed, as by Wolfler, suggests a
specific origin. Yet the thyroid cells often assume a cylindrical form, no
specific origin has been demonstrated for these growths, and it seems neces-
sary to assume that they arise from the thyroid alveoli by metaplasia.

Papillary epithelial tumors of the thyroid form a well-defined subgroup
which usually takes the form of adenocarcinoma. Yet some are relatively
simple and benign (adenoma), while others are atypical, malignant, and

878

N EOF LA STIC DISEASES

carcinomatous. They arise as single or multiple nodular tumors which fuse
in a single lobulated mass usually of moderate dimensions. They are soft in
the early stages but later there is fibrosis, thickening of stroma, and calcine
deposits. Small cysts (1-2 mm.) and a papillary structure are visible in the
gross and occasionally the cysts are of larger dimensions. In Rose' case the
cyst, contained 650 c.c. of fluid. Hinterstoisser makes a separate group of
large cystic papillary cystadenomas. The papillary tumors are usually
preceded by chronic enlargement of the thyroid and growth is relatively
slow, but the malignancy and rate of progress vary with the structure.
Local recurrence is common and probably results from the development of
new independent tumors. Barker observed five recurrences in one case.
The adenomas are slow to infiltrate capsule or nodes, while the adeno-
carcinomas recur locally, infiltrate the capsule, and generalize. A common
history is that the original tumor recurs after operation, becoming more and

FIG. 143.— Papillary adenocarcinoma of thyroid.

more malignant and eventually generalizing. Graves' symptoms are associ-
ated with many papillary adenomas.

The structure presents a complex network of vascular stroma enclosing
alveoli and small cystic cavities into which there are many papillary pro-
jections. The papillae are low and composed of epithelial buds, or higher
with connective-tissue strands, inclosing groups of epithelium and lined by
one or more layers of epithelial cells. These cells are cubical, cylindrical or
syncytial, and the cytoplasm may be clear or acidophile. The cylindrical
character is prominent and uniform in a group of cases which many authors
are inclined to separate from the others (Langhans, Kocher, Ehrhardt).
The connective tissue of the papillae may become very thick and hyaline,
while the lining cells desquamate. Colloid is scanty or absent. Calcine
granules may appear in stroma or alveoli. In three of five cases Langhans
found numerous lymph-follicles in the surrounding gland tissue.

Papillary adenoma in one of the thyroid tumors that may readily be traced
to an origin from the adult gland tissue, and the structure is throughout that
of an adult though often atypical and malignant neoplasm. In one early
case I find very numerous foci where the normal alveoli throughout a large

TUMORS OF THE THYROID 879

portion of the lobe are becoming transformed by a pronounced neoplastic
overgrowth of epithelium. In this case also there were transitions from regu-
lar adenomatous to infiltrating carcinomatous growth. In some cases
the tumor process becomes established on the hyperplastic gland of Graves7
disease, the symptoms of which long precede the appearance of a neoplasm.
A certain papillary tendency may also be observed in tumors of embryonal
type. In a series of cases papillary cystic tumors of the neck have been
traced to accessory thyroids (Madelung, Plauth, Kapsamer).

Struma postbranchialis (Getzowa). Small Alveolar, Large-Cell Adeno-
carcinoma (Langhans). — In a group of thyroid tumors, which in other respects
do not differ from malignant adenocarcinoma, the highly specific structure
suggests a peculiar origin. These tumors are composed of relatively small
well-formed alveoli lined by one or more layers of very irregular cells. Some
are clear, cuboidal, or cylindrical, or irregularly polyhedral. Others are
large, sometimes of giant size, finely granular, eosinophile and opaque, and
resemble granular adrenal or liver-cells. The nuclei are small, vesicular,
with visible nucleoli. In some alveoli the cells are twisted about one another
with concave and convex borders, or separated by clefts, and occasionally
syncytial masses appear. Rather numerous globules of colloid are usually
present, and the original structure reappears in metastases. The cells
contain neither fat nor glycogen.

Langhans considers the possibility of the origin of these tumors from
parathyroid or carotid gland, but concludes that they arise from certain
cell groups in the thyroid, identified by Getzowa as remnants of the lateral
thyroid anlage (post-branchial body) . I have examined two tumors answer-
ing this description and suggesting that the acidophile cells might represent
hypertrophic Hurthle's cells of the thyroid alveoli.

Carcinoma. — The separation between adenocarcinoma and carcinoma of
the thyroid is very imperfect and many transitional tumors are observed.
Langhans finds that the great majority of tumors which he would class as
carcinoma still show a tendency to produce alveoli which sometimes contain
colloid. The same tendency appears in many of Wolfler's carcinomas.
Aside from these pure carcinomatous growths which produce solid groups
of atypical infiltrating cells, the class of thyroid carcinoma must take account
of the gross anatomical characters, such as infiltration of stroma, capsule,
and blood-vessels, invasion of neighboring tissues and lymph-nodes, as well
as the formation of local and distant metastases.

Thyroid carcinoma is a disease of advanced life, 50 to 60 years, but
has been observed between 10 and 90 years. Berry described a round-cell
sarcoma in a boy of 3 years and Demme a carcinoma in a boy of 5 years.
This tumor is slightly more frequent in females than in males (85 to 65,
Ehrhardt). Three cases were imputed to trauma (Braun, Cornil, Suskind).
Not a few are attributed to or aggravated by gestation. Most cases arise in
goitrous glands, Ehrhardt finding this history in 104 of 200 cases, the goiter
dating from i to 50 years.

The average duration is about two years. Very acute and usually febrile
courses are occasionally seen (Braun, Hochstetter, Karst). I have observed
two such cases in young women. The structure was alveolar or diffuse,
with local and general metastases. Adenocarcinoma progresses more slowly,
v. Eiselsberg recording a duration of eight years. Papillary and cystic adeno-
carcinomas are even more prolonged, as in Wolfler's case (18 years) and
Smoler's (27 years).

In the gross thyroid carcinoma produces a single, firm, opaque, encap-
sulated tumor mass which grows steadily until it invades capsule, gland,

880 N EOF LA STIC DISEASES

and surrounding tissues. A multicentric origin in five separate nodules is
described by Langhans and is probably not infrequent. Or the growth may
begin as a diffuse infiltration, of which Hinterstoisser has collected 17 cases.
Friedland describes carcinoma without enlargement of the gland. Most
carcinomas grow to considerable size and yield symptoms from pressure,
local invasion, and metastasis. Occasionally the original tumor remains
small while metastases develop, and in a few cases the thyroid tumor has
been overlooked and a metastatic tumor in bone or lungs has first attracted
attention. The trachea is displaced, constricted, or flattened. Billroth's
scirrhus cancer encircled this organ like a band. The wall becomes in-
filtrated, or perforated, and polypoid masses may appear in the lumen or
fill a bronchus (Herb, Semon). A diffuse carcinomatous lymphangitis of the
tracheal mucosa is described by Mermet and Lecour. Beneath the obstruct-
ing growth the bronchi may be dilated, and some have assumed that pul-
monary metastasis may arise from inspired particles. The esophagus
suffers in much the same manner as the trachea. The blood-vessels are
early invaded by malignant as well as by some histologically benign tumors.

FIG. 432. — Solid carcinoma of thyroid.

The thyroid veins may contain tumor thrombi and in Ehrhardt's case the
thrombus extended to the jugular and the innominate.

Invasion along the vessel sheaths extends further, to the base of the
skull, to the axilla, and to the heart. The recurrent laryngeal nerve is
frequently compressed or infiltrated, the vagus and sympathetic less often.
Thus of 34 malignant tumors Meyer noted laryngeal paralysis in 20. Direct
invasion of muscles of neck, cervical spine, mediastinum and lungs are
commonly observed.

Metastases pass chiefly through the blood-vessels (47 cases), by lymph-
paths ( 1 6), or by both channels. Metastases were absent in 14 of 94 cases.
The organs in 238 cases of carcinoma and sarcoma were affected as follows:
lungs 129 cases; bones 66; liver 36; kidneys 20; pleura 16; brain 12; other
organs 13 (Ehrhardt).

The main lymphatics of the thyroid are: (i) the deep jugular plexus,
which drains the organ laterally and continues downward in the inferior
cervical nodes into mediastinum; (2) posterior trunks which run between
trachea and esophagus; (3) superior vessels leading to submaxillary and
lingual nodes; and (4) inferior vessels leading directly to the mediastinal
nodes. The blood-vessels first invaded are the main thyroid veins.

The pulmonary tumors are large or small and disseminated. The
bronchi may be surrounded and perforated by polypoid masses. Hemor-

TUMORS OF THE THYROID 881

rhage is early excited in the pulmonary parenchyma and hemoptysis is a
frequent result.

The bones are involved only less frequently than with mammary and
prostatic cancer, and in the following order: skull, sternum, spine, ribs,
humerus, femur, and pelvis. The metastatic growths appear at epiphyses
or along sutures, and produce large encapsulated tumors or diffuse central
or periosteal infiltrations. The process may be osteoplastic and the fractures
occurring may heal (v. Eiselsberg). The claim that bone metastases may
appear at points of hemorrhage following trauma, must be received with
caution (Ehrhardt, Lit.)- Pulsating bone tumors have in several instances
been identified as metastatic thyroid growths (Coats, Feurer, Middledorpf,
Morris). Swelling of such a tumor was interpreted by v. Eiselsberg as a
menstrual phenomenon. Retrosternal pulsating tumors were regarded as
aneurisms and treated by appropriate arterial ligatures, by Cramer, Langen-
beck and Sheen. Solitary benign bone metastases have been observed by v.
Eiselsberg and others. Here a thyroid adenocarcinoma produces a single
benign metastasis (sternum), which may be successfully extirpated although
the patient dies with later metastases in other organs. Ehrhardt shows that
many reputed cases of this type exhibit multiple bone metastases. In either
case the surgical procedure is of little avail.

Comparing the structure of primary and secondary thyroid tumors
Jaeger finds the following relations: (i) both are benign; (2) primary
tumor malignant, secondary benign; (3) primary tumor benign, secondary
malignant; (4) both malignant.

That many metastatic thyroid tumors functionate is indicated by
the presence of colloid and has been proven experimentally by v. Eiselsberg.
His patient suffered from tetany after extirpation of a large carcinomatous
thyroid but was gradually relieved upon the appearance of an adenomatous
tumor in the sternum, after the lemoval of which the tetany reappeared.
The influence of the parathyroids seems to have been ignored in the numerous
citations of this case. The presence of iodine in metastatic adenocarcinoma,
demonstrated by K. Ewald, is a further indication of functional activity, and
since the original tumor was free from iodin the result indicates a partial
restoration of function in the metastases.

Metastasizing Colloid Goiter. — That a simple colloid goiter, presenting a
structure that usually remains harmless for years, may give rise to metastatic
tumors of benign or malignant type is one of the striking anomalies of the
pathological thyroid. Such a case was first described by Cohnheim whc
found the structure of colloid goiter in both primary and secondary tumors.
The lobes of the thyroid were uniformly enlarged and presented the ap-
pearance of simple goiter, while in the left lobe were three large nodules
of ordinary gelatinous adenoma, one of which had penetrated the lumen of
the inferior thyroid artery. Extensive metastatic tumors were found in
bronchial nodes, lungs, femur, and lumbar spine. All of these tumors gave
the typical alveolar structure of thyroid tissue, and only in a very few cell
groups was a lumen with colloid absent. Other somewhat similar cases
are reported by Runge, Coats, Middledorpf, Feurer, Langhans, Honsell,
Deraun, A. Meyer.

Langhans found several opaque gelatinous nodules in the thyroids,
but no trace of invasion of veins. Hence he considers that the extension
occurred through the lymphatics. While none of the observers admits the
existence of suspicious actively proliferating areas in the original tumor,
they usually describe areas containing a few solid cell groups. It is evident
that the growth capacity of the cells in colloid goiter is greater than its

882

NEOPLASTIC DISEASES

clinical course indicates. Possibly an accidental access to the blood or
lymph-stream may release the cells from mechanical restraint and permit
them to exhibit malignant qualities in more favorable situations. In Litten's
case the metastases showed both colloid struma and carcinoma, and Hof-
mann's metastases were adenocarcinomatous. In a case of Jeffries' I found
in the dural growth the normal regularity of alveoli with colloid, but the
cells were large and nuclei hyperchromatic. In Middledorpfs case the
original " adenoma" had perforated a partly calcined capsule and the wall of

FlG. 433. — X-ray photograph of lungs showing multiple metastases in benign metas-
tasizing thyroid struma (adenocarcinoma).

ajvein. The natural tendency of the metastatic thyroid cells to develop
into normal thyroid tissue may progressively alter the structure of a second-
ary growth, so that an original carcinomatous area may eventually appear
adenomatous. This principle, first stated by Eberth, is occasionally
illustrated.

Metastases from the Normal Thyroid. — In a few instances tumors of
thyroid tissue have developed under circumstances which suggested an origin

TUMORS OF THE THYROID 883

from aberrant cells from the normal thyroid. Riedel removed a tumor of
the inferior maxilla composed of normal thyroid tissue, which recurred locally
after 10 years. The thyroid gland is said to have remained normal through-
out this period of observation.

Oderfeld and Steinhaus excised a perforating tumor of the skull, composed
of normal thyroid tissue. There was no enlargement of the thyroid 01 of
any accessory gland. Jeffries reported a parietal subdural tumor composed
of somewhat embryonal thyroid tissue, in a subject whose thyroid appeared
to be entirely normal.

In explanation of these cases it seems necessary to assume an origin
either from aberrant thyroid tissue or from dislodged cells from the normal
thyroid. Yet in none of the cases has the supposed normal thyroid been
submitted to microscopical examination. In Becker's case, a supraclavicular
tumor probably represented an aberrant thyroid.

FIG. 434. — Tumor of aberrant thyroid tissue in cerebral dura. So-called benign metas-
tasizing struma. (Specimen of Dr. Jeffries' .)

The structure of thyroid carcinoma presents an alveolar type with large
or small groups of atypical cells and nearly constant absence of colloid.

In some cases the structure approaches that of adenocarcinoma but the
alveoli are closely packed with hyperchromatic cells, and invasive tendencies
are pronounced. Langhans (his Fig. 20) classes as carcinoma a tumor con-
taining many colloid deposits in irregular masses of atypical cells. Wolfler
(his Fig. 48) describes as carcinoma a tumor composed chiefly of very small
groups, apparently alveoli, of large atypical cells. Such tumors seem to
belong among adenocarcinomas. In more typical cases the cell groups are
compact without a trace of colloid, and little or no evidence of formation
of alveoli. Considerable areas of diffuse cell-growth may appear and here
the cells may be small with very hyperchromatic nuclei, or fusiform resem-
bling sarcoma.

Scirrhus carcinoma, first described by Billroth as a ring-shaped growth

884 N EOF LA STIC DISEASES

surrounding the trachea, has been reported by later observers, and is not
infrequently found in portions of slowly growing and very hard tumors.

In the typical scirrhus the gland may not be enlarged but is extremely
hard, resembling cicatricial tissue. The groups of tumor-cells are small,
scanty, and limited chiefly to the peripheral portions. The exact nature
of some of the cases described as scirrhus appears uncertain (Ehrhardt, Lit.).
Other regressive changes are also observed, as fatty degeneration, cyst
formation, necrosis, and calcification. Glycogen is scanty or absent in most
carcinomas but abundant in parathyroid struma. It is probable also that
bone may form in the central areas of old carcinomas, and when the epithelial
cells are incorporated in fibrous tissue osteosarcoma may be simulated.

Histogenesis. — The question of the histogenesis of thyroid carcinoma is
involved with that of all other thyroid growths. Wolfler and Langhans
assume that all the ordinary epithelial tumors arise, not from the adult
vesicles but from cell groups which remain embryonal through disorders of
development and later give origin to fetal adenoma, gelatinous adenoma or
colloid goiter, adenocarcinoma and carcinoma. Yet neither the existence
of these embryonal cells nor their participation in many tumor processes
have been studied in sufficient detail to extend their significance over
such a broad field. Only the fetal adenoma can be certainly referred to
embryonal cell groups.

On the other hand Virchow, Ehrhardt, and others have found satis-
factory evidence that many adenomas, adenocarinomas, and carcinomas
arise from the adult follicles. Ehrhart pictures very early focal hyper-
plasia of follicular cells in carcinoma. I have seen such focal areas espe-
cially in papillary adenocarcinoma. This view accords with the usual
clinical history, which indicates that a long period of benign overgrowth
precedes the malignant tumor.

There are many indications that tumors of the thyroid, as in many
other organs, fall into two groups, embryonal and adult, and that each
variety includes forms of adenoma and carcinoma. Some atypical, usually
rapidly growing tumors, described as sarcoma, appear to find their true
explanation in an embryonal epithelial origin.

Squamous-cell epithelioma in the thyroid has been observed in a series
of cases and pursues the usual course of destructive acanthoma. It arises
not from branchial remnants but from the thyroglossal duct and its pyra-
midal process (Langhans). Secondary acanthoma from esophagus, larynx,
and branchiogenic cysts is frequently observed.

Sarcoma of Thyroid. — Tumors interpreted as sarcoma are almost as
frequent in the thyroid as carcinoma. Thus Ehrhardt collected 150 carci-
nomas with 99 sarcomas. Ewald states that the proportions are about 3 or 4
carcinomas to i sarcoma. In goitrous regions they are said to be very
common. Kocher states that the thyroid is one of the chief seats of "acute"
sarcoma.

The general etiology is identical with that of carcinoma. Sarcoma
occurs chiefly after 40 years, about equally in both sexes. An hereditary
tendency and a history of previous goiter is very common. The rapid course
of thyroid sarcoma is its chief distinguishing feature. Morf found the
shortest duration four weeks, the longest 17 months.

The gross anatomy fails to show any definite variations from carcinoma.
The tumors are large, circumscribed or diffuse, locally aggressive, invading
lymph-nodes and veins, and producing distant metastases, with or without
affection of the nodes.

The histological varieties are numerous. Of 40 cases analyzed by Morf

TUMORS OF THE THYROID 885

the distribution was: round-cell 10, spindle 6, mixed 7, alveolar 5, fibrous 3,
osteoid 2, etc. Giant-cells are prominent in some tumors. Lymphosar-
comas are described by Braun and Ehrhardt.

Notwithstanding the wide acceptance of numerous reported cases as
sarcoma of the thyroid, there is a strong reason for believing that the great
majority of these tumors are of epithelial origin. It is clear that the diagnosis
of sarcoma has usually been accepted on the most superficial resemblance
to a mesoblastic tumor, and without any effort to critically interpret the
structure and origin. Hence many authors have recognized the uncertain
standing of thyroid sarcoma, but dismissed the matter by stating that there is
no sharp dividing line between carcinoma and sarcoma. The close resem-
blance of the general etiology, clinical course, and gross anatomy of the two
conditions fully bears out this conclusion. There remain only histological
distinctions, but when these are examined in detail they fail to establish the
frequent occurrence of malignant mesoblastic tumors of the thyroid.

?IG. 435. — Spindle-cell area in thy:

Of the reported cases many showed an alveolar structure which is strongly
indicative of an epithelial origin (Forster, Newmann, Braun). Wolfler's
alveolar sarcomas (his Figs. 62, 63) are indistinguishable from small alveolar
or highly vascular embryonal carcinoma. C. Kaufmann based his diagnosis
of a round-cell sarcoma on a minute histological study, but his tumor was
alveolar, a striking resemblance to carcinoma was noted in some cases, his
drawing shows a typical adenocarcinoma with the common infiltration of
stroma by large polyhedral cells, and the intimate relation of blood-vessels
to tumor-cells, on which he lays chief stress, is characteristic of thyroid
carcinoma. He also describes carcinoma and spindle-cell sarcoma in
adjoining portions of the same tumor. Limacher traces in great detail the
origin of a typical fibiocarcinoma to the endothelial cells of blood-vessels.
Ehrhardt mentions the great difficulty of distinguishing many reported cases
of fibrosarcoma from scirrhus. Some osteosarcomas appear to represent bone
formation in old fibrous strumas. Pick's osteosarcoma was probably second-
ary to a growth in the maxilla, and Ehrhardt concluded that his case was sec-

886 N EOF LA STIC DISEASES

ondary to a tumor in the femur. Fraenkel 's melanosarcoma showed cutaneous
moles. Braun's lymphosarcoma presents none of the distinguishing features
of this disease.

My own material, which includes Lartigau's case, illustrates so fully
the transformation of thyroid epithelium into spindle-, round-, and giant-
cells, producing a structure resembling sarcoma, as to lead to the conclusion
that the mesoblastic origin of most of the sarcomas reported in the literature
is highly improbable, and that the occurrence of true sarcoma in man still
requires demonstration.

Tumors of the Parathyroid. — Hyperplasia of the parathyroids has been
found in a considerable number of cases of osteomalacia, osteoporosis, and
rickets, and has been interpreted as an indication of hyperfunction with
disturbance in calcium metabolism (Harbitz, Lit.). In several cases the
hyperplasia has been regarded as adenomatous.

The recognition of extrathyroid tumors of parathyroid origin may
be accomplished with sufficient certainty, but in the case of intrathyroid
growths it is difficult to establish a parathyroid origin unless the tumor pre-
sents very definite structural peculiarities. There is thus ground for the

FIG. 436. — Symmetrical tumors of para- FIG. 437. — Adenoma of parathyroid gland

thyroid glands. (After Harbitz.) in osteomalacia. (After Harbitz.)

doubt, expressed by Harbitz, regarding the nature of certain intrathyroid
tumors referred by various authors to the parathyroid.

The peculiar structure and rich glycogen content of certain thyroid
tumors was interpreted by Kocher, Jr., in 1899, as evidence of a parathyroid
origin. Very similar but smaller extrathyroid growths were later recognized
as of parathyroid origin, by Benjamins, Erdheim, and MacCallum. The
occurrence of aberrant parathyroid tissue in the thyroid (Getzowa, Erdheim)
accounts for the presence of these growths within the confines of the organ.

The parathyroid struma produces an encapsulated tumor involving
a part or the whole of one side, or appearing as a separate mass at the lower
pole of the thyroid. The extrathyroid tumors are small and adenomatous
(Erdheim, MacCallum), or large and malignant (Benjamins). Within the
thyroid they produce firm, nodular, adherent, rapidly growing and malignant
tumors, with pain, dyspnea, invasion of nodes and metastases (Kocher,
Sr.). Small cysts may form from dilated ducts.

The structure recalls that of the parathyroid and presents chiefly compact
columns of opaque epithelium often arranged in palisade foim. There is

TUMORS OF THE THYROID

887

much variation in the size and appearance of these columns. In one of my
cases they vary from very thin strands to large alveoli, bordered by palisade
cells and filled with large cuboidal cells. These areas are very vascular,
especially when the cell columns are small, and the vessels are very thin-
walled sinuses. Areas of very large clear cells with dense cell borders and
cytoplasm rich in glycogen, recalling the structure of hypernephroma are a
second characteristic feature. Occasionally there are canals lined with
cylindrical epithelium, which Langhans derives from the embryonal tubules
traced by Kursteiner from the parathyroid to the thymus. Groups of
strongly acidophile cells may also be present. The cell columns are not
always intact but there is a strong tendency in rapidly gi owing tumors
toward a diffuse growth of small round or spindle or giant-cells, producing
a pseudosarcoma. Such a structure is described by Langhans, and appears
in one of my cases. In the smaller tumors the structure is more regular and
adenomatous, and in MacCallum's case the question arose whether the
process was a simple hypertrophy or a neoplasm. Hulst's small tumor lay in
a calcified capsule. In several cases there were present droplets of colloid,

FIG. 438. — -Detail of adenoma of parathyroid. (After Erdheim.}

or definite alveoli filled with colloid or mucin, and these tumors may be
separated with difficulty from thyroid growths.

Cysts of Thyroid and Parathyroid. — The middle lobe of the thyroid is
developed from an invagination of the buccal epithelium, just behind the
tuberculum impar, which marks the junction of the second and third branchial
clefts and goes to form the anterior portion of the tongue. Behind this
invagination later rises a fold formed by the second and third branchial
arches, which goes to form the base of the tongue. The thyroid invagination
(thyroglossal duct) passes down in front of the hyoid bone and its lower
portion gives origin to the middle lobe of the thyroid. The upper end may
remain patent, opens at the foramen cecum, and is lined by pavement cells.
The middle portion usually atrophies but may persist as a canal lined by
ciliated epithelium. Bochdalek found many salivary gland acini opening
by lateral ducts into this canal (Bochdalek's duct or gland). Secretion in
the upper portion of this canal (lingual duct), is readily discharged through
the foramen cecum, but in the deeper portions (thyroid duct) secretion is
retained and gives rise to median cysts lined by squamous or cylindrical
cells and often containing thyroid follicles in the wall (Konig). Cysts
lined by ciliated epithelium, lying in the middle line between the base of the
epiglottis and the upper border of the hyoid bone, have been traced to dila-
tation of the ducts of Bochdalek's gland opening into the lingual duct

888 N EOF LAST 1C DISEASES

(Schmidt). Some of these cysts lie at or below the hyoid bone and are single
or multilocular, with a lining of squamous or ciliated cells, and mucinous
contents (Streckeisen). Others may appear in the floor of the mouth as
forms of ranula (Neumann).

Accessory thyroid gland tissue may be found along the entire length of
the thyroglossal duct, and according to their position have been termed
supra-, pre-, and intrahyoid. The uppermost glands are very prone to
hypertrophy at puberty and produce tumors presenting at the foramen cecum.
In two cases extirpation of these tumors was followed by myxedema, showing
that the lingual thyroid was the only portion of the gland which developed
(Seldowitsch, Chamisso).

In cases of thyroid aplasia in cretins, or of unilateral aplasia of adults,
small multilocular cystic tumors regularly appear in the region of the lingual
duct. The cysts are lined by squamous or ciliated cells and remnants of
the aplastic thyroid are found in the walls (Eidheim, Lit.).

As with the median lobe, so the lateral thyroid lobes develop from invagi-
nations of entodermal epithelium. These divide into a dorsal portion,
giving origin to the parathyroids and a ventral or thyroid portion. Either
of these ducts may persist and yield cysts in thyroid or parathyroid, or
separate ducts from third and fourth buccal pouches lead to the lower and
upper parathyroids, as well as to various accessory parathyroids, of which
Erdheim has found as many as eight. In cases of unilateral thyroid aplasia
Erdheim finds normal parathyroids and a cyst with tubular glands repre-
senting the atrophic lateral thyroid.

CHAPTER XLVI
THE THYMUS AND ITS TUMORS

No group of tumors has more successfully resisted attempts at inter-
pretation and classification than those of the thymus. The problems in-
volved include those which have complicated the embryological and histo-
logical study of the gland, while added difficulties arise from the comparative
rarity and considerable diversity of the tumors, and from the somewhat
imperfect knowledge of the general pathology of the thymus.

A short resume of the knowledge of the origin and structure of the gland
will facilitate the interpretation of its tumors (Hammar, Lit.).

Anatomy. — The thymus is a paired organ arising from evaginations of
the third branchial clefts (Thymus III). Its anlage is contiguous with that

Tm.3

FIG. 439. — Scheme of derivatives of branchial clefts in the human embryo. (After Sobotta.)
Tr, thyroid; e, parathyroids; Tm, thymus; p, postbranchial body.

of the parathyroids, arising from the same clefts, a relation which explains
the occasional presence of parathyroid alveoli in the thymus, as well as the
rare association of thymus tissue with parathyroid in the thyroid gland. A
second portion of the thymus arises from the fourth cleft, where it holds the
same relation to the parathyroids developed from this cleft (Thymus IV).
From these four sources the growing entodermal epithelium coalesces to
form a four-lobed fetal organ which, with the descent of the heart, becomes
drawn out in an elongated double-pear shape. In Hammar's early fetal
models the stems stretch from the lateral lobes of the thyroid down below the
sternal notch where the main mass of the gland develops, the stems disappear-
ing. This mode of origin only partly explains the occurrence of accessory
thymus lobes beside and below the thyroid (Erdheim), and laterally in the
neck. Sharp describes a large accessory thymus extending from the anterior
border of the trapezius behind sternomastoid and clavicle.

889

890

N EOF LA STIC DISEASES

The fully developed organ consists of a stroma and reticulum, paren-
chyma, and capsule. The supporting stroma is chiefly found in the net-
work of arterioles, capillaries, and venules, to which is confined practically
all of the connective tissue within the organ.

The finer stroma is a derivative of the original epithelium of the gland,
which becomes elongated into a fine reticulum in the meshes of which lie
the parenchyma cells. This reticulum has nodal thickenings or syncytia,
or may be stretched into fine fibrils. By accumulation of its cells in the
medulla are formed concentric groups of flat-cells (Hassall's corpuscles),
with which the reticulum is directly continuous, while on the periphery in
many fetal glands the epithelium appears in groups and cords in cubical or
cylindrical form. Hassall's corpuscles are therefore not remnants of embryo-

.•^

FIG. 440. — Structure of thymus of human embryo of 70 mm. Coarse epithelial reticulum,
beginning infiltration by lymphocytes. (Hammar.)

nal epithelium but collections of adult reticulum cells. In the medulla the
reticulum is far more abundant than in the cortex.

The parenchyma cells have the appearance of very small lymphocytes,
from which they have not been successfully distinguished by many studies
directed to their morphology, microchemical reactions, serological relations,
or behavior in most pathological conditions.

Their origin is as yet undetermined. In favor of the view that they
are epithelial derivatives, as claimed by Beard, Stohr and others, the following
facts may be cited: (i) The occurrence of transition forms between the
reticulum cells and the lymphocytes (Prenant, Bell). Yet Maximow is able
to distinguish between the small darkly staining epithelium and the lympho-
cytes. (2) The very early appearance of lymphocytes in the thymus.
(3) The apparent absence of any signs of infiltration by lymphocytes from
without. (4) The apparent transformation of small thymus cells into
epithelium. Against the epithelial origin stand chiefly the evident identity
of the cells with other lymphocytes, the development of other lymphoid
organs by the inwandering of lymphocytes, and the behavior of these cells
in pathological conditions. Most observers, including Maximow, Hammar,

THE THYMUS AND ITS TUMORS 891

and Wiesel, consider the thymus an organ with peculiar reticulum of epithelial
origin infiltrated by lymphocytes. Yet the organ never assumes, either in
structure or functions, the position of a simple lymphoid organ. In many
conditions it fails to participate with other lymphoid organs in systemic
diseases (Hart).

In addition to the lymphocytes other cells are often seen in the thymus.
Shaeffer observed many plasma-cells derived from the lymphocytes in the
involuting gland, and with these may occur eosinophile cells and mast
cells (Maximow). Watney describes giant phagocytes. Myoid cells with
cross striation are scanty but very constant derivatives of the epithelium.
Wasutoschkin however considers that they are derived from the muscle-cells
in the capsule. The formation of red cells appears to be limited to lower
animals, but evidences of the formation of leukocytes are frequently observed
in man. The efforts to establish the thymus as a gland of internal secretion
and a unit in the chromaffine system are reviewed by Wiesel.

General Pathology. — A horn of thymus tissue reaches upward to the
thyroid gland in 20 per cent, of young subjects (Rieffel), and strands of thymus
tissue may encircle the great vessels of the neck and the vagus nerve at the
level of the hyoid bone in the infant (Harman, Bien). Accessory lobes appear
occasionally in the thyroid and in connection with the parathyroids.

The weight of the thymus at birth varies greatly, from 2 to 14 gins,
but averages 7.7 gms. (Bovaird and Nicoll). It increases in size at least
to the fifteenth year, when the average weight is from 20-28 gms. (v. Sury,
Ronconi). It then steadily diminishes but persists in most subjects through-
out life. Its proportion to the body weight is highest at birth, 0.42 per cent.,
but after 25 years the permanent ratio of 0.3 per cent, is reached. Owing to
numerous accidental variations it is extremely difficult to establish the exist-
ence of hypertrophy unless of very marked degree. Involution takes the
foim chiefly of fat invasion of the parenchyma, with persistence of many
Hassall's corpuscles.

Simple hypertrophy of the thymus occurs in infants, in which the enlarged
gland exerts at least in part a mechanical effect in fatal thymic asthma by
compression of the trachea. The structure of these glands is usually normal.
In status lymphaticus the thymus usually exceeds the normal weight for
the age and weight of the patient, and at times the excess is very marked.
In Graves' disease thymus hypertrophy is nearly constant and often marked.
In all of these conditions the hypertrophy is due to lymphocytic hyper-
plasia, and does not reach the grade of a neoplasm. In aberrant thymus
tissue the hyperplasia has at times been very active, as in Sharp's lymphade-
noma of a cervical thymus. Hyperplasias interpreted as lymphadenomas
are described by Rolleston, Edmunds and McKenzie, Pepper and Stengel, and
Hektoen. In these cases the organ was several times the normal size, the
capsule was intact, the medulla largely obliterated, and Hassall's corpuscles
widely scattered.' Tarozzi describes as simple hyperplasia a veiy large en-
capsulated tumor occupying all the anterior mediastinum in a boy of 18
years.

Proliferation or, more correctly, increase in number of Hassall's corpuscles
occurs in Graves' disease i^Soupault) and in hemophilia (Acland). Exfolia-
tion of very numerous large reticulum cells in the involuting thymus has
been described by Lochte in gangrenous gingivitis and in leukemia. Hahn
and Thomas collected several cases of thymic tuberculosis. It is a notable
fact that in most cases of leukemia and pseudoleukemia the thymus fails to
participate in the process. In a series of such cases Schridde found no
thymic enlargement. Yet a leukemic blood pictuie has been observed in a
series of large sarcomatous tumors of the thymus (Fabian). In a case of

892

N EOF LA STIC DISEASES

Coenen's, with leukemic blood, it was difficult to determine whether the
thymic lesion was leukemic or granulomatous.

Cysts form in the thymus fiom several sources (Pigache, Beclere, Heuter,
Lit).

(i) The epithelial canals of the embryonal thymus may persist and form
one or several small or large cysts in or along the horns of the gland. They
are especially frequent in syphilitic infants. Each lobe of the organ may
be converted into a large cyst (Bednar). Pollosson and Piery describe a
congenital multilocular cyst of a cervical thymus, extending from behind the
sternum to the midcarotid region. It was lined by flat pavement cells.
In a sclerosed and luetic thymus in a man of 25 years Hueter found general
cystic alterations. The cysts were lined by flattened cells, filled with mucoid
and lipoid material, and into many of them grew polypoid masses of thymus
tissue. The origin was attributed to persistent epithelial cell groups.

FIG. 441. — Ciliated epithelial cyst in thymus of human embryo of 70 mm. (Hammar.)

Westernak recognized a mediastinal cyst, lined by ciliated epithelium, by
means of thymus tissue in the wall, and he attributed its origin to the thymus
duct. The demonstration of lymphoid tissue and Hassan's corpuscles in
the wall aided Funke in the recognition of a thymus cyst in the thyroid.
In Graves' disease Soupault describes multiple cysts lined by columnar
epithelium. In a man of 69 yeais, he found a thymus 15 cm. in length,
hyperplastic above, but in the lower half diffuse overgrowth of epithelial
cells, and small cysts filled with mucus.

(2) Dermoid cysts, of which Hare has collected nine cases, may arise
from portions of the ventral ectoderm, or from the branchial clefts. Rolles-
ton describes a compound cyst with adenomatous structures resembling
Lieberkiihn's follicles and areas of cartilage and sarcoma.

(3) Invasion and distention of HassalFs corpuscles by lymphocytes is
of common occurrence and many small cysts may form throughout the gland

THE THYMUS AND ITS TUMORS

893

by degeneration of these wandering cells. Chiari showed that Dubois'
abscesses consist of distended corpuscles filled with lymphocytes. The lining
of these corpuscle cysts is of cubical 01 flat epithelium. All these cysts
are regarded by Ribbert as derived from persistent embiyonal tubules.

(4) Cystic lymphangioma is described by Seidel in an infant of 2% years.
The entire organ was the seat of many small cysts filled with bloody fluid
and lined by flat endothelial cells.

PRIMARY TUMORS OF THE THYMUS

Primary tumois of the thymus aie probably not as raie as the scanty
reports would indicate. Rubaschow collected 69 cases, but questioned the
thymic origin of many. The age of incidence of 33 sai comas was: before

FIG. 442. — Anterior view of a large thymoma. The tumor covers the pericardium, sur-
rounds the bronchi and great vessels, and extends slightly to pleura and lung.

25 years, 18 cases; from 25 to 40 years, 8 cases; over 40 years, 7 cases. Carci-
nomas occur in latei yeais and usually aftei 50. Steudener found a laige
lymphosarcoma in an infant of one year. While Virchow believed that
thymic hypertrophy led to tumor growth, Bartel's statistics do not show that
cases of status lymphaticus are especially prone to develop thymic tumors.
Eisenstadt's case gave a history of trauma. The age of incidence and the
usual course of involution strongly suggest that thymic carcinoma is affected
by disturbances in the natural process of involution. The origin of the sar-
comas seems closely connected with that of lymphosarcoma in general, and not
a few of these cases show marked resemblances to, or a practical identity with,
granuloma malignum. Analogy suggests that the peculiar reticulum cells of

894

N EOF LA STIC DISEASES

the thymus may at times respond to infection by inflammatory and eventually
neoplastic overgrowth.

Classification.- — Thymic tumors fall into two main groups.

(1) Lymphosarcoma or thymoma, composed of a diffuse growth of round,
polyhedral and giant-cells. The chief source of this tumor is probablykthe
reticulum cell, but lymphocytes are often present in abundance.

(2) Carcinoma arising from the reticulum cells.

To these may be added very rare and somewhat questionable cases of
tumors attributed to the stroma and called (3) Spindle-cell or myxosarcoma.

Owing to the uncertainty which still surrounds the nature of the thymic
round-cells, the term "thymoma" has been suggested by Thiroloix and
Debret, Simmonds, and others, for tumors of this origin, while Schridde
employs the phrase " malignant thymus tumors."

The exact origin of the so-called lymphosarcomas of the thymus remains
undetermined. My own study of several cases has led to the conclusion

FIG. 442 a. — X-ray photograph of a thymic tumor. The growth forms a pyramid

capping the pericardium.

that'the thymic round-cell tumors differ from round-cell tumors of lymph-
nodes, that the reticulum cell is here the chief or sole source of the tumor, the
lymphocytes being largely passive, that many of these tumors seem to fall
in the class of granuloma malignum. The term thymoma may perhaps
deserve recognition as a parallel to lymphoma.

(i) Lymphosarcoma or thymoma is the most frequent form of thymus
tumor. The tumors occupy the anterior mediastinum in the position of the
thymus, and usually extend from the sternal notch, or as high as the thyroid,
down to the diaphragm. Many authors have questioned the diagnosis of
thymic origin based on the location of the tumor but the objections seem to
apply chiefly to clinical diagnosis. There is little difficulty in distinguishing
thymic tumors at autopsy from tumors of mediastinal lymph-nodes, lung or

THE THYMUS AND ITS TUMORS 895

sternum. They usually surround and compress the trachea, bronchi, peri-
cardium and great vessels. Both by compression and less often by invasion
of vessels and air passages, they cause death by asphyxia and venous obstruc-
tion, which may increase gradually or supervene suddenly. The more rapidly
growing tumors are soft, but as a rule they are found to be remarkably dense
from diffuse fibrosis. The soft tumors may be vascular and hemorrhagic
while the firm growths exhibit a characteristic lobulation from dense fibrous
septa. Rarely areas of softening and cyst formation are observed. In
many cases the tumors exhibit a characteristic creamy yellow or lemon
color.

A strict encapsulation within the mediastinum has been a notable feature
in some histologically malignant growths, but the more malignant forms

FIG. 443. — Malignant thymoma; extensions to axillae, neck, pharynx, and orbit.

regularly become adherent to surrounding organs, and invade pleura,
lung, pericardium, walls or lumina of vessels and trachea. The bronchial
and cervical nodes are frequently invaded. The axillary nodes may early
be enlarged and in Gabcke's case the invasion of nodes was very widespread.
Tumors of the axillary nodes without known origin should call for the in-
vestigation of the thymus by the a'-ray, especially before any operation is
attempted on the axilla. Occasionally theie are metastases in the organs,
spleen, liver, adrenal, pancreas, and kidney (Zniniewicz). Perforation of the
chest wall has occurred in several cases and was the first localizing symptom
in a case I have recently observed (Seebohm, Zniniewicz, Le Tulle). Fracture
of the humerus from bone-marrow metastases is recorded by Zniniewicz and
infiltiation of the orbits, brain and other organs by Meigs and de Schweinitz.
The structure of these tumors varies greatly. Exactly the same diffi-
culties are encountered in their histological classification as one meets with
tumors of lymph-nodes. In one group the structure resembles that of an

896

N EOF LA STIC DISEASES

infectious granuloma of the type of Hodgkin's disease. The tissue presents
lymphocytes, plasma cells, and larger polyhedral cells irregularly distributed.
Several cases of this type have been recorded, with emphasis on the presence
of many large polyhedral or giant cells (Ertmann, Weigert, and Laquer).
These large cells must be derived from the reticulum. When they become
very numerous the lymphocytes largely disappear and the tumor may be
classed as a carcinoma, as has commonly been done by French writers (Le
Tulle). In another group the reticulum cells are said to be missing and the
tumor is composed of a diffuse growth of small round cells (Le Tulle, Stock-
art). These tumors have not been distinguished from other lymphosarco-
mas, but it does not appear that any definite effort has been made to do so.

FIG. 444- — Malignant thymic tumor composed of large round polyhedral and columnar

cells.

The existence of a pure lymphocytoma of the thymus apart from leukemia
does not appear to have been established.

The blood-vessels may be very numerous and in some cases cells of
medium size may form sheaths about the vessels. When the perivascular
arrangement becomes very marked and lymphocytes are scanty the diagno-
sis of endothelioma or perithelioma may be suggested, as in the cases of
Hahn and Thomas, and Mandelbaum and Celler.

It seems highly probable that these cells arise from the reticulum, pro-
ducing an analogue of perivascular endothelioma of the lymph-nodes. In
the same manner may be explained the mixed tumors described by Gabcke
and Schneider who found round and spindle and many giant cells in their
tumors, all of which may readily be derived from the reticulum.

On close analysis the round-cell tumors of the thymus are found to differ
in structure from the round-cell tumors of lymph-nodes. The lymphocytes
are scanty. The chief cell showing mitosis is often polyhedral, with acido-

THE THYMUS AND ITS TUMORS

897

phile cytoplasm, vesicular nucleus and well-developed nucleoli. They often
cling to the walls of numerous small capillaries where they assume a cubical
or even cylindrical form. They may produce abortive Hassan's corpuscles.
The giant-cells are of two main types; (i) pale staining reticulum cells with
irregular outlines, distended with vacuoles and red cell detritus, and (2)
myeloid giant-cells with opaque acidophile cytoplasm and many vesicular
nuclei. These giant-cells differ from the smaller giant-cells of lymphatic
Hodgkin's disease. The marked fibrosis suggests the desmoplastic property
of carcinoma. In a report of three case I have described these and other
structural features in detail.

(2) Thymic Carcinoma. — In many cases the main tumor-cell appears in
the form of pavement, cubical, or rarely cylindrical epithelium and the growth
must be classed as carcinoma.

^<k_ -A *'*> v\ %A«M-%*

•*••>.& v^"^*^4^*^F^*^v>*r ** **~

kr-fl

FIG. 445. — Portion of thymoma perforating sternum. Note the many peculiar giant cells.

The gross anatomy of thymic carcinoma is identical with that of the hard
thymomas of round-cell type. Although metastases may occur it is notable
that the invasion of surrounding organs is less active than is usual with a
distinctly carcinomatous tumor. An aberrant thymic carcinoma, containing
lymphoid tissue and numerous bodies resembling Hassan's corpuscles, was
observed in the thyroid by Achard and Paisseau.

The structure in typical cases presents coherent sheets, cords, and columns
of large flat or polyhedral cells lying in dense connective tissue. Hornifica-
tion is absent, but concentric layers of flat-cells may form structures resem-
bling Hassan's corpuscles (Thiroloix, Debret, Paviot-Gerest). In other cases

898 N EOF LA STIC DISEASES

the pavement characters are less evident and the cells are chiefly cubical
and form alveoli. Le Tulle and Ambrosini found accumulation of mucus
in the spaces of an alveolar carcinoma. In many cases both round-cells
and epithelium participate in the tumor process, and the authors speak of
the growth as carcinosarcoma or adenosarcoma. Thus in Rubaschow's
case the main mass was composed of round-cells, in which lay many foci of
flat epithelium forming pearls or surrounding blood-vessels. Giant-cells
of a variety of forms are frequently present.

(3) Thymic Sarcoma. — Although it has been commonly assumed that
various spindle-cell or alveolar or perivascular tumors arise from the connec-
tive-tissue stroma of the thymus, this origin has never been fully traced and

•

., '

FIG. 446. — Thymoma. Duration three years. Structure resembling Hassall's corpuscles.

there are strong grounds for concluding that the so-called spindle-cell sarco-
mas and endotheliomas are varieties of thymoma. Congenital myxoma, 10
X 8 cm. in dimensions, weighing 182 gm., containing lymphocytes and Has-
sall's corpuscles in the tumor-tissue, was observed by Caso in an infant of
two and one-half months, and a similar case is described by Winogradoff.

Interpretation of Thymomas.- — The foregoing review of the structure of
thymus tumors reveals extreme confusion in the nomenclature employed by
different authors, great difficulty in establishing sharply defined varieties
and the existence of transitional forms connecting the two types. The great
polymorphism of the cells noted by Ambrosini has been emphasized by later
writers as the chief characteristic of thymic neoplasms and has led to the
use of the term thymoma.

It is significant that the carcinomas have been recorded almost entirely

THE THYMUS AND ITS TUMORS

899

by French observers, while practically all the German reports are of sarcoma.
Yet Le Tulle and Ambrosini describe as carcinoma tumors which have many
of the features which Ertmann and Zniniewicz have designated as sarcoma.
It is also clear, as in Dansac's, Mauser's, and Rubaschow's cases, that many
tumors present an overgrowth of both reticulum and parenchyma cells. A
full survey of the structural variations reveals at one extreme a mixed process
involving lymphocytes and reticulum cells, with giant, plasma, and eosino-
phile cells, producing a structure nearly identical with Hodgkin's granuloma.
At the other extreme are nearly pure tumors of rounded or polyhedral
reticulum cells, i.e., lymphosarcoma and carcinoma. Exactly similar rela-
tions exist between tumors of lymph-nodes, including Hodgkin's granuloma
and the "sarcomas" arising from it, pseudoleukemia, and pure endothelioma.
Hence the conclusion is reached that the great majority of thymus tumors

'•m8te&yj» •jHP** '^ZBt&iflE&ZS&i

fc^^BsS^iaJKlSJa

FIG. 447. — Thymoma of granulomatous type. Proliferation of large reticulum cells,

scanty lymphocytes.

and especially the mixed growths, represent infectious granulomas or particu-
lar forms of cell overgrowth arising on the basis of an infectious granuloma.
Detailed evidence supporting this conclusion is presented in the writer's
study of endothelioma of lymph-nodes. This etiological point of view offers a
simp'le explanation of the great variety of structural forms which thymus
tumors present.

In a series of cases of Hodgkin's granuloma the granulomatous
process has shown malignant properties both in local aggressiveness and
in the production of metastases. Such cases are recorded by Yamasaki,
Chiari, J. E. Welch, Symmers, Karsner, and Beitzke. In most of these cases
it is stated that the main tumor was mediastinal and occupied the region
of the thymus, while the structure presented a diffuse growth of cells larger
than lymphocytes and many giant-cells of myeloid type. In the report of

900 N EOF LAST 1C DISEASES

Symmer's case, studied in this laboratory, a thymic origin was suggested. I
have reexamined various portions of this tumor and find in it all the features
of thymoma, including Hassall's corpuscles, polyhedral reticulum cells and
myeloid giant-cells. ' In the light of this and other cases it seems highly
probable that the mediastinal Hodgkin's disease of the above writers is a thy-
mic tumor which should be separated from othei forms of Hodgkin's disease
and owes its malignancy to its origin from the peculiar reticulum cells of the
thymus.

Clinical Course. — Many thymus tumors are highly malignant and prove
rapidly fatal from asphyxia, but the actual duration is difficult to determine.
Ambrosini's five cases were all fatal in from two to nine months. The very
rapidly growing tumors are usually very cellular and vascular. In one of
Zniniewicz's cases, lasting ten weeks, there were general metastases, while in
Ambrosini's case of two months' duration the extensions were local.
Ertmann's tumor of two months' course was vascular, contained very large
polyhedral cells, areas of perivascular growth and collections of colloid,
but metastases were limited to the pleura. The tumor described by Hahn
and Thomas reached dimensions of 26 X 18 X 9 cm. in one year.

Constitutional symptoms suggesting a sympathetic disturbance of the
chromaffine system are not observed, but Gabcke records for his case that the
adrenals were very large and the skin pigmented.

In a notable group of cases thymic tumor has been associated with
myasthenia gravis (Oppenheim, Weigert and Laquer, Buzzard). Of 45
cases of myasthenia gravis, Mandelbaum and Celler found thymus lesions
recorded in eleven. The thymic tumor has usually shown the structure of
lymphosarcoma mingled with epithelioid cells. In Hun's case the epithe-
lioid cells were abundant but showed no tendency to form Hassall's corpus-
cles, while plasma-cells, eosinophile cells and focal hemorrhages aie often
present. Mandelbaum and Celler found a tumor composed of small con-
centric groups of polyhedral cells, while the numerous vessels were sheathed
with lymphocytes and surrounded by tumor-cells. The tumors are usually
of moderate size, and in several cases the lesion was regarded as simple
hyperplasia (Link, Burr, Buzzard).

Throughout the skeletal muscles and often in the organs are found foci
of lymphocytes with varying numbers of polynuclear leukocytes, and eosino-
phile, plasma, or epithelioid cells. Weigert and Laquei regarded these
lesions as metastatic foci, while others consider them as of local inflammatory
origin. Their occurrence favors the view that many thymic tumors are
manifestations of an infectious granuloma.

CHAPTER XL VII
TUMORS OF THE HYPOPHYSIS

Because of the remarkable clinical phenomena with which they are
associated, uncertainty regarding the origin and nature of the processes
concerned, and the peculiar problems involved in their diagnosis and treat-
ment, tumors of the hypophysis form one of the most interesting of all
groups of neoplasms.

The history of our knowledge of pituitary enlargements begins with
isolated anatomical reports dating from 1700 (Bonnetus) and 1705 (Vieus-
sens) and continuing until 1886, during which period tumors discovered at
autopsy were known to have caused chiefly cerebral pressure symptoms. In
1886 Marie initiated a second period of more minute clinical study, by pointing
out the essential connection between pituitary tumors and acromegaly,
while, later, gigantism was included among the clinical phenomena, by
Cunningham, Tamburini, Brissaud and Meige, and Launois and Roy.

Although the association of obesity with hypophyseal tumors was noted
as early as 1840 by Mohr, and hypoplasia of the genital organs as well
as obesity were described by Pechkranz, the considerable frequency of this
association was first emphasized by Froelich, 1901, and by Bartels and Gush-
ing, 1906. The modern period of elaboration of the clinical features may be
said to date from these observations which have led directly to more accurate
diagnostic methods especially by the o;-ray and to the development of physical
and surgical treatment. Gushing especially has demonstrated that the
natural history of primary hypophyseal disease passes through an initial period
of overactivity of the gland with acromegaly, into a later status of under-
activity with adiposogenital dystrophy.

The use of the .T-ray introduced by Beclere (1902) greatly facilitated
the diagnosis and clinical study of the tumors and this agent was successfully
employed in treatment by Gramegna and Beclere in 1909. Hypophysectomy
was first performed by Hoisley, SchlorTer, and v. Eiselsberg in 1907, and
successful results were soon reported by Hochenegg, Hirsch, Gushing, Lecene
and others. Minute histological studies were contributed by Benda (1900—
4), Erdheim (1904-10), Lowenstein, 1907, Gushing, Lewis, and many others
and considerable success has followed the attempt to attach the various syn-
dromes to different types and locations of the tumors. The discovery of
accessory pharyngeal pituitary tissue by Haberfeld served to elucidate
some problems, while complicating others. The obscurity surrounding the
interrelations of the ductless glands includes the functions of the hypophysis
and its influence on glycosuria, polyuria, and many other disturbances of
internal secretions, and most of these questions still await final answer.
This phase of the subject is at present being rather actively pursued.

General Etiology. — Tumors conveniently regarded as hypophyseal are
relatively uncommon and many of the recorded cases must be interpreted
as simple hyperplasia. Nevertheless the series of cases now available for
statistical study is numerous. Collarit in 1905 collected 52 cases without
acromegaly or glycosuria. Creuzfeld, 1908, in 60 autopsies on cases of
acromegaly, reported 47 hypophyseal tumors and collected 55 tumors without

901

902 N EOF LAST 1C DISEASES

acromegaly. Eleven tumors were associated with gigantism. Frankl-
Hochwart, 1909, collected 85 cases of various types of tumors. Strada, 1911,
collected 33 cases of tumor without acromegaly but with obesity and genital
hypoplasia.

Among 3620 autopsies at Prague, four hypophyseal tumors were found by
Klebs, while Boyce and Beadles collected 6 tumors in 3000 autopsies.

Owing to the uncertainties of histological diagnosis the relative frequency
of the different types of tumors cannot be accurately estimated. Epithelial
neoplasms of the anterior lobe, with much excess of eosinophile or chromo-
phobe cells and associated with acromegaly, are the most common. Of 47
such cases Creuzfeld found 15 described as sarcoma, to which he added one
glioma of the posterior lobe. On the other hand this author collected 55
cases without acromegaly, of which 15 were designated as sarcoma, 18 as
glandular, 19 as squamous-cell growths, one teratoma, and one lipoma of
the posterior lobe. Frankl-Hochwart's series contained 12 carcinomas (7
squamous); 22 glandular (13 adenomas); 27 sarcomas; 15 cysts, 3 gliomas, and
2 teratomas. Of Strada's 31 cases with obesity and genital hypoplasia two
were described as simple struma, 5 as adenoma, 5 as carcinoma, 10 as acan-
thoma of infundibulum, and 9 as sarcoma. It is probable that all the sarco-
mas were really epithelial tumors. Gushing reports about 29 hypophyseal
tumors examined microscopically with analyses of symptoms and refers to 148
cases of hypophyseal disease observed clinically.

An hereditary element appears distinctly in certain cases of gigantism
which has affected several members of the same family (Gushing, case 31,
de Neuville). Cerebral trauma occurred in six of Cushing's cases of hypo-
pi tuitarism, in five of which there was an interpeduncular tumor. The
marked functional hyperplasia of pregnancy appears to have led to pro-
gressive changes with acromegaly and secondary hypopituitarism. Lowen-
stein and Erdheim found several definite adenomas in the glands following
pregnancy. Ascenzi observed acromegaly develop after ten rather rapidly
succeeding gestations, the hypophysis containing a large cystadenoma.
Occasionally acromegaly has followed attacks of pulmonary tuberculosis,
typhoid fever, or pneumonia (Massedaglia, Gushing).

Acromegaly has been referred to severe fright by Ingermann and Poin-
decker and has followed ovariotomy in reports of Strumpell and Goldstein.

Anatomy of the Hypophysis. — The normal anatomy of the hypophysis is complex and
several embryological and histological features are of prime importance in tracing the origin
of tumors of this organ. The weight of the hypophysis from the third to seventh decade
averages 61.2 gm., and its size 21.5 X 14.4 X 5.5 mm. Variations in weight from 30 to 75
gm. are probably normal (Erdheim).

The organ consists of (i) an anterior glandular lobe which is developed by an upward
evagination of oral ectoderm, (2) a posterior nervous portion which is an elongated portion
of nervous tissue derived from the tuber cinereum at the floor of the third ventricle, and (3)
a stalk or pedicle which passes through the arachnoid and connects the organ with the tuber
cinereum.

(i) The anterior lobe or pituitary gland proper, is partly subdivided into two lateral
portions by constriction of the encircling posterior lobe. A long lingual process of this lobe
encircles the stalk as a glove over a finger, covering the anterior surface below and com-
pletely surrounding it above and almost to the optic chiasm. A cross-section of the stalk
therefore presents a central cavity, the prolongation of the third ventricle (infundibulum),
surrounded by a zone of nervous tissue which is sheathed in turn by the lingual process of
the anterior lobe. This lingual process is often designated as pars intermedia. The
lingual process often contains small cysts, and Erdheim showed that it very frequently
contains groups of squamous epithelium, remains of the oral ectoderm, which give rise to
tumors. The presence of such epithelial debris had previously been described by Luschka,
Saxer, and Launois, who also suggested its probable relation to tumors of the brain.

The anterior lobe is separated from the posterior by a connective tissue septum which

TUMORS OF THE HYPOPHYSIS

903

usually contains a multilocular cleft, the remains of Rathke's ectodermal pouch. About
this cleft Erdheim describes the remains of salivary gland alveoli.

(2) The posterior lobe '.pars nervosa) is a club-shaped mass of glia- tissue which descends
from the stalk and partly surrounds and constricts the anterior lobe. It is largely sur-
rounded by a thin sheathing of neutrophile epithelium merging with a similar sheathing of
the stalk, and continuous with the epithelium of the anterior-lobe from which it is derived.
The glia-cells contain variable amounts of insoluble pigment which is probably derived from
the wandering cells of the anterior lobe or pars intermedia (Kohn, Vogel).

FIG. 448. — Median sagittal section through pituitary of monkey; semidiagrammatic.
(Herring.) a, Optic chiasma; b, third ventricle; c, g, pars intermedia; d, epithelium of pars
intermedia extending round neck of pars nervosa; e, pars glandularis seu epithelialis; /,
intraglandular cleft, lying between pars glandularis (e) and pars intermedia (g) ; h, pars
nervosa.

FIG. 449. — Salivary gland alveoli in the neighborhood of Rathke's cyst between anterior
and posterior lobes of hypophysis. They give rise to cysts of the hypophysis. (After
Erdheim.)

The pars intermedia is all that sheath of epithelium which surrounds the posterior lobe
and stalk, including the lingual process. Its peculiar relations to the inclosed nervous tissue
render it of much physiological interest. Its epithelial cells exhibit evidences of secretion, in
the form of many colloid globules which collect in round masses between the cells and have
been traced apparently passing through the pars nervosa into the infundibulum and thence
to the third ventricle and cerebrospinal fluid (Herring, Gushing, Goetsch).

904

NEOPLASTIC DISEASES

(3) The stalk or pedicle connects the organ with the tuber cinereum, passing through the
dural septum and arachnoid. It contains a central cavity, infundibulum, which is the
downward prolongation of the third ventricle, surrounded by a mass of nerve tissue which
enlarges below to form the pars nervosa, while externally it is sheathed by the lingual process
of the anterior lobe.

The whole organ is enclosed in a dural capsule which has an upper diaphragm stretching
from the four clinoid processes and is perforated by the pedicle. Pressure of an enlarging
gland is therefore slightly limited above and laterally, while below there is bony resistance.

The blood-supply of the posterior lobe is derived from one of three slender vessels enter-
ing below from the internal carotid, while the vessels of the anterior lobe pass down the
stalk. Sympathetic nerve-fibers also pass down the stalk (Dandy).

Accessory Pituitary Glandules. — Rathke's pouch, which is the remnant of the oral
ectodermal evagination, does not always undergo complete involution, but regularly in
some lower animals, and occasionally in man, it persists and gives rise to accessory gland-
ules. These were first observed by Erdheim in the pharyngeal mucosa and later by Arai

a',1 •»»' *-i Vv, *

f- Sfev?
w- ££ wVif?:

FIG. 450. — Topography of dog's hypophysis. AL, Anterior lobe. Note hyaline material
in epithelial investment of pars nervosa. (After Gushing.)

and Civalleri. Haberfeld in 51 human subjects of various ages regularly found a thin
glandular strand, 3 to 9 mm. in length, 5 to 5^ mm. in breadth, in the pharyngeal submucosa
just behind the alae of the vomer, and extending inward to the base of the skull. These
glandules are composed chiefly of chromophobe cells, but acidophile cells are commonly
present and flat epithlieum may be observed at the lower pole. Dandy and Goetsch found
similar glandules in a central pit in the sellar floor of dogs. Erdheim has described an intra-
osseous tumor of acidophile cells, with acromegaly, which probably arose from such an ac-
cessory glandule, and he derives certain squamous-cell tumors from this same source.
Distinct heterotopia of the entire pituitary body below the sella has been reported (Haber-
feld, Lit.).

Histology. — The structure of the pituitary body is subject to wide variations which are
of much significance in the interpretation of functional changes and neoplasms of this
organ.

The normal gland contains two main classes of cells, chromophile and chromophobe
(Flesch). A third cell type is chromophobic or neutrophile. The chromophile cells are

TUMORS OF THE HYPOPHYSIS

905

either (a) acidophile or (6) basophile, by virtue of the microchemical reactions of their
abundant granules (Schoneman). The acidophile cells are usually more numerous along
the central sinuses while the basophiles occupy the periphery and anterior portion of the
lobe. It is not yet clear whether the two types are distinct or represent different functional
phases of the same cell order. Benda and others accept the former view, while Erdheim
supports the latter. The acidophile granules after fixation in Muller-formol stain deeply
with eosin, black with Heidenhain's hematoxylon, deep red by Mallory's stain, and usually
decolorize in Gram's stain. These cells are normally the most abundant of the three
types. The basophilic cells are less numerous but larger than the acidophiles, and the
large granules stain deep blue by Mallory or Gram, violet with hematoxylon, and are de-
colorized by complete differentiation in iron hematoxylon. The nuclei are large and pale.

The chromophobe cells are the least numerous of the cell types, and the smallest.
The cytoplasm is scanty and the nuclei are relatively compact. They often appear in
groups resembling acini, and surrounded by chromophile cells.

In the pars intermedia the cells lie in small groups surrounded by connective tissue.
Often they form alveoli of cubical or cylindrical cells surrounding colloid globules, and they
have a close relation to the blood-vessels. The cytoplasm is clear, chromophobic, and
lacking in specific granules (Lewis). Numerous special methods for the _ demon-

!*^t&

FIG. 451. — Normal hypophysis of a subject of 37 years. Stain, hematoxylon and eosin.
E, Eosinophile cells, large and small; B, basophile cells, large and granular; Cc, chief
cells, small with little cytoplasm. (After Erdheim and Stumme.)

stration of cell granules have been recommended but none appears to have an essential
advantage over fixation in Muller-formol and staining by hematoxylon and eosin. For
demonstration of basophilic granules Erdheim prefers long staining in kresofuchsin, pre-
ceded by lithium carmine as a nuclear stain. Many prefer Zenker fixation.

Functional changes in the pituitary gland are frequent and so pronounced
as often to simulate neoplasms. The range of alterations associated with
disturbed function is even greater than occurs in the thyroid gland, and it is
probable that true tumors develop on the basis of functional hyperplasia.
Probably the most marked series of changes occurs in gestation, in which
extensive and specific hyperplasia has been described by Comte, Launois and
Mulon, Erdheim, and others. According to Erdheim, hyperplasia begins early
in the first gestation, reaches its height at term, persists several weeks or
months after parturition, and is more pronounced in succeeding pregnancies.
The size of the normal hypophysis averages 61.2 gm. in adults, but reaches an

906

N EOF LA STIC DISEASES

average size of 84.7 gm. in primiparae, and 106 gm. in multipart. The
hyperplasia affects only the chief or chromophobe cells which greatly increase
in size and number, becoming more abundant than the chromophiles. The
cytoplasm contains many fine granules staining slightly with Heidenhain's
hematoxylon. These cells multiply by mitosis, form large solid groups,
and displace the chromophile elements. In 10 per cent, of the cases the
specific cells of pregnancy form single or multiple focal adenomas 1-4 mm. in
diameter, free from fat globules but without marked variation from the nor-
mal type and without encapsulation. They probably regress after the puer-
perium and are not true tumors. Transitions to atypical adenoma of malig-
nant appearance may be observed, in which the cords are narrow or very broad
or present a peritheliomatous arrangement, but the clinical course of such
adenomas cannot be predicted from their structure. In four cases of gesta-
tion-hypertrophy Erdheim saw adenomas of chromophile cells. Pressure

FIG. 452. — Structure of hypertrophied hypophysis of a recent multipara. The cords
are composed chiefly of the hyperplastic cells of gestation, among which are many large
basophile cells. The eosinophiles are black. Stained by Heidenhain's hematoxylon.
(After Erdheim and Stumme.)

symptoms, as hemianopsia, may apparently result from the hyperplasia of
gestation (Reuss).

Varying grades of pituitary hyperplasia have been observed in infectious
diseases. Experimental studies of the effects of extirpation or ingestion
of the substance of other glands of internal secretion have supported the view
that there is a close interdependence of all these glands, but the exact types
of pituitary hyperplasia produced by these methods still remain to be accu-
rately defined.

Gross Anatomy of Hypophyseal Tumors.- — The several portions of the
hypophysis each give origin to tumors which may be classified accordingly
as:

(1) Tumors of the pituitary body;

(2) Tumors of the hypophyseal duct and its derivatives;

(3) Tumors of the pars intermedia;

(4) Tumors of the pars nervosa.

TUMORS OF THE HYPOPHYSIS 907

i. Tumors of the pituitary proper include:

(a) Diffuse hyperplasia and focal adenoma;

(b) Adenocarcinoma;

(a) Diffuse hyperplasia arising from functional overgrowth occurs in
most advanced form after multiple pregnancies when the gland may reach a
weight of 165 gm. (Erdheim). The growth distends the dural diaphragm,
spreads laterally, may produce hernia of the capsule and in cases with some
anatomical predisposition may press upon the optic chiasm with hemianopsia.
Considerable widening of the sella may exist with all the simple hyperplasias.
On section the overgrowth may be diffuse, or in about 10 per cent, of the cases
focal adenomas may appear as opaque spots 3-7 mm. in diameter.

The natural course of these hyperplasias is slow regression but some
probably pass into malignant and progressive adenocarcinoma. The struc-

FIG. 453. — Hypophyseal adenoma of gestation. (After Erdheim.)

ture presents compact groups or narrow or wide cords of chromophobic cells
derived from the chief cells of the gland.

In many cases of acromegaly the glandular lesion takes the form of a
diffuse hyperplasia often with adenomas. In 56 cases of aciomegaly Creuz-
feld found 12 glands with simple hyperplasia, 8 designated as stiuma, 12 as
adenoma, 15 as sarcoma, and 5 without demonstrated hypophyseal lesions.
There is thus a wide variety in the extent of the glandular lesion associated
with acromegaly and it appears that this disease may result from veiy mod-
erate hyperplasia or from very small adenomas. As a rule the changes in
acromegaly pass far beyond those observed in gestation, and yet in many
instances the hyperplasia is succeeded by regression and the signs of over-
activity are followed by glandular insufficiency.

Many of the glandular lesions in acromegaly aie therefore not true tumors
but self-limiting functional hyperplasias. The structure of these enlarged
glands often presents an overgrowth of eosinophile cells which are increased
in size and number, form compact masses or adenomatoid accumulations
and displace the other cell types. The arrangement of the cells is orderly

908

N EOF LAST 1C DISEASES

and mitoses are rare. While the gland usually remains solid and firm, small
cysts filled with colloid may develop and hemorrhages may occur.

The areas of eosinophile cells accord with the view that the overactivity
of the gland resides in these cells. Yet many of the moderately enlarged

: * 1S*SF - r-^fc^^3Ziir^

*^5*V''

FIG. 454. — Miliary basophile adenoma of hypophysis. (After Erdheim.)

glands of acromegaly contain not acidophile but chromophobic cells (Gush-
ing). Eosinophile adenomas are observed also in gestation.

Roussy and Clunet describe a form of pathological hyperplasia occurring in
alcoholism, nephritis, Parkinson's disease, and arteriosclerosis, and signifying
a reaction to the failure of thyroid function. Hyperplasia of the basophilic
cells with the production of small adenomas is described by Erdheim, who
found such a nodule i^ mm. in diameter in the anterior lobe. In a case of
acromegaly he found both eosinophile and basophile adenomas of small size.

FIG. 455. — Detail of miliary basophile adenoma of hypophysis. Stain, kresofuchsin,

(After Erdheim.)

Nothdurft describes a small basophilic adenoma in the posterior lobe. In
none of these cases does it appear that the adenoma was responsible for any
local symptoms. In the giant acromegalic subject of Huchard and Launois
the tumor appeared to be composed chiefly of basophilic cells. A malignant
tumor of such cells has not yet been demonstrated, although Nagaeli assumed

TUMORS OF THE HYPOPHYSIS 909

that a large perithel.iomatous growth composed of nongranular cells had
such an origin. Pick describes an extensively calcified tumor in a case of
adiposogenital dystrophy which he designated as basophile adenoma or
adenocarcinoma.

(b) Adenocarcinoma. — True adenoma of the pituitary may be difficult
to recognize by its size and structure but it is probable that true neoplasms
of this gland are always atypical in structure and malignant. In a consider-
able group of ^cases the gland exceeds in size the limits of simple hyperplasia,
the structure is distinctly atypical, the capsule is ruptured, extension beyond
the limits of the sella is observed, pressure symptoms are marked, and the
process must be classed as malignant adenoma or adenocarcinoma.

The size of these tumors varies greatly but they regularly distend or
rupture the dura! diaphragm, they widen and absorb the sella so that the
a--ray shows extensive excavation, the clinoid processes are often destroyed
and the basilar portion of the sphenoid may be extensively eroded. Growing
beyond the sella the tumor compresses the optic chiasm, extends along the

FIG. 456. — Cross-section through a large hypophyseal adenoma.

frontal lobes, and penetrates the third and even the lateral ventricles. With
reference to their bony relation the growths may be described as intrasellar,
with uniform widening of the bony wall, or as extrasellar when the clinoid
processes are absorbed, and as voluminous when tumors absorb much of the
bone and extend into the brain. Usually the tumors long remain solid, but
cysts form from colloid secretion, hemorrhage, and necrosis. In one group
the tumor tends to become cystic from the first and many areas filled with
soft colloid material are traversed by thin strands of epithelium, or well-
marked papillary outgrowths develop. These tumors are difficult to dis-
tinguish from papillary epithelioma of the ventricles, but their location
emanating from the sella is usually decisive. While the majority of growths
long remain encapsulated and preserve the general form of the organ, exten-
sion into the brain is often accompanied by diffuse invasion of this tissue.

In advanced cases the tumor has perforated the cavernous sinus, invaded
frontal and temporal lobes, compressed many of the cranial nerves, and ex-
tended to the peduncles, medulla, and even to the cerebellum. Pechkranz's
tumor penetrated the orbit, and Kruger's large round-cell " sarcoma"

910

NEOPLASTIC DISEASES

eroded the atlas at the base of the skull. In several cases the growth has
communicated with the superior nares and produced a watery or bloody
discharge (S. Ingermann, O'Malley, Sommer). Access to the ventricles
may be accompanied by hydrocephalus.

Metastases occasionally occur. With comparatively typical glandular
tumors Smoler found a cerebellar metastasis; Stolpe reports a large secondary
growth in the occipital lobe; Bruns saw a nodule in the tongue; Cagnetto
describes subpial nodules along the spinal cord from a colloid adenocarcinoma
in a remarkable case of acromegaly.

The structure of the pituitary adenocarcinomas varies extensively.
Some resemble the adenomatoid hyperplasia with solid cords or compact

FIG. 457. — Hypophyseal adenoma, with large imperfectly walled blood sinuses.

groups of atypical polygonal epithelium. These tumors are of moderate
malignancy and while most of the cells are distinctly chromophobic traces
of the chromophile differentiation may at times be detected. Chiefly acido-
phile cells occurred in the cases of Benda, Tamburini,Zak, Alquier, Presbeanu,
Marinesco, Cagnetto, and Erdheim (1903-04, 09, 10). Gushing describes
most of his cases as chromophobe struma, as do Carbone, Lecene, Strada,
Krumbhaar, and others. In general the latter group is more distinctly
neoplastic.

Other tumors are more atypical, composed strictly of chromophobic
cells, arranged in cords or groups, or often forming distinct acini in which
colloid secretion may accumulate. Excess of colloid or fluid may yield
soft cystic growths in which a papillary structure may appear. A perivas-
cular arrangement of cubical or cylindrical cells is common (Moskalew),

TUMORS OF THE HYPOPHYSIS

911

and the numerous blood-vessels with their epithelial sheaths may simulate
a papillary adenoma or angiosarcoma. Many cellular growths fail to show
any subdivision of the cells into groups or acini and the structure is diffuse.
In different portions of the same tumor the structure may vary widely.
Thus Launois and Roy and Strada describe an alveolar structure* in intra-
sellar portions, and a diffuse growth in extrasellar areas of their tumors.
Meyer describes newgrowth of nerve cells in the pars nervosa of a case
of acromegaly and diabetes with hypophyseal tumor.

(c) Malignant atypical carcinoma has usually been reported as sarcoma,
angiosarcoma, myxosarcoma, perithelioma or endothelioma, and a consider-
able proportion of pituitary tumors falls in this class. Of 243 tumors collected
by Marie, Creuzfeld, Frankl-Hochwart, and Strada, 64 or 26 per cent, were
entered as sarcoma. Since the demonstration by Benda of specific epithelial
cell granules in the cells of supposed sarcomas and the recognition that

FIG. 458. — Section of large hypophyseal adenocarcinoma.

epithelial growths of the pituitary very readily assume various atypical
structures, the diagnosis of sarcoma has practically disappeared from the
literature. With very rare possible exceptions all these tumors must be
classed by atypical carcinomas. Only in their more atypical structure do
they differ from malignant adenocarcinoma.

Angiosarcomas are described by Pechkranz, Jakubowsky, Kon and others, and peri-
thelioma by Kon, but the descriptions strongly recall the structure of vascular pituitary
adenocarcinomas. Roth, Beck, and others described spindle- and round-cell sarcomas but
the data are inadequate to exclude an epithelial origin. In many cases the epithelium
of the gland merged with the sarcoma so that the author was in doubt as to the nature
of the growth, and employed the term adenosarcoma (Hippel, O'Malley). The presence
of colloid in round-cell tumors sometimes warns against the diagnosis of sarcoma (v. Benin).
"Sarcomatous struma" was the term applied by Hansemann to a tumor of the pituitary
composed of large ovoid cells. Benda, whose minute studies threw many sarcomas into
the epithelial class, accepts the occurrence of true sarcoma of the hypophysis and Inger-
man's case in particular. This was an actively growing circumscribed, soft, gelatinous
tumor 7 X ^A X 3 cm., producing pressure symptoms and obesity in a woman of 35

"912 N EOF LA STIC DISEASES

years. It was composed of closely packed cells slightly larger than lymphocytes, while
some cells were polygonal or spindle. Intercellular substance was lacking. The structure
resembled overvascular splenic pulp and a perithelial arrangement was prominent. This
description varies little from that of many atypical gland-cell tumors. Caussade and Laubry
describe a nodular growth, 3^X3 cm., involving the anterior lobe. There were many
spindle-cells arranged in whorls, groups of polygonal cells, and some acidophile cells. This
tumor resembled certain dural endotheliomas, but its exact nature appears uncertain. Wolf
designates as sarcoma cylindromatodes a structure with hyaline changes in the vessels.

Agostini in a prolonged case of dyspituitarism with mental symptoms described a
spindle-cell melanotic fibrosarcoma with ossification of the capsule.

Degenerative changes occur in the advanced simple hyperplasias and
frequently in the true tumors. Colloid secretion may be very abundant,
diffused through the stroma, and lead to myxomatoid softening. From this

FIG. 459. — Hypophyseal adenoma. (After Martins.)

source as well as from central necrosis and hemorrhage large tumors may be
converted into cysts with mucus or chocolate colored fluid. Calcification
appears in granules in and between cells, in the blood-vessels, and diffusely
(Pick). In Konjetzny's cases the entire tumor was calcine.

2. Tumors of the Hypophyseal Duct and its Derivatives. — Owing chiefly
to the studies of Erdheim, a well-defined group of hypophyseal tumors has
been traced to the remnants of the hypophyseal duct. These growths are
usually of squamous epithelial type, but many present the features of basal-
cell carcinoma, and it is probable that certain mixed tumors, or teratoids of
the salivary gland type, arise from epithelium of the duct or from salivary
gland acini carried along with the oral evagination. The distribution of these
epithelial derivatives has been discussed with the anatomy of the hypophysis.

The hypophyseal duct tumors arise from any point along the course

TUMORS OF THE HYPOPHYSIS 913

of this embryonal structure, from the squamous epithelial nests in the lingual
lobe from the chiasm downward, from Rathke's cyst between the anterior and
posterior lobes, beneath the hypophysis in the floor of the sella or the sphe-
noidal spaces, and in the wall of the pharynx at the entrance of the duct.

The gross form of these tumors presents a number of variations.

(a) Simple cysts develop from distentions of Rathke's pouch. They
arise between the anterior and posterior lobes, compress both portions, and
contain serous or gelatinous or chocolate-colored material. According
to Erdheim they are relatively common in infants. In adults they may reach
a considerable size, chiefly by distention with fluid derived from the salivary
acini in their walls. Occasionally they may rupture or the walls become so
richly infiltrated with lymphocytes as to resemble a lymph-node. It is prob-
able that some of the cysts lined by ciliated epithelium are derived from this
source (Weichselbaum).

Cysts are believed to arise from separated portions of the infundibular
extension of the ventricular cavity into the nervous portion of the stalk.
They develop above the hypophysis, are lined by ependymal, rarely ciliated,

FIG. 460. — Relations of a cystic papillary epidermoid carcinoma of hypophyseal duct.

(After Strada.)

epithelium, and contain serous fluid. From them may possibly develop
some of the papillary tumors of ependymal epithelium (Saxer, Hart, Langer).

Cystic tumors also develop from distention of dermoids and other
tumors derived from the hypophyseal duct, as well as from liquefaction of
pituitary adenomas. Some cystic tumois of Boyce and Beadles appear to be
of this type. In one of these the wall was partly ossified and the contents
inspissated.

(b) Epidermoid carcinoma is the most frequent type of tumor derived
fiom the hypophyseal duct. It arises from the remnants of oral epithelium
found by Erdheim in the lingual piocess along the pedicle, or from similar
remnants lying between the lobes (Launois). That the ependymal cells of
the infundibulum may give rise to squamous epideimoid carcinoma remains
unproven and appears improbable, although many papillary tumors of
cylindrical covered by flat cells have been referred to the ependyma or cho-
roid plexus (Fahi, Selke, Saxer, Boudet, Clunet). It appears impossible
to determine where many recorded cases really belong, and quite likely that
too many have been referred to misplaced remnants of the hypophyseal duct.
The simple squamous-cell tumors of the duct are to be separated from more

914

NEOPLA S TIC DISEA SES

complex dermoids and teratoid growths, and probably from cholesteatomas,
which Bostroem and Erdheim. trace to invaginations of cranial epidermis
carried into the brain vesicles in the closure of the neural canal. This latter
group of tumors contains true skin and appendages, hair and sebaceous
follicles, the tumors are scattered widely over the base of the brain, and Erd-
heim pointed out that they rarely lie in the median line. The occurrence of
chorda-like tissue in Kon's case also indicates an origin apart from the duct.
Yet it is not easy to sharply distinguish all tumors of these two classes-
The absence of keratohyalin granules emphasized by Erdheim is not invari-
able, for both granules and keratin have been demonstrated in duct tumors by

/- ifagp /^jw* V ~*: vs£' :*>V£*

:>>•'* '•''. '£• &&K5 'JNk J% ; J&b*. StfeJSK % «'.•''>

FIG. 461. — Epidermoid carcinoma of hypophyseal duct. Adamantinoma.

Allgayer, Bartels, and Strada. Intercellular spines occur in both groups.
In some of the duct tumors extensive scaling occurs, recalling cholesteatoma,
and metaplastic changes in the stroma may yield bone and cartilage (Breg-
mann and Steinhaus). The presence of hair and much sebaceous material
points clearly to a dermal origin.

The distinction between epithelial tumors of the hypophyseal duct
and papilloma of the choroid plexus is also difficult and must be based chiefly
on the location and attachments of the tumor. The structure in both groups
may be very similar. Most tumors of the choroid plexus lie well within the
ventricles and only when they involve the third ventricle do they suggest an

TUMORS OF THE HYPOPHYSIS 915

hypophyseal origin. For the demonstration of an hypophyseal origin one
may demand a close relation to the pituitary gland, destruction of the stalk
alone or both stalk and gland, and an intact choroid plexus. Many of
these tumors are separated by a membrane from the cavity of the ventricle.
The structure of the hypophyseal growths is more solid, or cystic with inverted
papillae, and the squamous characters are prominent. Tumors of the plexus
are very vascular, even angiomatous, the papillae are everted, mucoid degenera-
.tion of the stroma is common, and the cells are usually small and delicate,
while squamous changes are less prominent or absent.

Epidermoid carcinoma as a rule develops from the hypophyseal stalk,
lies above the hypophysis, widens the chiasm and circle of Willis, protrudes
toward the ventricle, and compresses the hypophysis below. Arising within
the gland the tumor may destroy the organ. The growth is solid, spongy, or
cystic. Erdheim describes a unilocular cyst 6 cm. in diameter, lined by
squamous epithelium. From the wall many low warty projections may form,
and it is probable that the epithelial lining may be lost, giving rise to cysts
of uncertain origin containing chocolate fluid, such as are described by
Benda. Saxer's markedly papillary tumor was composed of very vascular
connective tissue covered by squamous-cells. Other tumors are compara-
tively solid or contain only few and small cysts. While commonly well
encapsulated there may be invasion of surrounding soft tissues and bone.
Metastases do not occur. The main structural type is that of adenoid
cystic epithelioma. In acellular connective-tissue stroma lie anastomosing
masses of epithelium the outer layers of which are cylindrical while the inner
layers become flattened and vacuolated. There is often a distinct tendency
to reproduce the reticulated structure of adamantinoma. and many small
cysts form in the liquefied central areas, as well as in the edematous stroma.
Or squamous metaplasia is pronounced, pearls and intercellular bridges
form, and keratohyalin granules appear. In some cases squamous-cells are
wanting and the tumor is composed of many closely packed papillae lined
chiefly by cylindrical cells (Lewis). Either in the epithelial masses or in the
walls of vessels calcific concretions may form.

The stroma may present a variety of features. The cellular connective
may be infiltrated with blood and contain cysts with chocolate fluid. Por-
tions of the nervous tissue of the posterior lobe or the gland tissue of the
anterior lobe may be scattered through the tumor. By metaplasia areas of car-
tilage or bone may form as in the salivary gland tumors. Walker described
his tumor as osteoma. Benda's teratoma in a dwarf contained epider-
mold cysts with cholesterin and bony plates in the wall. All the so-called
teratomas (teratoids) of the hypophysis may safely be included in this group.
While there is thus a wide variety of structure attributable to this origin and
illustrated in many reported cases the great majority of these tumors are
comparatively simple and resemble adamantinomas.

3. Tumors of the Pars Intermedia. — In three cases the relations of an
hypophyseal tumor have strongly suggested an origin from the pars
intermedia.

Boyce and Beadles describe a firm tumor as large as a pea attached to
the pedicle of the hypophysis above the sella. It was composed of large
polygonal cells with single or multiple nuclei, lying in slightly acinar arrange-
ment in a vascular stroma. Erdheim mentions a similar growth composed
of large polygonal cells with densely staining cytoplasm. Gushing studied
a large adenomatous tumor which compressed the anterior lobe in such a
way as to indicate an origin from the pars intermedia alone. The structure
resembled that of the thyroid gland.

916 N EOF LA STIC DISEASES

4. Glioma of the posterior lobe is briefly reported by Bury. A soft cellu-
lar growth with colloid deposit and composed of small round- and spindle-
cells merging with the normal tissue of the posterior lobe was regarded by
Roxburg and Collis as a glioma or sarcoma.

Two small lipomas were found replacing the posterior lobe by Weichsel-
baum. They might arise from fat tissue occasionally seen about Rathke's
cyst. W. Hutchinson describes a fibrosed gland in a dwarf.

Miscellaneous Tumors of the Hypophysis. — Cholesteatomas and true der-
moids containing hair and sebaceous material occasionally appear in or near
the sella turcica, but they seldom originate within the hypophysis. Bostroem
has shown that they take origin from ectodermal rests carried in with the
closure of the brain vesicles. Erdheim has collected a series of 15 tumors of
this group in various locations, none of them strictly hypophyseal. Complex
teiatomas are described by Beck, Hecht, Gushing, and others. They are
probably autochthonous teratoids developed by metaplasia from hypophyseal
duct remnants. Margulis records an adult tridermal teratoma in the rab-
bit's hypophysis. Fetal implantations apparently attached to the hypophy-
sis were recorded by Wegelin and Rippmann.

Symptomatology. — The combined clinical, anatomical, and experimental
studies of tumors of the hypophysis have not only thrown much light on the
nature and behavior of these growths but rather unexpectedly have opened up
fields of research which have a broad relation to many problems in the
physiology and pathology of the glands of internal secretion. The outline
of a brief presentation of this complex subject, which is an essential part of
the study of hypophyseal tumors, includes first, a clinical classification of
the tumors, and second, a discussion of the pathogenesis of symptoms.

In general, hypophyseal tumors are associated with two main groups of
symptoms. Some produce almost exclusively cerebral pressure symptoms,
and thereby greatly lose in interest. Others not only yield pressure symp-
toms but are accompanied by peculiar forms of general dystrophy usually
involving other glands of internal secretion and thus adding greatly to their
interest as well as their clinical complexity. Rarely the tumors are found
at autopsy, having run a latent course. These groups may be termed (i)
cephalic, (2) dys trophic.

(i) Cephalic Type. — The usual symptoms of headache, vertigo, and
vomiting are typical signs of onset which are common to many cerebral
tumors. Rising beyond the sella, ocular symptoms first appear and take a
variety of forms which may permit very accurate localization of the point
of pressure. Dimness of vision often appears very early on one or both
sides, and results in blindness of one eye in 33 per cent, of the cases and of
both -eyes in 16 per cent. In Henneberg's case ocular disturbance appeared
13 years before death. Bitemporal hemianopsia, with loss of pupillary reac-
tion to light, is a characteristic symptom resulting from pressure on the chiasm
with atrophy of the nasal half of the retina. Later, homonymous hemianop-
sia occurs from pressure on the whole optic tract. The directness of the
pressure on the optic tract renders stasis of the retinal papilla relatively rare
(15 per cent.). Bilateral non-pulsating exophthalmos occurs in 10 per cent,
of acromegalics and without acromegaly (Scalincie).

Oculomotor paralysis occurred in 10 of 174 cases of acromegaly (Hertel)
and in 29 per cent, of tumors without acromegaly (Lapersonne, Cantonnet).
Any of the cranial nerves may be affected. When the tumor reaches the
peduncle hemiplegia or more extensive paralyses result. Diffuse cerebral
symptoms characterize many cases and are exclusively present in some.
Narcolepsy, brief or prolonged, occurs in 25 per cent, of the cases without

TUMORS OF THE HYPOPHYSIS 917

acromegaly (Fr. Hochwart) but is not observed in acromegaly itself
(L'Hermitte). In 775 cases of cerebral tumors with psychoses, mania,
hypochondria, hallucinations, or dementia, Schuster found 61 tumors of the
hypophysis, 12 of which were associated with acromegaly. Glycosuria and
diabetes, at times very severe, is comparatively frequent in acromegaly.
Launois and Roy collected 16 cases. Without acromegaly glycosuria "is
rare, but simple polyuria is more frequent.

Radiographic examination is constantly indicated in hypophyseal tumors,
but the interpretation of enlargements of the sellar outlines is surrounded by
many uncertainties. Individual variations in the size of the sella, physiolog-
ical swelling of the hypophysis, widening of the sella by increased intracranial
pressure from other cerebral tumors, and tuberculous or syphilitic lesions
of the bones, are possible sources of diagnostic error. Actual erosion of bone
beginning with the posterior clinoid processes is far more reliable evidence
than simple enlargement of the sella.

(2) Dystrophic Type. — Three forms of general dystrophy occur with
hypophyseal tumors; giantism or dwarfism, acromegaly, and obesity with
genital hypoplasia.

Giantism is the result of precocious activity of the hypophysis in infancy,
while dwarfism follows loss of pituitary function in early life (Brissaud, Meige,
Launnois, Roy). Acromegaly results from overactivity of the hypophysis
in the adolescent or adult. The adiposogenital syndrome is the expression
of functional underactivity of the gland, chiefly of the posterior lobe. There
are giant acromegalics in whom the overactivity established in infancy
persists after the limit of height has been reached and many cases of giantism
reveal traces of the adiposogenital dystrophy when the glandular function
is exhausted. The passage of acromegaly into the adiposogenital dystrophy
is easily conceivable and this tendency has been emphasized especially by
Gushing in cases showing symptoms of both classes. While the relation of
these dystrophies to the functional state of the gland appears with sufficient
clearness to constitute a general principle, yet numerous apparent violations
of the principles are observed, and other complicating factors are found in
associated disturbances of other glands of internal secretion and in combina-
tions of individual features of the various dystrophies. Hence it has become
increasingly evident that each case of dystrophy connected with hypophyseal
disease is best analyzed as a form of polyglandular disturbance. The neces-
sity and the difficulties of this method are well illustrated in Cushing's studies.

(a) Giantism. — Pure cases of giantism fully studied from the polyglandu-
lar standpoint are rare. In Cushing's case (32), age 37, the body measured
251.5 cm. in length, the brain weighed 1884 gms., spleen icoogms., thymus
atrophic, thyroid not enlarged, adrenals extremely small, testes atrophic,
pancreas fibrosed. There were marked signs of pituitary insufficiency with
impotence, hypotrichosis, and obesity. The sella measured 2.2 X 2.7 cm.
and was occupied by a large cystic tumor in the walls of \vhich were irregular
alveoli of chromophobe cells. This case represents a preadolescent hyper -
pituitarism with terminal insufficiency.

In Bassoe's case (Winkler) there were leontiasis of the skull and a large
osteosarcoma compressing hypophysis and brain. The enlarged hypophysis
contained focal eosinophilic adenomas, areas of small, round, densely staining
cells, alveoli filled with colloid, hyaline vessels, hemorrhages and pigmenta-
tion. There was a large colloid goiter, thymus and testes were atrophic,
adrenals and pancreas normal.

Giantism with acromegaly is a relatively numerous class. Sternberg
states that 40 per cent, of all giants are acromegalic, but the literature con-

918

NEOPLASTIC DISEASES

tains few fully reported cases. The increase in height begins in early life and
ceases after a period of years, but the acromegalic changes continue, and
evidences of dyspituitarism are often added.

In Dana's acromegalic giant there was extensive enlargement of the
pituitary which led to central hemorrhage and softening, probably a pure
adenoma (cf. Hutchinson).

In the case of Lady Aama, Hutchinson found the hypophysis as large
as a pigeon's egg, but no microscopical study could be made.

(b) Infantilism. — Various types of imperfect development of the skeleton
and especially of the genital organs are associated with hypophyseal disease.
In general, pituitary infantilism results from pre-adolescent hypopituitarism,
but the influence of disorders of the thyroid, thymus, and adrenal are often

FIG. 462. FIG. 463.

FIG. 462. — Preadolescent hyperpituitarism with giant overgrowth. Enlarged sella, con-
taining a cystic struma pituitaria. No neighborhood symptoms. Terminal glandular
insufficiency (hypopituitarism). Note extreme length of arms and thighs in relation to
usual 1 8-inch chair. (Gushing, " The Pituitary Body and Its Disorders.")

FIG. 463. — Pituitary dystrophy, Lorain type. Pituitary tumor, small adult body, re-
tarded sexual development, no adiposity. (After Stewart.)

added. Considering the very numerous clinical forms and complex etiology
of the conditions designated as infantilism it is evident that pituitary lesions
have a very restricted importance in this field (cf. Strauch). Dwarfism
in pronounced form was associated with a diffuse fibroma or fibrosis of the
pituitary in Hutchinson's case.

A combination of gigantism with infantilism is described by Lemos.
There is excessive growth of long bones and some facial hypertrophy, but
the general bodily conformation is infantile and there is genital hypoplasia.
The mentality is defective. It is referred to a congenital hypertrophy of the
pituitary which manifests itself early in life.

Lorain described a form of infantilism characterized by a general smallness

TUMORS OF THE HYPOPHYSIS

919

and delicacy of body with correspondingly small genitals, but without obesity.
Growth is arrested but adult proportions' of the body are maintained. While
Gushing, Levi, Leman and others have demonstrated by radiographs enlarge-
ment of the sella in such cases, microscopical studies of the glands I have been
unable to find.

Infantilism reversif of Gandy, or tardif of Brissaud and Bauer, is marked
by traces of myxedema, atrophy of genitals, and loss of hair. In such cases
Gandy found atrophy of thyroid and hypophysis, while Sainton and Rathery
observed atrophy of thyroid, genital organs, and adrenal, but the hypophysi's
was represented by a large cystic carcinoma contain-
ing altered blood. They review several cases of myx-
edema with tumors, chiefly chromophile hyperplasia,
of the hypophysis and interpret the condition as a
compensatory effect from thyroid hypoplasia. Claude
and Gougerot in a similar case of polyglandular dis-
turbance report atrophy of thyroid, adrenals and
testis with a diminutive hypophysis, sclerosed but
otherwise normal.

Ateliosis is a term used by Gilford to indicate a
form of infantilism in which active growth ceases and
an infantile or adolescent body type persists. It is
probably a polyglandular syndrome in which the
hypophysis is functionally deficient.

(c) Acromegaly. — The dictum of Marie that acro-
megaly is essentially the result of pituitary disease
has been strongly supported by the observations and
debates of recent years. Coincidentally it has been
shown that acromegaly is associated chiefly with
hyperpituitarism, that numerous subvarieties of this
disease are referable to complications, chiefly those
resulting from gradual functional failure of the gland
and involvement of other glands of internal secretion.
The further claim advanced by B. Fischer and others,
that hyperplasia or a tumor of the pituitary is in-
variably present may not be admissible, but is not far
from demonstration. Petren reviews the consider-
able list of reported cases of acromegaly without
hypophyseal lesion and accepts six as fully attested
by microscopical examination (Dallemagne, Mitchell,
LeCount, Huchard, Launois, Lewis, Widal, Roy, Froin,
and Petren).

B. Fischer, however, rejects all such cases, and
affirms that there is no recorded instance of acro-
megaly in which the absence of specific changes in
the pituitary has been proven. This position may
be too radical, but it is obvious that changes once
present may disappear. Thus Huchard's and one of
Cushing's cases, showed a small sclerosed pituitary in an enlarged sella. The
primary pituitary origin of acromegaly is strongly indicated by the fact that
the great majority of cases show pronounced hyperplasia or tumors of this
organ. The hypophysis, however, is not the only organ involved in acro-
megaly. The disease is of complex etiology and pathogenesis and several
clinica'l varieties depend upon associated lesions.

Many cases of pituitary enlargement fail to give acromegaly, even

FIG. 464. — A typical
case of infantilism of
type Lorain, with an
enlarged 2 cm. sella.
Patient aged 20 years,
6 months; height 4 ft.
5 in. (133 cm.). (Ettore
Levi.}

920 N EOF LA STIC DISEASES

when, as in Cagnetto's and Zak's cases, the eosinophile cells are greatly
in excess. The disease is observed with pineal tumors, and the thyroid
and sex glands are commonly involved. Hypophyseal disease is therefore an
essential but not a sufficient cause of acromegaly (Parisot). Acromegalic
changes are also observed with hydrocephalus from cerebellar cyst (Gush-
ing), in neurofibromatosis (Nichols and Favre), and in syringomyelia
(Petren).

An hereditary element is observed, especially in negroes. Infantile
acromegaly has been observed in a series of 20 cases collected by Hutinel,
and Babonneix and Paisseau. Matassari has shown that this condition may
be prevented by precocious ossification of epiphyseal cartilages (Claude,
Franchini, Giglio). There may be, however, very marked overgrowth of
skull, face, hands and feet. Many cases show acromegalic overgrowth with
adiposogenital dystrophy.

Acromegalic conditions of moderate degree combined with myxedema and
associated with hypophyseal tumors are of not infrequent occurrence
(Grahaud, Lit.). In such a case Calderara found an atrophic thyroid, while
the pituitary was doubled in size by a chromophobe struma. Boyce and
Beadles in a myxedematous obese subject found the hypophysis much enlarged,
while in a similar case Dalton reports an atypical "sarcoma" destroying
pituitary and posterior lobe. Other reports worthy of mention include a
" sarcoma" (Pechkranz), en dothelioma compressing the hypophysis (Stewart),
carcinoma extending into the face (Zollner), and a cystic tumor as large
as an orange (Sainton, Rathery).

Colloid goiters are frequently observed in acromegaly, but hyper-
thyroidism rarely. Exophthalmos may result from the pituitary tumor.
Thyroid hyperplasia occurred after partial hypophysectomy in two of
Hochenegg's cases (Exner).

Acromegalics, especially in the late stages of dyspituitarism, may give
evidence of adrenal insufficiency in the form of pigmentation of the skin,
extreme asthenia, low blood pressure and hypoglycemia. While the adrenals
are usually reported as normal, yet in a giant acromegalic with cystic pitui-
tary struma (32) Gushing found atrophic adrenals. Hyperactivity of the
adrenal is sometimes indicated in acromegaly and Renon and De Lille
observed adrenal hypertrophy after injections of hypophyseal extracts. In
rare cases of acromegaly there is marked hypertrophy of the adrenals.
Schultze and Fischer report cases in which hyperplasia of the Z. fasciculata
reached an almost adenomatous grade.

Glycosuria and diabetes are often associated with acromegaly. The
pancreas is usually reported as normal but Hansemann found interstitial
pancreatitis and a colloid goiter, and pancreatic lesions are reported by
Dallemagne and Pineles. In one case with malignant hypophyseal adenoma
I found interstitial pancreatitis and giant-cell formation in hypertrophied
islands. Although polyuria is induced by injections of extracts of the pars
nervosa its occurrence with hypophyseal tumors is probably to be classed
with the polyuria of other brain tumors.

Grahaud has collected n cases of young acromegalics with marked or
extreme obesity. Such a condition is referred by Fischer to a tumor of
the anterior compressing the posterior lobe. It may also be explained as
a combination of acromegaly with primary testicular hypoplasia. Analysis
of the case reports shows that both these explanations may apply. Fischer's
case was a perivascular round-cell tumor with an epithelial colloid cyst
compressing the remainder of the pituitary and pars nervosa.

Nearly all cases of acromegaly are accompanied by genital dystrophy,

TL\}fORS OF TUP: HYPOPHYSIS 921

a fact which accords with the view that a slight long-continued pressure on
the pars nervosa affects the genital glands (L. Pick, Fischer).

In the adult evidence of hypophyseal failure appears in the tendency
of most acromegalics to lay on fat. This feature is pronounced in Dercum''s
disease, adiposis dolorosa, marked by local or general adiposity, pains and
tenderness, asthenia, and psychoses. Hypophyseal lesions observed in this
condition include; pituitary glioma (Burr); adenocarcinoma (McCarthy);
alveolar carcinoma (Guillain, Alquier); processes suggesting carcinoma,
2 cases (Price); epithelial tumor (Launois, Clunet); aneurism compressing
hypophysis (Lyon). Dammann, however, reports a normal hypophysis
and emphasizes the frequency of various phases of chronic thyroid disturb-
ance in this disease.

Status lymphaticus with persistent thymus and lymphoid hyperplasia
is occasionally observed in acromegaly but belongs more clearly with adipose-
genital dystrophy. In two such cases Gushing reports a chromophobe ade-
noma, and a cerebellar cyst. Epileptic seizures are also common in this
group of cases. Amenorrhea has long been recognized as an early symptom
in many acromegalics, and most male subjects of the disease are sexually
deficient (Marie, Gushing). The ovaries are usually cystic or atrophic, and
in the testes the interstitial cells are deficient or absent (Gushing). In a
peculiar syndrome of precocious sexual development, hypertrichosis, obesity,
asthenia, and blindness, Gushing observed some hyperplasia of the inter-
stitial cells.

Finally, in a group of cases, many organs and tissues are affected by
developmental anomalies and acquired disorders, revealing a disturbance
of growth and function which is nearly universal. Thus in Harbitz' case,
there was a large chromophobic adenoma with apparent destruction of
pars nervosa, associated with acromegaly, hemiatrophia facialis, overgrowth
of lung, tiachea, liver, spleen, kidney, heart, larynx, thyroid, pancreas, and
adrenals. In Amslers case an adenoma, chiefly eosinophile, was associated
'with enlargement of tongue, spleen, liver, kidneys, thyroid and heart, and
atrophy of testis.

(d) Dystrophia adiposogenitalis is the most characteristic form of hypo-
physeal dyscrasia. Its numerous subvarieties suggest the implication of other
glands of internal secretion. Both clinical and experimental studies indicate
that the glandular insufficiency affects chiefly the posterior lobe. The
secretion of this lobe raises blood pressure and exerts a peculiar influence
on the metabolism of fats and carbohydrates. The subjects exhibit hypo-
glycemia and high sugar tolerance, 300-400 gms. of glucose by mouth
failing to produce glycosuria. Apparently carbohydrates are converted
into fats and deposited in the depot regions, subcutaneous and subserous
tissues and the liver. The associated genital hypoplasia doubtless favors
fat deposit by some other mechanism. While other glands may be seconda-
rily concerned the predominance of the hypophysis is indicated by the
remarkable improvement observed after operation. V. Eiselsberg, Gushing
and others have reported improvement in pressure symptoms, restoration
of sexual function, growth of hair, etc., after extirpation of various tumors.
Moreover Gushing has shown that partial extirpation of the anterior lobe
leads to obesity and genital hypoplasia. In subsequent experiments, how-
ever, he attributed this result to injury to the pars nervosa.

The cases differ chiefly in the feature of overgrowth and in the condition
of the genitals. In the type described by Froelich an hypophyseal tumor is
associated with diminished growth, genital hypoplasia, and adiposity. In
childhood the condition produces many of the characteristic excessively fat

922

NEOPLASTIC DISEASES

children with genital hypoplasia (Neurath). The fully developed condition
presents many or all of the following features; fat deposits in the skin of hips,
abdomen, and genitals; atrophy and loss of function of the genital organs,
amenorrhea, anaphrodisia, hypotrichosis; limitation of skeletal growth and
traces of infantilism, malformation of genitals, cryptorchismus, hypospadias,
absence of one testicle, transformation of sexual characters, hypertrophy
of breasts, and widening of pelvis in males. In many details these cases may
present the features of status lymphaticus, but the hypoplasia of the aorta
and hyperplasia of the lymphatic structures are usually not noted.

Genital hyperplasia and skeletal overgrowth with obesity are observed
without hypophyseal tumor in cases of hydrocephalus (Marburg). Or

hydrocephalus without hypophyseal tumor
may yield skeletal overgrowth, obesity, and
genital hypoplasia (Gushing, Case 24).

In adolescence the male develops feminine
outlines, genital hypoplasia, hypotrichosis,
and adiposity, and when lymphoid hyperplasia
and persistent thymus are added, the con-
dition merges with status lymphaticus (Gush-
ing, 5, 8, 10), Mixter and Quackenboss, Strada,
Souques and Chauvet.

In genera] the tumors associated with
adiposogenital dystrophy are characterized
by a wide diversity of origin and structure,
by a frequent failure to involve the pituitary,
by a tendency to grow into the third ventricle
and to destroy the infundibulum, and by
their comparative inaccessibility to surgical
attack. Of 34 cases collected by Strada,
Ottenberg and Pick, six left the hypophysis
normal, eight were derived from the hypo-'
physeal duct, twenty-three represented nearly
all the histological varieties of pituitary
neoplasms, and some arose from the choroid
plexus or ependyma, or from the pial en-
dothelium. Pick emphasizes the bipartite
character of many tumors, which present a
small intrasellar and a larger extrasellar or
intraventricular portion connected by a
pedicle.

Relation between the Type of Tumor and the
Symptom Complex. — Throughout the above

clinical types of hypophyseal disturbance a certain relation may be
traced between the type and location of the tumor and the symptoms.
Skeletal and tissue overgrowth and the various form of acromegaly and giant-
ism, at least during their active stages, are associated with hyperplasia of the
eosinophile cells of the pituitary. Although the gland may be considerably
enlarged by this process it is doubtful if any of the eosinophile hyperplasias
can be regarded as true neoplasms. Even in actively progressive and early
acromegaly it cannot be claimed that eosinophile cells are exclusively con-
cerned, since acromegaly develops from the hyperplasia of gestation which
affects the specific cells of Erdheim. Moreover the great majority of glands
examined microscopically from advanced cases of acromegaly show, not
eosinophile overgrowth but adenomas of chromophobic or quite atypical

FIG. 465. — Hypopituitarism.
Adiposo-g enital dystrophy,
type Froelich. No sign of
tumor. (After Batten.)

TUMORS OF THE HYPOPHYSIS

small or large round-cells. Such cases usually show evidences of dyspitu-
itarism. Hence the pituitary lesion beginning with hyperplasia of specific
functionating cells, if it assumes the character of a neoplasm, does so at the
expense of form and function of the secreting cells. It is clear that the same
type of atypical adenoma may occur in both acromegaly and in adiposogenital
dystrophy (Wurmbrand).

The natural course of these hyperplasias varies considerably. Some
appear to be long maintained as simple functional hyperplasia and are found
in this condition at operation or autopsy. Others reaching a large size tend to
suffer central softening and terminate in cysts with gelatinous or blood-
stained contents. Gradual atrophy with calcification, which may be com-
plete (Pick, Konjetzny), may supervene. In
many cases the functional hyperplasia passes
rapidly or slowly into a neoplastic process
and distinctly malignant features may appear.
In these relations the hypophysis presents a
close parallel with the thyroid. Yet it is
frequently noted that malignant histological
structures are associated with slow clinical
course, and in several instances the symptoms
have regressed after partial removal of the
tumors (Pick). Nearly all the extreme forms
of pituitary overgrowth are associated with
functional insufficiency, \vhile the period of
functional excess is early and transient. In
this stage there appears to be little relation
between the various histological peculiarities
of the tumor and the clinical symptoms.
The former represent local phases of tumor
growth, while the latter reveal an increasing
participation of other glands of internal
secretion, and the complicating pressure
symptoms.

While cases of pure acromegaly are com-
paratively rare, signs of glandular insufficiency
overtake most cases of acromegaly, and vari-
ous forms of primary hypophyseal atrophy are
relatively common. The lists of pronounced
adiposogenital dystrophy contain a large pro-
portion of atypical overgrowths and true trophy, from bullet wound of
tumors (Strada, Ottenberg). Extrapituitary hypophysis. (Madehmg.)
tumors and those derived from the hypo-
physeal duct almost invariably lead to primary dystrophy without acro-
megaly. Wurmbrand and others have noted a prompt response of the
thyroid and genital organs after operations on hypophyseal adenoma.

Three theories have been advanced in explanation of the adiposogenital dystrophy, (a)
deficiency of the internal secretion of the hypophysis (Frohlich), (6) pressure from any
source on a supposed cerebral center (Erdheim), and (c) a lesion of the posterior lobe or
the infundibulum. In most cases the anatomical condition is consistent with any one of
the three theories. In considering the evidence bearing on these theories it is necessary to
distinguish between the secondary adiposogenital dystrophy which follows acromegaly and
the primary form which develops without a preliminary period of hyperpituitarism.

(i) The chief evidence in favor of the theory of pituitary deficiency is the fact that
dystrophy overtakes most acromegalics in later stages and is associated with destructive
tumors of the hypophysis and in general with chromophobic strumas. This condition has

FIG. 466. — Adiposogenital dys-

924 N EOF LAST 1C DISEASES

also arisen from a bullet wound of the pituitary (Madelung), and from solitary tubercle
of the anterior lobe (Gushing). An old hemorrhage destroying two- thirds of the pituitary
was the sole lesion found in a case of Maranon's. On the other hand there have been
many destructive lesions of the pituitary, including tumors, tubercle, and gummas, which
have failed to produce dystrophy (L. Pick, Lit.). Atrophy of the pituitary leads to dwarf-
ism rather than to adiposogenital dystrophy. Many considerations favoring the theory
of pituitary insufficiency are collected by Marburg, Melchoir, and Strada.

(2) While a certain grade of cerebral adiposity has appeared with miscellaneous brain
tumors and hydrocephalus, yet the existence of such a center as Erdheim assumes is quite
hypothetical, and in many cases of dystrophy the element of cerebral pressure has been
absent.

(3) Many observations favor the importance of disturbed function of the pars nervosa
in adiposogenital dystrophy. In many cases there is a tumor of the hypophyseal duct
which compresses the infundibulum and the pars nervosa while leaving the pituitary intact.
It appears to be the location rather than the type of tumor which determines the dys-
trophy. Tumors involving the third ventricle frequently give rise to dystrophy, apparently
by occluding the infundibulum (Erdheim, Selke, Bartels, Zak). Fischer describes a
tumor of the third ventricle which he details as meeting these conditions exactly. Exten-
sive lesions of the anterior lobe without involvement of the posterior, as by tubercle or
gummas (Pick), have repeatedly failed to yield the characteristic dystrophy (Stroebe,
Schmidt). There is a theoretical difficulty in assuming that hyperf unction with acromegaly
can coexist in the same gland with hypofunction. Finally, Gushing has shown that
experimental lesions of the pars nervosa alone lead to adiposogenital dystrophy, and in
not a few cases marked improvement has followed operative removal of cystic tumors
compressing chiefly the posterior lobe and infundibulum. The weight of evidence is thus
distinctly in favor of the mechanical theory of pressure on the pars nervosa. L. Pick, also,
after a critical review of much of the literature, is inclined to favor the mechanical theory.

CHAPTER XLVIII
THE PINEAL GLAND AND ITS TUMORS

Histology. — The pineal gland at full development measures 10 to 12 X 5 to 8 mm., but
suffers gradual atrophy beginning at the seventh year. Its normal weight in children is
20-25 centigrams. It is surrounded by a thin capsule of connective tissue which closely
invests the gland, joins with many septa supporting groups of parenchymal cells, and is
connected with a loose vascular tunic derived from the choroid plexus. The stroma
steadily increases in amount with age, fine acellular strands appear sub-dividing the cell
groups and fusing with them, while hyaline or calcine granules appear in increasing numbers.
Blood-vessels are scanty.

The parenchyma is composed of groups of polyhedral cells irregular from mutual
pressure. The cells are finely granular and often contain small vacuoles. The nuclei are
somewhat peculiar in their reticular network, small nucleoli, and large size, in comparison
with the cytoplasm. They stain more deeply in young subjects. At this age both nuclei
and cytoplasm may contain hyaline globules which Dimitrowa regards as secretion. The
lipoid mitochondria demonstrated by Ruggeri are much more definite indications of a
secretory function. Krabbe in 100 human glands always found basophilic granules in and
about the nucleus which he regarded as secretory. The cells are distinctly epithelioid in
infancy and form well-defined groups without lumina, but in adults they are less regular
and the groups are less compact. By Weigert's or Heidenhain's stains glia fibrils may be
demonstrated arising from the cells, passing between cells, and surrounding cell groups.
Compact areas of glia fibers may appear in the adult. Marburg demonstrated medullated
fibers. This structure suggests that the gland is composed essentially of modified glia-
cells which first resemble neuro-epithelium with secretory functions and later assume the
form of glia-cells.

About the vessels may sometimes be seen small cells with compact nuclei and acido-
phile cytoplasm (Galasescu, Urechia). According to Marburg the gland always contains
ependymal cells derived from the ependymal recess in which it lies.

Striated muscle-fibers, common in the beef, have occasionally appeared in the stroma
of the human gland. Pappenheimer regards them as analogues of the myoid cells of the
thymus and as derivatives of epithelium.

General Pathology. — Hypertrophy of the epiphysis is recorded by Virchow in an infant
and in an aged woman with dural psammoma: by Heurot in myxedema; and by Marburg
in a case of general cerebral hypertrophy. In a polyglandular syndrome with hypophyseal
adenoma Bartlett describes hyperplasia of the pineal gland. Atrophy of the gland of
quite unusual degree has been observed by Laignel, Lavastine.

Calcific deposits are constantly present after the seventh year. While usually limited
to coarse granules the process reached an extreme degree in the case of Drelincourt in which
the gland was a stony mass as large as a pigeon egg. Schnepf in an idiot found the gland
replaced by two small concretions. Extensive hematomas are described by Ziegler and
Simon.

Cysts are frequently observed at all ages. Many small cysts without definite lining
may form during involution by softening of the increasing areas of gliosis. Ependymal
cysts lined by cubical or high epithelium arise from distention of alveoli of included epen-
dymal cells (Marburg). Either variety may be found without symptoms and some have
produced hydrocephalus and fatal tumor syndromes. (Bouchut, Joukowsky, Xieden,
Neumann, Campbell, et al.)

TUMORS OF THE PINEAL GLAND

Of the very rare tumors those of the pineal gland are of much interest
because of the peculiarities of their structure and origin and because of the
remarkable disturbance of growth with which they are often associated
(Seigneur, Lit.).

925

926 NEOPLASTIC DISEASES

Occurrence. — Sixty cases were collected by Bailey and Jelliffe in 191 1,
while Seigneur, 1912, found reports of sixty-five. To these may be added the
cases of Wood, Goldzieher, and Rorschach. Other reports, as those of
Pellizzi, are of clinical diagnoses.

Classification. — Pineal tumors form three well-defined groups:

(1) Cysts.

(2) Teratomas.

(3) Ependymal gliomas.

Cysts of various types constituted 12 of the 65 tumors collected by
Seigneur. Most of them were simple cysts without tumor growth, but their
general and local symptoms did not appear to be influenced by that fact.
The simple cysts vary in size from that of a pea (Garrod) to a tumor
containing 20 c.c. of fluid (Joukowsky). They project into or fill the third
ventricle and compress the corpora quadrigemina or the optic tracts. By
pressure on the veins of Galen and occlusion of the ventricle they almost
invariably lead to hydrocephalus. They have occurred in the newborn and
at the age of 59 years (Joukowsky, Friedreich). They produce the usual
symptoms of pineal tumors, but simple cysts have not as yet been observed
with genital overgrowth.

The simple hydrops cysticus produces multiple small cysts filled with clear
fluid and lined by flattened, cubical, or cylindrical epithelium. Very simi-
lar multiple cysts from softened areas of gliosis fail to show a definite cell
lining. In 5 cases the cyst formed in a true neoplasm, usually of the type
of gliosarcoma (Ogle, Verger, Neumann). The wall in Falkson's tumor con-
tained cartilage, and in Friedrich's tumor the solid tissue waspsammomatous.
Teratoma. — The pineal teratoma is exclusively observed in young
males, from 4 to 16 years of age and is regularly associated with precocious
sexual development, hirsuties and sometimes with adiposity and general
overgrowth. About a dozen cases have been recorded but the distinctly
teratomatous nature of some of them is doubtful. Thus Oestreich and
Slawyk describe as cystic psammosarcoma a cystic growth as large as an
apple, which Askanazy regarded as a teratoma on account of the presence of
islets of tissue resembling cartilage.

The complex teratomas are of moderate size, solid or cystic, circumscribed,
and produce the usual local changes from pressure. They may be largely
dermoidal, containing hair, sebaceous material, epidermoid cysts, and carti-
lage (Bailey and Jelliffe). Weigert's tumor was a complex growth con-
taining cysts lined by squamous or cylindrical cells, hair, sebaceous glands,
sebum, calcine grains, cartilage, fat tissue, and nonmedullated nerve-fibers.
Gutzeit's tumor presented skin, sebaceous glands, fat, and smooth muscle.
A layer of normal or adenomatous pineal tissue may be found alongside
of the tumor (Hochwart, Gutzeit). Less complex growths classed as tera-
tomas have yielded the structure of adenochondrosarcoma with smooth
muscle (Coats). Somewhat uncertain data are available in the cases of
Gauderer, Ogle, P. Neumann.

In a hemorrhagic growth Askanazy found the typical structure of cho-
rioma with well-defined syncytium and glycogen-holding Langhans' cells.
The significance of the teratomas has been variously interpreted. The
development of the tumor anteriorly from the gland and the presence of
nerve-fibers, seemed to Marburg to support the theory that the tumor repre-
sents an abortive third eye. Ogle ventured to liken the high epithelial lining
of a cyst to the retina of a third eye. Askanazy applies the theory of origin
from a totipotent sex cell and traces in the condition a form of pseudoges-
tation. It may be noted that the breasts were enlarged in Oestreich's

THE PINEAL GLAND AND ITS TUMORS

927

case. This change as well as the genital overgrowth he would refer to the
presence of fetal tissue in the body. Yet the same genital precocity occurs
in simple tumors of the epiphysis.

Were it not for the presence of hair, skin and sebaceous glands it would
be possible to regard all these simple tumors as autochthonous teratoids.
A partial choriomatous structure is produced in testicular tumors by altera-
tions in the cylindrical cell lining of blood-spaces. While the structure
of Askanazy's tumor closely approaches that of chorioma, Goldzieher's very
similar tumor was traced to the cells lining numerous blood-spaces. The
presence of cartilage may be satisfactorily explained by metaplasia. Smooth
and striated muscle is an occasional element of the normal epiphysis.
Ependymal epithelium may become high and cylindrical or flat and squa-
mous and sharp transitions from one to the other type are observed in the
so-called teratomas (Weigert). Thus all the elements except dermal struc-
tures may be derived from the pineal gland itself. The dermal structures, as

FIG. 467. — Chorioma of pineal gland. (After Askanazy.,

hair and sebaceous glands, if they have been correctly interpreted, seem to
require an ectodermal tissue, which may possibly reach the pineal gland by the
same developmental disturbance that yields dermal cholesteatomas at the
cerebral base. The pure pineal lipoma of Hirtz indicates that misplaced
tissue may rest in this gland as well as in the hypophysis.

The few recorded cases, especially those of Falkson and Hochwart and
Coats, seem already to furnish many transitions from autochthonous mixed
tumors, as adenochondrosarcoma, to teratomas, so that the pineal teratomas
are not so sharply separated from teratoids as to warrant their final accept-
ance as genuine tridermal neoplasms.

Ependymal Glioma. — The majority of pineal tumors present a structure
best interpreted as formal variations of the modified ependymal cells from
which the human epiphysis is immediately derived.

They occur at later ages than the other tumors, raising the average
age of incidence of all pineal growths to 20 years for males and, for the 14

928 N EOF LA STIC DISEASES

cases in females, to 21 years. The usual duration is from one to eighteen
months (Falkson, Oestreich). A hard tumor of Blane's, not examined
microscopically, and Hertz's lipoma, progressed for three and four years.
Hempel's patient died three years after trauma. As a rule they grow more
rapidly and reach a larger size than other pineal tumors, although many are
soon fatal. Turner's mixed tumor reached the size of a kidney and Hempel's
solid carcinoma was as large as a hen's egg. The larger growths may distend
the third, lateral, and fourth ventricles, with hydrocephalus which in children
may widen the cranial sutures. Finkelburg's sarcoma involved the corpora
quadrigemina, hypophysis, floor of third ventricle, chiasm and posterior
commissure. Howell's first case was quite as extensive. Forster's carci-
noma with general metastases is out of line with all later reports. The
exact origin of some other large tumors of this region must also be accepted
with reserve.

The structure of the mixed pineal tumors is extremely varied and
these growths have been reported under many terms which served to desig-
nate the main structural type. Thus there appear 3 pure gliomas, 4 glio-
sarcomas, 4 angiosarcomas, 4 psammosarcomas, 2 chondrosarcomas, and
4 round-cell, or spindle-cell sarcomas, while one tumor was called adenoma,
and 3 carcinoma (Seigneur). There is no good reason to doubt that all
these types represent variations in the growth tendencies of the fully differ-
entiated cells of the gland.

An adenomatous structure is approached by tumors which reproduce
the features of the normal gland and in which many well-defined groups of
polyhedral cells appear in a scanty fibrous stroma. The polyhedral cells
are, however, fused with the stroma and lumina are absent or illdefined, so
that the resemblance to a glandular adenoma is seldom pronounced.

Ependymal neuroglioma is the term employed by Pappenheimer to desig-
nate a cellular mixed tumor, and may well be extended to cover the entire
group, to the exclusion of such terms as adenoma, carcinoma and sarcoma.
The cells are usually abundant and are arranged in groups surrounded by
stroma, or they grow diffusely between fibrous strands, or sheath numerous
blood-vessels. They are polyhedral with clear cytoplasm and sharp borders
resembling ependymal epithelium and such cells may inclose fine lumina.
Wide lumina lined by high cylindrical cells appear in teratomas and also in
mixed tumors without other teratomatous characters. Many cells are
rounded, loosely distributed, and exhibit many fibrils. Lymphocytes may
be mingled with the tumor cells. Diffusely growing tumors of this type re-
semble round-cell sarcoma, but are properly interpreted as gliomas or gliosar-
comas. Excessive development of blood-vessels may produce the appearance
of perithelioma or angiosarcoma. In these very vascular tumors syncytial
masses may form, probably from ependymal epithelium. In Wood's tumor
flattened or spindle cells surrounded many small blood-vessels. Heidenhain's
or Mallory's stains may demonstrate neuroglia fibrils running from and be-
tween the cells. Best's stain demonstrates glycogen in cell vacuoles.

In the stroma calcific deposits are very common and chondromatous
metaplasia may yield the masses of cartilage occasionally observed. Marburg
traced the origin of the tumor-cells from the pineal parenchyma, finding an
external zone of gland tissue, an intermediate layer of proliferating cells of
epehdymal type, and a central area chiefly gliomatous. In Howell's cases the
central area was composed of diffuse large round-cells without intercellular
substance, while the periphery yielded alveoli somewhat larger than those of
the normal gland.

Symptomatology. — The chief interest in pineal tumors lies in their symp-

THE PINEAL GLAND AND ITS TUMORS 929

tomatology, the study of which is susceptible of the same elaboration as
has been given to hypophyseal growths.

The clinical features present two phases: (i) Pressure symptoms,
general and specific, and (2) disturbances in the physiology of growth.

(1) Pressure symptoms common to this and other brain tumors, headache,
vomiting, paresthesias, and vertigo, mark the onset of most cases. The
usual absence of brachycardia is referred by M. Neumann to early closure
of the aqueduct of Sylvius which spares the vagus in the fourth ventricle
from pressure. More specific of the location of the tumors are the staggering
gait, cerebellar ataxia from pressure on the vermis, and peculiar ocular
disturbances including nystagmus, ophthalmoplegia and loss of pupillary
reactions. Seigneur found paralysis of the common oculomotor nerve in
18 cases, of the pathetic in 7, and of the externus in 9. The oculomotor is
affected by destruction of its nucleus and the pathetic and externus by pres-
sure on the trunks. Auditory disturbance may be referred to pressure on the
auditory nerve or corpora quadrigemina. Unilateral facial palsy may occur.
Failure of mentality is marked by dulness, delirium or prolonged somnolence
in which hydrocephalus probably plays a part. Epileptic convulsions
frequently occur. Polyphagia, polyuria, and glycosuria have been observed.

(2) The disturbance of growth affects chiefly the genitals but is often
associated with adiposity and occasionally with general and symmetrical
overgrowth. Hypertrophy of the penis and testes, growth of pubic hair and
precocious sexual instinct, have been observed with most tumors classed as
teratomas, as well as with simple, benign and malignant tumors. In the testes
there is marked development of the interstitial cells (Goldzieher). In
Oestreich's case the enlarged breasts in a boy of four secreted colostrum and
the testes were much enlarged. In the case of Raymond and Claude the
genital organs were small, but there was a growth of fine hair on the lip and
cheeks. Hirsuties has been much more frequent than hypertrophy of the
genitals. Hochwart mentions a deepening of the voice. In Schmidt's case
conception occurred at 15 years and menstruation ceased at 22 years. Gen-
eral overgrowth of the body is described by Oestreich, Raymond, Hochwart,
and Bailey and Jelliffe. Daly's patient, aged 23, with a large carcinoma,
had polyphagia and gained 30 kilos in 6 months.

Adiposis has been observed in all varieties of tumors and is apparently
not to be distinguished clinically from hypophyseal obesity. Marburg
stated expressly that the hypophysis was normal in his case and yet the usual
obesity was present.

The pathogenesis of the metabolic symptoms remains obscure. The
combination of genital overgrowth with obesity is contrasted with the genital
hypoplasia and adiposity of hypophyseal tumors. It may be assumed that
the pineal tumor excites genital overgrowth by a sympathetic influence on the
interstitial cells of the testis, which in some cases have been found hyperplastic.
The obesity may then be attributed to pressure on the hypophysis, pars
nervosa, or distension of the infundibulum. This interpretation rests on the
theories of hyperpinealism and hypophyseal insufficiency. It is not entirely
consistent \\ith Raymond's case of large glioma, hydrocephalus, obesity, and
testicular atrophy.' Yet most observations indicate that pineal overgrowth
stimulates growth of the testes.

Adrenal tumors are often associated with overgrowth, obesity, and
genital precocity. With hypophyseal tumors the adrenals were found normal
by Marburg and Goldzieher, but were hyperplastic in Raymond's case. In
each of these cases there was genital overgrowth. A direct influence of the
adrenal may therefore be eliminated.

930 NEOPLASTIC DISEASES

Signs of status lymphaticus with persistence of thymus were noted by
M. Neuman and Marburg.

Experimental studies are already not without suggestive results (Dana,
Berkeley, Lit.). Exner and Boese destroyed the pineal in 95 rabbits without
observing any change in 22 surviving animals. Foa, however, observed
increase of weight and genital overgrowth in three roosters deprived of the
pineal gland in the fifth week of life. Biach and Hulles produced marked
atrophy of the pineal gland by castrating kittens. Berkeley produced accele-
ration of growth in young animals by injections of pineal nucleoproteid,
and he with Cornell and Goddard observed considerable mental improvement
in backward children fed on gland substance. McCord also observed
considerable acceleration of growth and sexual precocity in chicks and guinea-
pigs fed on the substance of calves' pineal.

The foregoing clinical, pathological, and experimental data seem to point
rather strongly to the conclusion that normal activity of the pineal gland
tacilitates normal growth in general and sexual development in particular.
Acceleration of these functions occurring in the course of pineal tumors may
therefore be interpreted as hyperpinealism. In the absence of further data
the obesity and hypertrichosis may be regarded as a part of the general and
sexual overgrowth, but the hypophyseal failure must be considered as a pos-
sible factor in the adiposity. The existence of hypopinealism is less clearly
established. There is evidently a close relationship between pineal and
testicular functions which is probably not of an antagonistic nature, but the
observations are as yet inadequate to define the exact position of the pineal
with reference to other glands of internal secretion.

CHAPTER XLIX
TERATOLOGY

Only a very limited portion of the extensive subject of teratology is of
interest to the oncologist, and that portion is probably of least importance to
teratology. Hence in the great scope of Ballantyne's "Antenatal Pathology"
one finds an impressive catalogue of the multitudinous types of human de-
formities and monsters, but little regarding human teratomas. Marchand in
Eulenberg's Realencyclopedia (1911) presents an orderly and very exhaustive
list of forms and ably discusses the subject of causal genesis of double mon-
sters, without entering exactly into the details of many other questions.
Schwalbe's elaborate treatise presents the sum total of knowledge up to 1906,
the scope of which necessarily renders specific details somewhat inaccessible.
He emphasizes the existence of an unbroken series from identical twins,
through double monsters, teratomas, and mixed tumors down to some simple
tumors. In tracing the origin of these structures he introduces the
term " teratogenic termination period" to indicate the latest period of embry-
onal development at which a given structure could have originated. A
recent compilation is that of Hubner.

It must be admitted, I think, that while teratological studies have nar-
rowed down the range of possibilities in the origin of identical twins and have
defined the probable origin of most double monsters, yet the divergent views
regarding the nature of fetal inclusions and adult teratomas are almost as
numerous as ever.

Experimental teratology, as presented by Fischl, illuminates the principles
of embryogenesis but points out how teratomas may develop rather than
demonstrating how they actually arise.

Under these conditions it seems most serviceable for the present purpose
to indicate the present position of the various forms of abnormal growths
which belong to oncology, their general relation to one another in a series of
diminishing complexity, and to briefly review the factors probably present
in their origin. For the more complete discussion of all these subjects, the
reader should refer to the above-mentioned works.

There are, however, two important tendencies discernible in recent
embryological research which seem to be insufficiently considered in most
text-books on teratology. These are the growing recognition of frequent
impurities in specific germ layers and the increasing scope now being given
to the process of budding in embryogenesis.

It must be admitted that the doctrine of the rigid specificity of the germ
layers has suffered some limitation in recent years. The possibility that
in the formation of these layers the separation may be incomplete and that
portions of one layer may be carried over into another has been entertained
with increasing freedom. The further possibility that the formative capaci-
ties of anatomically pure germ layers may not always be restrained within
the rigid limits formerly set must also be considered. Especially in the
field of teratogenesis these infractions of the set laws of growth become of
first importance, for the practical inviolability of these laws has always been

931

932

N EOF LA STIC DISEASES

assumed as a necessary basis in the construction of theories of origin of tera-
tomas. To what extent recent studies in this direction will remodel the
conceptions of teratomas remains for the future to determine.

Secondly, the importance of budding of originally simple embryonal
tissues as a source of complex teratomas has probably been underestimated
by many observers who have been inclined to attribute all such complex
growths to originally complex sources, as isolated blastomeres, totipotent
sex cells, or embryonic inclusions. This principle, long since recognized
and amplified by R. Williams, applies especially to the parasitic implanta-
tions and complex mixed tumors, although it may be of less importance than
that author seems to imply in the origin of the irritation group of malignant
tumors. In many respects this conception appears in the references to the
" genius loci" and the development of secondary growth centers, which
appear in many discussions of the origin of teratomas.

Oncology is usually assumed to deal with the following list of develop-
mental anomalies and their sequelae.

(1) Asymmetrical double monsters, parasitic fetuses, or fetal inclusions.

(2) Teratomas.

(3) Complex dermoids or teratoid tumors.

(4) Mixed tumors.

(5) Simple dermoids and epidermoids.

DOUBLE MONSTERS

Double monsters are (i) symmetrical or (2) asymmetrical.

(i) Symmetrical double monsters consist of two equal or nearly equal
fetuses which are joined together at the cephalic ends (cephalopagi) ; or at
the thorax (thoracopagi) ; or at the pelvis (ischiopagi). Such conditions
may result from the partial fusion of two originally separate embryos derived

FIG. 468. — Case of ischiopagnus duplicatus, born at Hanau, Germany, Alar, n, 1643,

(After Wilder.)

from one ovum, or from the incomplete splitting of one original embryo.
Which of these two events actually occurs cannot at present be determined.
According to Marchand, all symmetrical double monsters have a single
chorion, as do monochorial twins, and nearly all have a single placenta.

In the causation of symmetrical double monsters there are several possi-
bilities. In the case of the asymmetrical double monster, the parasitic

TERATOLOGY

933

fetus is rudimentary, c>,nd this fact is the chief basis of the view that it origi-
nates from a structure of much reduced embryonic value. Marchand holds
that the parasitic fetus is derived either from a polar body or from an early
isolated blastomere. In the first instance the isolated structure is derived
from an unfertilized, in the latter from a fertilized ovum. Yet the possibil-
ity of fertilization of polar bodies even in the human subject may perhaps be
entertained, since in the flat worms this event is of regular occurrence and has
a definite function in the early embryo. The sacral parasites and epignathi,
from their structure, position, and mode of attachment, may be regarded as
developing within the amnion, while the abdominal parasites may arise
on the belly stalk outside the amnion and
become included during the closure of the
abdominal wall. A development from two
separate embryos is inconsistent with the
position of the parasite, which would
have to lie free on the yolk sac of the
autosite without connection with the chori-
on, as held by Ahlfeld and Taruffi. Yet
umbilical cords and even rudimentary
placentae have been observed with epi-
gnathi (Rathke) and abdominal inclusions.
Bonnet has accepted and elaborated this
view of the origin of parasitic inclusions
and many teratomas.

Schwalbe concludes that epignathi and
other teratomas arise from isolated blasto-
meres, but regards the development of
polar bodies as improbable. Fischel argues
at length against the origin from polar
bodies, and reasons that all fetal inclusions
arise (i) from a second fertilized ovum
attached to the first, or (2) from isolation
and dislocation of portions of the germ
layers. This point of view renders most
intelligible the apparently unbroken series
of complex to simpler structures occurring
at the caudal and cephalic extremities,
but as Marchand says, it probably over-
estimates the potencies of fragments of
differentiated germ layers. The ovum
may be abnormal and contain multiple
germ discs, which have often been observed
in human ovaries, or there may be an ab-
normal distribution of germ material. The
entrance of more than one spermatozoon into an ovum occurs in reptiles
but in man it probably entails an abnormality of the ovum which tends to
result in its death. Yet this outcome cannot be assumed as certain. The
occurrence of double headed and other abnormal spermatozoa has been
emphasized especially by Bromann and by Hofer and considered as a
possible source of double monsters. The formation of the double germinal
areas necessary for the origin of double monsters must occur after the
union of male and female pronuclei, since twinning is hereditary.

Experimental studies have demonstrated some of the conditions which
may exist in the origin of double monsters. Roux produced one-sided

FIG. 469. — a and b. Case of im-
perfect ischiopagnus duplicatus, show-
ing on one side a double bilateral
limb, composed of halves belonging
to each component. Born in Cadiz,
May 30, 1818; c, Monstrum Angli-
cum, born in Salisbury, Eng., Oct. 26,
1664. (Licetus.} (After Wilder.)

934

N EOF LA STIC DISEASES

embryos some of which were able to develop almost perfect embryos of
reduced size. This process he called "post-generation." The bilateral char-
acter of the human embryo may favor complete splitting but there is no
evidence that double monsters result from such factors. Mechanically

FIG. 470. — Lateral view of two cephalothoracopagi (Janus monsters), showing different
degrees of separation. The face which is toward the observer is duplicated by another
on the opposite side. Each face is contributed by the two components. (After Wilder.)

inverting the ova to 180° (Schultze, Wetzel), and the distorting effects of
distilled water (J. Loeb), have produced double embryos, but this method is
probably not followed in nature. Two primitive streaks and embryonal areas

c.a.

FIG. 471. — Position, form, and grouping of primordial germ cells in 33 somite chick
embryos. Pr.o., Germ cells; sp.m.. Splanchnic plate of mesoderm; c.a., Ccelomic angle;
ent, Entoderm. (After Swift.)

have often been observed in ova, and double monsters of this origin have
been traced in the chicken egg by Dareste. Marchand concludes that all
cases of symmetrical double monsters arise from two originally separate
embryonal areas which imperfectly fuse by ectoderm or en to derm and meso-

TERATOLOGY 935

derm, and that this process occurs during gastrulation. In symmetrical
monsters either member of the pair may be considerably dwarfed through
defects of the ovum or disturbances in placenta, cord, or amnion.

The importance of aberrant sex cells as sources of fetal implantations
has been emphasized by the observations of Nussbaum, Allen, and Swift,
who have found groups of such cells marooned in considerable numbers
all along the embryonal entoderm from which they are derived. In some
cases only a portion of these cells reach their normal haven in the sex glands.
That the teratomas of the sex glands are derived from primitive sex cells is
now generally accepted and it is highly probable that many extragenital
teratomas have the same origin. Since most observers agree with Schwalbe
and Marchand that no essential morphological distinctions separate the
genital and extragenital teratomas and the fetal implantations, it seems
not impossible that the entire group may be referred to a single origin.
At present the collateral evidence hardly justifies the extension of this theory
to the epignathi and sacral parasites, but the sex-cell theory has one great
advantage in that aberrant sex cells have been observed in numbers and
their common occurrence in man is established, whereas isolated blasto-
meres and developing polar bodies in the human subject are hypothetical
structures.

It thus appears that while the possible modes of morphogenesis of fetal
inclusions have been fully covered, the real source or sources of these
structures remain undetermined. It can only be stated that they arise from
nearly or quite totipotent material. The field of divided single, or fused
double, embryonal areas appears to be exhausted in the fused twins, thora-
copagi, etc. The weight of opinion seems to favor the view that the fetal
implantation arises from material of much less growth energy than is
possessed by any form of double embryo and niust be referred to isolated
blastomeres, to marooned sex cells, possibly in some instances to polar
bodies, and very probably in many in stances to the process of budding.

Of the causal genesis of double monsters and fetal implantations nothing
is definitely known. Clinical observations have given no hint of the under-
lying conditions. Signs of syphilis are rarely present, and no case of repeated
births of double monsters has been recorded. The extensive field of experi-
mental teratology, has, in the opinion of Schwalbe, added nothing to our
knowledge of causal genesis. Hubner's review consists of a repetition of the
data regarding multinucleated ova, multiple germ discs and embryonal areas,
abnormal or supernumerary spermatozoa, excessive germ material, and other
conditions which form the basis of the discussions of formal genesis.

THE PARASITIC FETUS

This form of parasitic growth appears chiefly in the sacral region, or
protruding from the pharynx (epignathi), or in the thoracic or abdominal
cavities. Its structure presents the organs of a fetus but always in imper-
fectly developed or rudimentary form, and often in disorderly arrangement.
An umbilical cord is often present and fetal membranes and even a placenta
or its homologous structure may be found. Schwalbe and Nakayama are
unable to separate sharply between such complete fetuses and much less
complex growths occurring in the same situations.

The origin of the fetal implantation may in certain cases be attributed
to a second embryo which in some way becomes attached to the tissues of
its host the autosite. This mode of origin is, however, probably the rarest
of events, for the evidence of comparative embryology points to the process

936 N EOF LA STIC DISEASES

of budding as the most probable source of parasitic implantations, especially
when the parasites are multiple and their development markedly im-
perfect.

Therefore in the origin of the parasitic fetus a wholly different process
is probably concerned from that which gives rise to true twin fetuses. True
twins may result from the fertilization of two separate ova derived from one
Graafian follicle, or from simultaneous ovulation from both ovaries as shown
by the presence of bilateral corpora lutea, or by rupture of more than one
follicle in the same ovary, an event which is common in lower animals. In
these cases the sex and form of the twins may differ and there are two sepa-
rate placentas and fetal membranes.

Identical twins develop from one ovum and are of the same sex and
characteristics, but the conformation of the placenta and membranes varies.
Several theories of the origin of identical twins are maintained, including
multinucleated ova, formation of two germinal vesicles, or complete separa-
tion in equal parts of an originally single fertilized ovum, fusion of two embryos,
post-generation, separation of the two initial blastomeres. Of these Wilder
favors the last.

TERATOMAS

The term teratoma has a restricted application to a group of tumors
composed of recognizable tissues and complex organs derived from more than
one germ layer. While in the parasitic fetus the organs are arranged in
normal or nearly normal relations producing a rudimentary fetus, in the
teratoma there is a notable lack of orderly arrangement, producing merely a
veritable pot pourri of fetal tissues. The less complex tumors of this class
may be designated as teratoids. The term "embryoma" is applied by
Wilms and others to various members of this group. It is best limited to
teratomas closely resembling embryos. The tissues of teratomas may be of
adult or embryonal type and on this ground some authors refer to the former
as co-etaneous, the latter as embryonal. Since both types of tissue occur in
the same teratoma the analysis furnishes no indications of the origin of the
growths, and it must be assumed that secondary factors determine the rate
of differentiation of the cells of origin.

While the parasitic fetus does not give rise to secondary blastomatous
processes, the teratoma frequently originates true tumors, benign from the
adult elements, malignant from the embryonal structures

An important principle of the growth of teratomas is the tendency of one
element, either adult or embryonal, to overgrow and suppress the others.
The obverse of this principle, viz., the progressive degeneration of germ layers
is probably of equal importance. Thus bidermal teratomas are frequently
observed, but such cases seem to diminish with the increased persistence of the
search for a third germ layer. Saxer observed a single tooth as the sole
element of an ovarian teratoma, and all chondromas of the testis are of
teratoid nature (Ribbert). The studies of Wilms on ovarian dermoids,
by showing the uniform tridermal nature of these tumors, furnished the basis
of this principle, which has been elaborated by L. Pick and many others.
The application of the rule is open to error when the various germ-layer
derivatives are not rigidly scrutinized. Borst and others warn against the
unscrupulous identification of embryonal derivatives in teratomas. Yet
the tridermal nature of certain groups of teratomas is well established
and the warning may apply chiefly against fantastic interpretations of
organ rudiments. Another source of error lies in the possibility that meta-

TERATOLOGY

937

plasia or abnormal self-differentiation may occasionally break clown the
barriers formerly erected between the germ layers. It is assumed that the
separation of germ-layers of the normal embryo holds also for the teratoma,
but if the abnormal environment of the teratoma may serve to disturb the
normal laws of differentiation the views of the origin of teratomas may
have to be altered. The "genius loci" has already been invoked to support
the local origin of certain apparently heterochthonous sacral teratomas. The
overgrowth of one element in an embryonal teratoma produces a malignant
tumor of nearly uniform type, since it has been shown that many malignant
tumors of the sex glands originate in this way. The same principle probably
applies to many embryonal tumors of other regions, but to what extent re-
mains for future observations to determine.

FIG. 472. — Ependymal structures surrounded by brain tissue in a small teratoma of

ovary.

In discussing the morphogenesis of teratomas it must be admitted that
no sharp dividing line can be drawn between these disorderly embryomas
and fetal implantations on the one hand and the complex teratoids and mixed
tumors on the other. Yet this fact does not lessen the probability that spe-
cial conditions determine the growth of the large group of typical teratomas
and that a particular material, not connected with fetal implantations or
simple mixed tumors, gives origin to teratomas. The clinical evidence in
the field lies in favor of this view but is somewhat neglected. The age inci-
dence, location and course of many typical teratomas strongly suggest a
peculiar formal and causal genesis.

The chief source of teratomas is probably the aberrant sex cell. Inis
origin alone adequately accounts for the predilection of teratomas for the sex
o-lands. The observation of numerous sex cells displaced along the entire

938 N EOF LA STIC DISEASES

length of the embryonal entoderm offers abundant source for most abdominal
and thoracic teratomas. Some reported abdominal and thoracic teratomas
may possibly represent metastatic growths from minute teratomas of ovary or
testis. I have recorded a mediastinal teratoma secondary to a small testicu-
lar growth which escaped several examinations during life.

For the pharyngeal and sacral teratomas no single mode of origin can be
adduced. The most highly developed of the sacral tumors are fetal implan-
tations. Another larger group, of which Nakayama traces many transitions
from comparatively simple up to very complex growths, are true teratomas.
Others probably represent forms of partial reduplication or are of strictly
local origin. Exactly similar variations are observed in the structure and
complexity of the epignathi (cf. Arnold). The complex developmental
processes and the definite growth centers located at the cephalic and caudal
extremities offer unusual opportunities for the appearance of complex teratoid
structures derived by budding from purely local sources. An extreme
variety of structural defects in neighboring tissues is observed with this class
of growths, including cranial fissures, spina bifida, rhachischisis, etc., and the
discovery of such defects is of much value in establishing the nature of the
growth.

For the majority of extragenital teratomas an origin from isolated blasto-
meres is maintained by Marchand and accepted in some form by many
authors. The occurrence of these growths in median positions and in much
the same localities with fetal implantations, the difficulty of separating them
morphologically from the parasitic fetus, and their obvious origin from totipo-
tent or nearly totipotent material, strongly suggest an origin very similar
to that of the asymmetrical double monster. The isolation of an early
blastomere would theoretically account for such structures, but this theory
has little if any advantage over the origin from sex cells The process of
budding, however, presents strong claims for consideration in this field.

Thus, three main groups may be recognized of tumors containing adult
or embryonal organs in disorderly arrangement: (i) Teratomas derived from
aberrant sex cells and found chiefly in the sex glands. (2) Extragenital
teratomas, many of which approach the development of the parasitic fetus
and which may be derived from isolated nearly totipotent blastomeres, or
from early budding of the blastoderm. (3) Teratomas (or teratoids) derived
from multipotent material of distinct regional stamp and reproducing the
organs of these regions. These tumors are usually associated with a defect
in the formation of the parts from which they spring.

Regarding the causal genesis of teratomas there are few data. The isola-
tion of blastomeres is not known to occur — much less the causes of such isola-
tion. For the teratomas of sex glands there is much clinical evidence that
trauma figures in many cases and excites the parthenogenetic develop-
ment of the aberrant sex cell. Harvey has tabulated many methods for the
artificial production of parthenogenesis, some of which, including trauma,
are successful in frogs. Teratoma testis arises at the junction of rete and
spermatic tubules, and at this junction Kirkbride has shown that there may
be very marked disorder in the structure of the fetal testis favoring the
displacement of cells. Teratoma testis is also relatively frequent in the
rudimentary undescended testis.

COMPLEX DERMOIDS

The great majority of complex dermoids are imperfectly developed tera-
tomas and in the sex glands it is very probable that all dermoids are of this
nature. Since the bulk of the early embryo is composed of ectoderm, the

TERATOLOGY 939

overgrowth of this germ layer in the development of teratomas is a natural
result and favors the theory of origin from sex cells. The comparatively
frequent chorioma testis is the embryonal equivalent of the testicular der-
moid. Chevassu's series contains intermediate stages between the embryonal
and the adult ectodermal tumor.

A local origin by budding off of multipotent material appears to be respon-
sible for certain complex dermoids of the cephalic and caudal extremities.
They are usually associated with defects in neighboring structures. Medias-
tinal and retroperitoneal dermoids may be of comparatively simple structure
but it is unusually difficult to refer such growths to a local origin.

MIXED TUMORS

The scope of this term has been greatly restricted especially by the studies
of Wilms, who reviewed the once numerous group and demonstrated the tri-
dermal and teratomatous nature of many of the tumors included therein.
Through his work and that of many later observers the mixed tumor has
largely become the modified teratoma, and the idea of a predominant meta-
plasia in the growth of many tissues has been replaced by the conception of a
natural unfolding of embryonal cell potencies. Hence the term "mixed
tumor" is now confined to comparatively simple, chiefly embryonal growths,
of purely local origin, resulting from overgrowth of embryonal structures
with or without misplacement.

Most of the accepted forms of mixed tumors do not contain derivatives
of three germ layers but are bidermal or monodermal. Yet tridermal tumors
of local origin are observed, especially at the caudal and cephalic ex-
tremities. Since it is not always possible to determine whether a tumor is a
poorly developed teratoma of heterochthonous origin or a complex neoplasm
of local origin, a rigid classification of such cases cannot be accomplished.
In general one may follow the rule of designating as mixed tumors growths in
which embryonal and blastomatous features are prominent and grouping as
teratomas those growths in which the structure is more complex and rudi-
mentary organs are present. It is obvious that the mixed tumors are closely
related 'in origin to the extensive series of simple embryonal tumors occurring
in many regions.

The restricted group of mixed tumors is designated by Adami as terato-
blastomas. Yet many true teratomas are blastomatous and it seems
desirable to separate as far as possible between teratomas and mixed tumors.

In the true mixed tumor the blastomatous process affects both germinal
derivatives, producing adenosarcoma or carcinosarcoma, etc., and the tend-
ency of one element to overgrow the other appears to be less marked than
with teratomas.

The mixed tumor may therefore be defined as a complex embryonal tumor
of local origin which reproduces the normal development of the tissues and
organs of the affected part. They may be classified according to the region
in which they occur, as renal, genito-urinary, salivary and facial, and
mammary.

The most typical examples of the restricted class of mixed tumors are
found in a series of complex embryonal and congenital tumors of the kidney.
These are mesodermal growths derived from the primitive kidney and
neighboring tissues and reproduce the structure of the nephrotome and sclero-
tome. They are called adenomyosarcoma. Muus found also epidermal
inclusions. "Certain mixed tumors of the male bladder and gubernaculum
testis are probably of the same origin.

940 N EOF LA STIC DISEASES

The congenital sarcoma of the vagina contains spindle-cells, striated
muscle-nbers, and myxomatous tissue, and is derived from mesoderm
misplaced during the development and degeneration of the Wolffian duct.
More complex sarcomas of the adult cervix uteri contain muscle and carti-
lage. The adenomyoma uteri and its malignant derivatives constitute
a well-defined variety of mixed tumor derived from the mesonephros or
paroophoron.

The salivary and lachrymal glands are the seat of mixed tumors con-
taining mesodermal derivatives and basal-cell carcinoma, and are probably
derived from buccal ectoderm with a possible admixture from the maxillary
periosteum, or bronchial cartilages.

The mixed tumors of the breast probably originate from aberrant and
superfluous material derived from the fetal ectoderm and m'esoderm during
the early development of the breast. They contain glandular tissue and
carcinoma and various mesodermal derivatives. It is probable that meta-
plasia is responsible for some of these mesodermal structures (Beneke).

Carcinoma sarcomatodes constitutes a miscellaneous group of tumors of
variable and uncertain origin (Lippmann, Herxheimer, Lit.). Most of these
tumors have occurred in the uterus, but out of a considerable number Herx-
heimer found only five which could withstand critical analysis. Others
have been observed in the ovary, and in Lippmann's case there were both
carcinomatous and sarcomatous metastases.

In the thyroid several cases of supposed carcinosarcomas are reported.
Especially difficult is the interpretation of Schmorl's case, of thyroid adenoma
recurring as carcinoma with sarcomatous stroma and with sarcomatous metas-
tases. Tumors of the esophagus containing epithelioma and sarcoma are
described by Hansemann and Herxheimer, and the former has described
similar tumors of pharynx and gall-bladder. Lands teiner reports a tumor
of the gall-bladder in which acanthoma and myosarcoma encroached upon
each other. Of two cases occurring in the stomach that of Lindemann gave
numerous metastases in which both elements were intimately mixed. In the
liver Lubarsch cautiously interpreted a large tumor as an adenocarcino-
sarcoma. In many respects it recalls the complex pictures of primary carci-
noma of liver-cells. Michelsohn believed he could trace the origin of a carci-
nosarcoma from the gland-cells and stroma of the pancreas. Arising in the
nasopharynx and invading the orbit, Klein found a vascular round-cell
sarcoma containing islands of acanthoma.

In the lower animals tumors of mixed structure are not infrequently ob-
served, especially in the mammae of dogs and in the thyroid in rats (Wilms,
Loeb).

The transformation of carcinoma into carcinosarcoma, followed by elimination of the
epithelial element in the course of transplantation of tumors of mice and rats, observed by
Loeb, Ehrlich and Apolant, Bashford, and others, is an interesting experimental contribu-
tion in this field. Loeb saw the sarcomatous element in the first transplant, but it usually
occurs much later, either gradually or suddenly, and with or without persistence of the
carcinoma. That the original tumors contained mixed tumor elements is improbable.
That the spindle-cells are modified epithelium is rejected, although transitions of cell forms
have occasionally been observed. It is generally assumed that the carcinoma cells exert
a stimulating influence on the stroma-cells, which in the course of the transfers yields a
tumor of fibroblastic origin.

The correct interpretation of the carcinosarcomatous structures in man and lower
animals is a matter of much difficulty. No single explanation will probably apply to all
cases. The chief source of these structures is, I believe, the transformation of epithelial
cells into spindle-cells. This change is of widespread occurrence in epithelial tumors
but only rarely is it interpreted as carcinosarcoma. It is frequently observed in the course
of recurrences and metastases of melanoma, basal-cell epithelioma, adamantinoma, ade-
nocarcinoma of thyroid or ovary, primary carcinoma of liver, and in embryonal epithelial

TERATOLOGY 941

tumors. The change is facilitated by rapid growth, relief of pressure, and inflammatory
exudate. Krompecher's studies of the metaplasia of squamous epithelium have an impor-
tant bearing on this subject. The change may often be traced in the same tumor where
polygonal cells merge into spindle forms. The most striking instances are furnished in the
recurrences and metastases of epithelial tumors. Especially in thyroid tumors the form
of the epithelial cells is subject to wide variations, a fact which renders Schmorl's interpre-
tation of his carcinosarcoma very questionable. I have seen pure spindle-cell metastases
in epithelioma of lip, melanoma of skin, adamantinoma and other epithelial tumors. In
experimental tumors of mice, I have twice found convincing indications of change of epi-
thelial cells into more actively multiplying spindle-cells in cases now figuring as carcino-
sarcoma. Thus in several departments there is reason to think that transformation of
polygonal into spindle-cells contributes a share of carcinosarcomas.

A second group of cases may be referred to the intermingling of contiguous primary
tumors of the same region, and on this ground Herxheimer rightly discards certain reported
cases of carcinosarcoma.

That certain tumors originate through neoplastic growth of both stroma
and epithelial cells of a tissue complex, the epithelial cells at first outstripping
the fibroblasts, must be conceded, but it is difficult to determine which if
any of the so-called carcinosarcomas originate in this manner. Known
examples of this type, as the adenomyoma uteri and its malignant forms, are
rather well defined. It is possible that some of the uterine and ovarian
adenosarcomas originate thus and constitute a special variety of mixed
tumor.

In the lower animals the ready response of fibroblasts to various stimuli
renders more acceptable the belief that transplanted stroma may occasionally
assume neoplastic properties during a series of transfers but does not guaran-
tee the existence of such a process in the course of tumor growth in man.

SIMPLE DERMOIDS AND EPIDERMOIDS

The simple dermoid consists of epidermis, derma and dermal glands and
usually appears in the form of a cyst. In the epidermoid definite dermal
structures are wanting.

The simple dermoid commonly originates by the inclusion of a portion of
ectoderm during the closure of embryonal fissures, or at the point of union
of ectodermal with other structures, along the course of ectodermal invagina-
tions (hypophyseal duct), or from persistent embryonal ectodermal struc-
tures. In the sex glands, especially the ovary, a simple dermoid may be the
sole remnant of a true teratoma. A traumatic origin of both dermoids and
epidermoids has been demonstrated in many regions. Epidermoids are
usually of traumatic origin, but certain well-defined forms are of embryonic
derivation and produce characteristic tumors, as cholesteatoma. A defect
of the overlying skin or other abnormality is sometimes present with con-
genital dermoids (Heschl). The dermoid cyst is single or multilocular, and
the contents are sebaceous material and hair. The character of the hair
corresponds to that of the region affected. Torok concluded that very early
separation of ectodermal material is followed by the development of dermal
structures, late separation giving origin to the epidermoid.

Secondary changes in dermoids are frequent and include suppuration,
rupture, papillary ingrowths, overgrowths of dermal structures, and neo-
plastic changes.

The experimental production of dermoids has been successful in the hands
of many authors, the result being a variable period of growth of the implanted
skin, a "long period of quiescence, followed in every instance by slow atrophy.

942

NEOPLASTIC DISEASES

SPECIAL FORMS OF EPITHELIAL CYSTS, DERMOIDS, MIXED TUMORS,
TERATOMAS, AND FETAL IMPLANTATIONS

A regional classification of this extensive group of tumors is the most
serviceable, and is rendered almost imperative on account of the difficulty of
separating the different types on the basis of formal genesis.

Epithelial Cysts of Skin.— The variety of cystic structures lined by squa-
mous epithelium in skin and subcutaneous tissues is considerable.

(i) Atheromatous cysts arising from retention in dermal glands, chiefly
sebaceous, are of frequent occurrence. They are usually connected with
the epidermis. Chiari, however, from the study of a notable case, showed

FIG. 473. — Fat crystals in a dermoid of skin.

that the common multiple cysts of the derma may arise, as does the smaller
comedo or milium, by retention in hair, sebaceous and sweat-glands, and that
these retention cysts may grow deeper as they enlarge and may eventually
lose all connection with the epidermis. The lining is of simple stratified
epithelium which is compressed and atrophic.

(2) Congenital Epidermoids. — The origin of true dermoids of the skin
from ectodermal cysts was established by Remak. The majority of small or
multiple epithelial cysts of the skin was also shown by Chiari, Heschl, and
Franke, to be the result of congenital misplacements of epithelium. The
lining of these cysts is of well-formed epidermis, often with papillae but with-
out other structure of the derma. On account of the simple epidermal lining
Heschl called them epidermoid cysts. It is probable that deep epitheliomas
of the skin arise from such cysts, including certain reticulated epitheliomas.

(3) Implantation Dermoids (Sutton). Cystes Epidermiques (Reverdin). —
Traumatic misplacement of iragments of epidermis produces simple cysts

TERATOLOGY 943

which are of widespread distribution and may reach considerable dimensions.
The importance of this oiigin has been emphasized especially by Reverdin,
Jonnesco and others, who have pointed out their occurrence' in exposed
portions of the body, as the palms and soles, their main clinical features,
and the varying character of the lining. Schwenninger, Kaufmann and
Dooremale showed that such cysts may be produced experimentally by im-
planting portions of epidermis in deep tissues, or in the interior chamber of
the eye. The character of the resulting cyst depends much upon the con-
formation of the displaced fragment. A complete fragment of skin with
epidermis and derma yields cysts with papillae, while the epidermis alone
produces smooth-walled cysts or pearly nodules (Garre, Le Fort). Yet
Hoesch and Aschoff concluded that definite growth of displaced epithelium
and cyst formation required that some connective tissue must accompany
the epithelium. Fetal epithelium is more active than adult (Nicholls). The
extent of the misplacement is often surprising, and the original injury may
excite little notice. Although usually found on exposed surfaces in working
people, traumatic epidermoids occur 'in the cornea and iris (Franke, Graefe).
Yet the origin of these intra-ocular cysts is not fully determined (Collins,
Greef). A traumatic frontal intracranial dermoid resembling cholesteatoma
is described by Hartley. The growth capacity of the traumatic dermoid is
moderate, and malignant changes are not observed.

(4) True Dermoids. — The true or congenital dermoid is, as a rule, a larger,
more complex and more deeply situated structure than the retention cysts
and traumatic dermoids. It is situated in locations which connect it with
the embryonal disturbances of development to which it owes its origin
(fissural dermoids). The structure presents all the elements of the skin,
including epidermis, derma, and dermal glands, which may become atrophic
but usually exhibit overgrowth or at times malignant changes. Accessory
structures are sometimes added, as lymphoid tissues, fat tissue, muscle,
bone, cartilage, and normal or cystic blood- and lymph-vessels.

Dermoid cysts present particular clinical, pathological, and embryological
problems in the several situations in which they occur. It is especially
difficult to distinguish between certain complex dermoids and teratoid
growths with predominance of ectoderm. The congenital dermoids occur in
the scalp, neck, back, along median line of chest and abdomen, sacral region
and buttocks, where they are readily connected with embryonal fissures, clefts,
and junctures. Teratomas are usually found in deeper organs and along the
vertebras from neck to coccyx. Some observers give a very wide scope to the
congenital dermoid at the expense of the traumatic forms and would include
not only those which occur at points of recognized predisposition (clefts,
fissures) but those in many other regions, especially when a traumatic history
is missing. Thus Labougle found a traumatic history in only 16 of 42
dermoids of the vola manus; the others he would refer to congenital separa-
tion of epidermis at interdigital folds.

Cervical Dermoids.- — An extensive variety of congenital anomalies in the
neck results from irregularities in the closure of the branchial clefts, which
give rise to reduplication, partial or complete, of organs; fistulous tracts;
epidermoids; dermoids; blood- and lymph-cysts; and true tumors. Various
combinations of these conditions may be observed, as multilocular prolifer-
ating cystoma with dermoid cyst, or multilocular cysts of various types with
cystic lymphangioma (Samter). The location of the different clefts and
of the abnormalities referable to them may be seen from the accompanying
sketch from Cusset. This subject was e'xtensively investigated by many
early observers, more recently by Kostaniecki and Mielecki, who conclude

944

N EOF LAST 1C DISEASES

that the great majority of cervical dermoids arise from the second cleft.
Yet many fissures, cysts, dermoids and tumors in particular locations are
connected with each of the other clefts (Virchow, Konig).

(1) The first branchial cleft locates a series of abnormalities which are
chiefly found in the aural and submaxillary regions. These consist of
supernumerary ears (Sutton), aural fistulas, chondromas from, the aural
cartilages, and many outgrowths of the skin which often contain cartilage
(Virchow, Hennes). It is probable, however, that most of the superficial
anomalies in and about the ear result from secondary disturbances in the
formation of this organ and are not connected with the branchial clefts.

Congenital epithelial cysts of the
external ear result from irregular
closure of the fistula auris con-
genita (Steinbrugge).

Dermoid cysts from the first
cleft appear to be relatively rare.
Hildebrand out of 20 epithelial
cysts of neck observed one which
he referred to the first cleft. It
lay in the suprahyoid triangle
away from the middle line. Konig
reported a cyst and fistulous tract
probably derived from the first
cleft, which ran under the angle
of the jaw along the facial nerve
and terminated between tragus
and antitragus. Another group is
found along the floor of the mouth,
constituting the sublingual der-
moids (Kostanecki, Lit.). These

FIG. 474.-Situations of congenital fissures in are lined bX epidermis and COn-

neck and face, i, 2, 3, 4, First, second, third, tain sebaceous material, and the
and fourth clefts. 5, Intermaxillary cleft, walls are free from lymphatic

6, Frontomaxillary cleft. 7, Nasomaxillary tissue> • They Originate from the

ectoderm of the first branchial arch

which goes to form the lateral portion of the base of tongue. Incomplete union
of kthe two opposite portions of the first branchial arches may leave a tri-
angular defect beneath the skin in the middle line in the submental region
(mesobranchial space of His). Thus, portions of ectoderm may become
adherent to entoderm and form mesobranchial dermoids which lie at base
of tongue in middle line, or may appear anteriorly in suprahyoid region.

(2) The course of the second branchial cleft follows the stylohyoid liga-
ment from the styloid process to the lesser cornu of the hyoid bone. It
thus runs from beneath the ear externally and from the tonsillar fossa in-
ternally, along the posterior belly of the digastric muscle. According to
Kostanecki and more resent observers, the great majority of branchial fistulae
and cysts originate from this cleft. They lie anterior to the sternomastoid
muscle and may develop at any point from the external ear to the sphenoid
bone, or they may extend along the whole length of this region. Konig
suggests that the position may be influenced by the course of the facial nerve
or artery. Portions of the cyst may lie within the parotid gland and numer-
ous lateral sacculations may develop.

Structure. — The lining reproduces the structure of ectoderm or of entoderm.
Both embryonal layers may be represented when the membranous septum

TERATOLOGY 945

is ruptured and both inner and outer layers contribute to this lining. Some
• cysts present a lining of epidermis with dermal glands. Their contents are
usually sebaceous and they may contain hair. Others show squamous
epithelium of a mucous membrane with basal layer of columnar cells and
their contents are mucoid. • A third group shows ciliated epithelium as well
as squamous. These variations depend on the character of the embryonal
structures involved, the mucous membrane and ciliated cells being derived
from the entoderm which originally possesses a ciliated lining. Foreign body
giant-cells often replace much of the epithelial lining, especially when the
contents are fatty or oily. Groups of thyroid alveoli may be present in the
wall. Lymphoid tissue is abundant in the embryonal entoderm and reap-
pears in cysts derived from this layer, but is absent in the others. In the
wall may be found striated muscle, mucous glands, and islands of cartilage,
derived from the mesodermal tissues of the branchial arches.

Secondary changes in cervical dermoids are of much importance. Extra-
vasation of blood into the cyst not infrequently occurs from the small vessels
in the wall. Rarely a communication is formed with the jugular vein, pro-
ducing a blood-cyst (Thomas). The dermal glands in the wall may become
cystic or may develop cystadenomas (Zahn, Samter).

Branchio genie Carcinoma; — That many cervical carcinomas and primary
epitheliomas of the neck arise from branchiogenic cysts and epithelial rests
was first shown by Volkmann. These tumors occur usually after the fortieth
year, producing globular, cystic or solid, often externally ramifying growths
which are extremely difficult to extirpate. Pharyngitis, difficulty in swallow-
ing, inflammatory edema, and lymphadenitis often mark their onset and
course. Invasion of lymph-nodes is early or late depending on the integrity
of the cyst capsule. The structure is commonly that of adult acanthoma.
To what extent other carcinomas of the neck of obscure origin are referable
to branchial remnants is at present undetermined. Many of the multilocular
blood-cysts of the neck probably arise in this manner. The lymph-vessels
may be' highly developed and it is probable that these vessels may be the
source of hygroma colli (Lucke, Zahn). Virchow designated as fissural
angioma certain vascular tumors of this region. The fragments of car-
tilage in the wall are held to be the source of certain branchiogenic
chondromas.

The diagnosis of branchiogenic carcinoma, after .it has advanced to
the cervical lymph-nodes, may be difficult. It should be emphasized that
the usual form of the tumor is a cystic growth in and about which are carcin-
omatous areas, and that most cases are encountered when the cysts are
recognizable, and when a squamous-cell cover is present or predominant.
In the same region are observed carcinoma of the lymph-nodes secondary
to lesions of adjoining mucosae, buccal, nasal, ethmoidal; carcinoma from
aberrant thyroid follicles; tumors of the carotid gland; and primary endothe-
lioma of lymph-nodes. In all the secondary carcinomas it should be possible
to demonstrate the primary growth. The structure of carotid gland tumors
is specific and that of endothelioma is partially so. There remains a group
of apparently primary carcinomas of the cervical lymph-nodes whose origin
is obscure, and some of these may be derived from the entodermal epithelium
of branchial cysts. Definite observations in this field are lacking, but in
Samter's case 'of complex branchiogenic cyst there were adenomatous pro-
liferation in several of the compartments and infiltrating carcinoma with
metastases in lungs and abdomen.

Cervical Teratoids and Teratomas— Complex teratoid tumors of the
neck are comparatively rare and are found chiefly in connection with the

946 N EOF LAST 1C DISEASES

branchial clefts and the thyroid gland. Partial reduplication of the lower
jaw has given rise to large tumors of the neck containing bone, cartilage,
teeth, muscle, connective tissues, and fat (Wilms). More complex tumors
containing bone, teeth, muscle, ectodermal, and entodermal cysts, portions
of respiratory tract, and brain tissue, are described by Pupovac and Wetzel,
and interpreted as of bigerminal origin. Several cervical teratomas have
been connected with the thyroid gland (Poult, Lit.). In Henle's case a large
congenital tumor contained nerve tissue and choroid plexus, cysts lined by
cuboidal and ciliated epithelium, thyroid follicles, and connective tissue.
Some cystic sarcomas, as in the thyroid, are of complex structure (Zahn).
In Pupovac's case the lymph-nodes contained metastases of ganglionic nerve
tissue.

A headless but otherwise well-formed fetus was found imbedded in the
cervical tissues by Rosenstiel, and Grass observed a complete fetus of the
size of the finger lying in the neck of a woman. Several reports of fetal
implantation in the branchial clefts have been collected from the older litera-
ture by Heusinger.

Cysts of Thyroglossal Duct. — The thyroglossal duct is a rare source of
dermoid cysts.

When the base of the tongue is formed by the union of two lateral arches
an epithelial-lined canal persists, leading from the foramen cecum to the mid-
dle lobe of the thyroid. The upper portion of the duct may remain patent
(lingual duct), while the lower region from thyroid isthmus to hyoid bone
forms the thyroid duct. Bochdalek in several cases found segments of this
canal, 2-3 cm. in length, patent and with lateral sacculations lined by ciliated
epithelium. Streckeisen found small mucous cysts lined by ciliated cells
along this tract, and Hildebrand has collected other similar cases in some of
which the wall contained thyroid tissue (Berard, Chalier, Erdheim, Lit.).
Dermoid cysts in the middle line of the tongue are probably derived from
portions of this duct. They may reach a large size, appearing in the floor
of the mouth and displacing the tongue upward (Bryck, Dirmstrey). Rarely,
cysts are found behind the right lobe of thyroid. They are lined by ciliated
epithelium, and are probably derived from the esophagus, the upper part of
which in the early embryo is covered by ciliated epithelium.

Mediastinal Dermoids. —These tumors are located below the sternal
notch in the anterior mediastinum or between the heart and root of lung
or in the lung, or they occupy the pleural cavity (Christian, Lit.). They
form single or multilocular cystic growths which may reach large dimensions.
Most of them appear in young adults, and run a slow course of one to 16
years. Symptoms may be wanting but most cases show the results of pres-
sure on the bronchi and trachea, with cough, hemoptysis, and in eight
cases with expectoration of hair, as well as sebaceous material.

According to structure they fall into two classes, (i) Simple dermoids.
(2) Teratoid tumors.

The simple dermoids are single or multilocular cysts with smooth or
polypoid epidermal lining containing dermal glands and with contents of
hair and sebaceous material. Teeth are frequently present. The epidermal
lining may be lost, and plates of bone or cartilage may be present. Some
have been connected with portions of thymus (Marchand). The complex
tumors are tridermal and contain besides epidermis, bone, cartilage, nervous
tissue, intestinal tract, respiratory ciliated epithelium (Loewenmeyer),
and thyroid (Mandelbaum) (Dangschaat, Lit.). The older cases have been
collected by Riegel. Malignant changes were observed in three cases, all
of which were probably teratoid. Pinders described lymphosarcoma prob-

TERATOLOGY 947

ably from the thymus, Jores spindle-cell sarcoma extending into lung, and
Virchow carcinoma and sarcoma with nodules in liver.

A single origin through one-sided developments of teratomas cannot
be excluded for the entire group. Ekehorn points out that the great ma-
jority of mediastinal dermoids prove to be tridermal teratomas. Yet most
authors regard the simple tumors as derived from the third branchial arch
which produces the deep sinus cervicalis and the thymus. The intimate
relations of ectodermal and entodermal layers of the third and fourth arches
may explain the variety of epithelium and the connection with the thymus
and thyroid, while the descent of the heart may carry these structures deep
into the thorax.

Dermoids of the lower mediastinum may result from imperfect closure
of the anterior chest wall, which gives origin to pr external dermoids (Andoly).
Bergmann observed a dermoid divided into two compartments by the ster-
num but joined by a canal through the bone.

Congenital dermoids occur along the orbitonasal fissures, (i) at the outer
angle of the orbit next to pericranium covering external process of frontal
bone. (2) At inner angle of orbit. (3) In upper eyelid between the fronto-
nasal plate and the cutaneous fold from which the eyelid is formed.

At the root of nose, over the fontanelles, at the occipital protuberance,
and elsewhere in the scalp, congenital dermoids are also found (Hartley).
The origin of these dermoids is explained by the imperfect separation of
dura and skin during the intramembranous formation of the cranial bones.
As the bone forms between the dura and skin, portions of the latter may
adhere to the dura, become enclosed in bone and form dermoids which
lie within the skull and may be connected with the skin by a pedicle. With
the formation of intra-orbital dermoids the invagination of ectoderm in
the development of the lens is prominently concerned.

Orbital Teratomas.- — Teratomas occur in the orbit, usually as bulky
growths present at birth (Hippel, Lit.). Their analysis reveals as a rule
derivatives from three germ layers, but only two layers may be identifiable.
The development of rudimentary organs is not pronounced, but segments
of intestine, ocular cups, and portions of central nervous system have been
identified. Hippel suggests that certain orbital dermoids are of teratomatous
nature, since ganglia and gland alveoli lined by mucous cells have been
found in the wall of the dermoid. Monogerminal mixed tumors of the orbit
are illustrated by the case of Weigert, Broer, which contained fat, bone,
cartilage, and cysts lined by cylindrical or ciliated or squamous epithelium.

Pharyngeal Dermoids, Teratomas and Epignathi. — A somewhat numerous
group of complex tumors and developmental anomalies appears in the form
of polypoid growths of the nasopharynx, which may be subdivided into
three main classes: (i) Dermoids, (2) teratoid tumors, and (3) epignathi
(Arnold, Lit.). All these conditions are congenital and are usually encoun-
tered in deformed stillborn fetuses, but the simpler pharyngeal polyps may
first be recognized as late as the twenty-second year.

(i) The dermoids are usually complex. They appear at birth or after
some years, producing dysphagia, or dyspnea, or are described as cases of
hairy tongue. They are attached to the hard or soft palate, or wall or vault
of pharynx, in or near the middle line, and fill the nares or buccal cavity.
Some may show an intracranial portion connected through a perforation in
the skull with the pharyngeal tumor.

The tumors are covered by skin, often hairy and containing dermal glands.
The main mass is composed largely of fat tissue, with occasional fragments
of striated muscle, cartilage or bone. They are therefore bidermal.

948 N EOF LA STIC DISEASES

(2) The teratoid tumors differ from the dermoids chiefly in the greater
complexity of structure, larger size and earlier development, and they are
frequently associated with extensive deformities of the skull, as anencephalus
(Otto), hemicrania (Wollmann), and palatal fissures (Sonnenberg). The
presence of these local deformities suggests that the overgrowth of tissue
constituting the teratoid results entirely from local factors and that they are
not true embryomas. These tumors are all tridermal and Schwalbe further
subdivides them into two groups, in one of which the three germ layers
produce definite organs, i.e., into teratoids and teratomas.

The structures which form the basis of the classification as teratoids
consist of tridermal elements, fat, muscle, cartilage, bone, acinous glands,
teeth, cysts lined by various forms of epithelium, and nervous tissue. Cases
in which the bony masses imitate a rudimentarv skull form a transition to

FIG. 475. — Epignathus. (Low, Studies in Pathology, Univ. of Aberdeen, 1906.)

the epignathi. In Koch's case the growth was composed chiefly of brain
and glia-tissue. In several cases the structure has suggested an involvement
of the branchial arch, as when there are deformities of tongue, palate, jaw,
and ear, and the tumor contains rudiments of the ear (Wallmann).

(3) Epignathi. — These remarkable anomalies differ from other pharyn-
geal teratomas in presenting well-formed organs and limbs of a parasitic
fetus. There has been much variation in the criteria demanded for identi-
fication of this group, but since the studies of Arnold and Schwalbe the term
"epignathus" has been limited to the growths that present unmistakable
parts of a fetus. Even thus the observed cases are rather numerous. The
extent to which the fetal organs are represented varies greatly. In some
the main tumor consists of a rudimentary head with or without brain tissue
(Ahlfeld). In many cases well-formed extremities with fingers, toes, and

TERATOLOGY 949

nails are present. Otto observed a cystic growth containing portions of
intestine and a rudimentary testis. Vrolich found intestinal canal with
appendix, long bones, and a placenta-like mass. Wegelin identified sacrum,
foot with five toes, intestine, crystalline lens, choroid, and brain. Rind-
fleisch described a large tumor at' the base of the brain attached at the sella
turcica, and containing fetal extremities with fingers and toes, normal
liver, brain, and navel, while passing through a fissure in the base of the skull
and projecting from the mouth was a bulky polypoid tumor containing
chiefly mesodermal structures. He assumed an origin from the hypophysis
and characterized this organ as a veritable mine of undifferentiated tissues.
The case of Baart de la Faille is thus reported by Schwalbe. In a case
of quadruple pregnancy the first fetus was well developed; the second fetus
formed a large enignathus hanging from the mouth of the first; while the

FIG. 476. — Complex epignathus. (A case of Baart de la Faille.)

third and fourth were joined by a forked umbilical cord to the palate of the
first, where its vessels joined with the sphenopalatine branches.

In the genesis of pharyngeal dermoids and teratomas various theories have contended
for recognition. In the extensive discussions of this subject it has been recognized not only
that the general principles of teratogenesis are involved, but that special local factors in
development must be considered.

Arnold maintained that the simpler bidermal and the complex tridermal growths must
be referred to local disorders of development, while the true teratomas, which according
to his definition must present definite rudimentary organs, were true fetal implantations.
Here as elsewhere an effort has been made to distinguish between autochthonous teratomas
(developed from local tissues), and heterochthonous (developed from sources alien to the
locality). From this point of view two entirely different embryonic disturbances must be
held responsible for the present group of conditions, (i) Local disturbances of develop-
ment involving the buccal cavity, the hypophyseal duct, and the first branchial arch; (2)
the aberrant growth of a totipotent blastomere, polar body, sex cell, or tissue bud.

The hairy polyps and the simpler tridermal teratoids have been regarded by nearly alt
authors as adequately explained by the first mentioned factors. The invagination of ecto-
derm in the formatio'n of the buccal cavity and the fusion of this cavity with the fore-gut
through the primitive pharyngeal membrane give opportunity for the separation of ecto-
dermal and mesodermal rests which may explain some of the growths attached to the
palate. Rather more definite sources are provided in the course of development of the
hypophysis and its duct, for some of the pharyngeal growths are clearly connected with

950 NEOPLASTIC DISEASES

these structures and many of them are attached at the sella turcica or perforate the skull
at this point. The hypophysis may be missing. That the first branchial arch may also
be concerned in some cases is indicated by the occurrence of other anomalies in the course
of this arch and by the complex teratoids and epignathi located in the course of other
arches. Finally, the theory of local origin is favored by analogy with parallel conditions
at the caudal extremity and by the series of simpler embryonal tumors of the nasopharynx.
The definite teratomas and epignathi Arnold, Askanazy and others interpret as forms of
fetal implantation without designating their particular history.

Somewhat definite discrepancies, however, exist between the above theory and the
observed facts. The sharp separation attempted between complex autochthonous and
only slightly more complex heterocthonous growths proves extremely difficult, for no
sharp distinction in morphology exists. In fact, in the not overnumerous series every
gradation seems to be represented, from the simple bidermal polyps up to the well-formed
epignathi, so that a single origin for the entire group is strongly indicated. Hence,
Schwalbe concludes that all the complex pharyngeal growths are derived from isolated
blastomeres, and that the varying structure of the growths depends upon the stage of
development of the blastomeres at the time of their isolation. It is more probable that they
result from early budding. He employs the term "teragogenic termination-point" to
indicate the stage of differentiation which the separated blastomere or originating cell group
must possess in order to produce just the particular form of teratoid, teratoma, or parasitic
fetus observed. When, however, Schwalbe includes with isolated blastomeres more
complex and differentiated cell complexes, his theory closely approaches the standpoint of
Arnold.

Adami explains epignathi and sacral monstrosities as the result of overgrowth of cells
at the two "growing points" of the embryo, after the rudiments of the local organs have
been laid down. After the brain vesicles are formed any further growth of the superior
growing point, which lies in the region of the sella turcica, would produce superfluous tissue
involving three germ layers.

In the origin of the nasopharyngeal dermoids three possible sources must be con-
sidered, (i) Incomplete absorption of the membrane separating buccal cavity (stoma-
deum) and fore-gut. (2) The ectodermal pouch, hypophysis. (3) The first branchial cleft
in its relations especially to the Eustachian tube, which, however, is wholly endodermal in
origin. The relation of the hairy pharyngeal dermoids to the complex teratoid tumors of
this region remains undetermined, but since their structure is comparatively simple and
they contain only such elements as may arise from normal tissues in that neighborhood,
they probably originate from a local disturbance in the first branchial cleft and not from a
totipotent cell or cell group (Askanazy).

Hypophyseal Dermoids. —Closely related to the pharyngeal growths is
a group of more complex intracranial dermoids lying at the base of the
skull, in the sella turcica (Beck), near the olfactory lobes (Bonorden), or
at optic chiasm (Rokitansky). The neighboring pineal gland may be
hyperplastic. These tumors are lined by epidermis and filled with granular
or lamellated detritus as in cholesteatoma and the wall may contain bone,
cartilage, muscle-tissue, and fat. Bonorden found 14 teeth, cysts lined by
ciliated epithelium, and fragments of thyroid tissue, in a case which suggests
a teratoid origin. These tumors are commonly referred to buccal ectoderm
misplaced in the development of the hypophysis (Wilms, Lit.). While
there are some grounds for assuming a teratoid origin of the entire group,
the structural scope is somewhat limited, and represents chiefly the local
organs from which different elements might well be contributed by some
early embryonal disturbance, such as budding at the cephalic extremity.
The alternative hypothesis would explain these growths as abortive epignathi.

A few cases of intracranial teratoid tumors have been referred to the
hypophysis. Beck found in the sella turcica a small tumor containing
cartilage, bone, myxoma, cysts with ciliated epithelium and fourteen teeth.

Intracranial Dermoids. — The relations of the medullary groove to the
ectoderm, the complex steps in the formation of the brain and ventricles,
and the formation and union of the cranial bones, give abundant sources
for the development of epidermal growths in the skull. The interpretation
of these tumors is further complicated by certain properties of endothelial

TERATOLOGY 951

growths to copy the structure of cholesteatoma, and finally traumatic
implantation of portions of ectoderm accounts for a small proportion of
intracranial processes. Several types of epidermal tumors are included in
this group.

(1) Cholesteatoma is a tumor composed of lamellated waxy or scaly
material, enclosed in a wall of stratified squamous-cells. It occurs in all
parts of the brain, ventricles, and basal regions, usually near the midline
and is regularly connected with the meninges. Bostroem, in an elaborate
study, concludes that all cholesteatomas arise from embryonal epidermal in-
clusions. Beneke and Bonorden support this view, and refer a basal cholestea-
toma to an inclusion from the pharyngeal wall connected with the hypophysis.
Erdheim reports thirteen cholesteatomas at the base of brain, none of which
seemed to be connected with the hypophysis and few were in the median
line. He finds only one case of cholesteatoma of the inf undibulum (Beneke's) .
Blasius, in a tumor of the convexity, found epithelium resembling that of
the skin. A traumatic origin must be accepted for Hartley's frontal choles-
teatoma. An endothelial origin for the deep tumors is assumed by Glaeser,
H. Frank and others, and Borst distinguishes intracranial dermoids, epider-
moids, and endothelial cholesteatomas. Finally, Benda holds the epen-
dymal epithelium responsible for some deep cholesteatomas. In several
cases I have found no evidence of any other than an epithelial origin.

(2) The intracranial dermoids are walled by epidermis and derma with
sebaceous and hair glands, and contain sebaceous material and hair. They
lie (i) between the olfactory lobes and corpora mammillaria, or (2) between
medulla and pons, and their positions indicate that the embryogenic dis-
turbance occurred at the formation of the second brain vesicle. Bostroem
collected 18 cases, all of which were connected with dura or pia.

(3) Dural dermoids lie close to the skull but grow deeply, pushing the
pia before them. They usually lie in the median line in tentorium cerebelli,
at internal occipital protuberances or torcular herophili, or they may be
epicranial. They are often connected with the skin by an epithelial canal or a
fibrous strand, and there may be a defect in the skull or an absence of hair
in the overlying scalp (Heschl) . They must arise late after the skin is formed,
from adhesions between skin and dura, and they are observed at birth or in
infancy (Bostroem, Ziegler). Some of the tumors of the hypophyseal duct
described by Erdheim contained cysts lined by derma in which were bony
trabeculae. Benda has also described an hypophyseal dermoid containing
bone in its wall.

Multiple complex dermoids scattered over pia of cord and brain and in
ventricles, appearing as yellowish nodules of connective tissue, fat, nerve
cells and fibers, smooth muscle, and flat epithelium, occurred in a remarkable
case recorded by Trachtenberg. The large complex intracranial dermoids
are probably to be interpreted as teratomas (Askanazy).

Intracranial teratoids and teratomas have been observed in a few cases,
the position of which it has often been difficult to determine. Arnold de-
scribed a frontal tumor partly extracranial, but extending into the ventricles,
which contained fat, cartilage, and bone, and which he interpreted as a
fissural mixed tumor. Eberth observed an intracranial tumor connected
by a pedicle with the dura, and composed of fat, muscle, lymphoid tissue,
and nerves.

In the ventricle, Strassmann and Streker described in a boy of three years
a tumor of the right choroid plexus, composed of connective tissue, fat, bone,
cartilage, muscle, nerve cells, glands, and cysts lined by epithelium. In the
third ventricle of an infant Saxer found a complex teratoid containing carti-

952 N EOF LAST 1C DISEASES

lage, bone, muscle, chorda tissue, gland alveoli, cysts lined by cylindrical
or ciliated or squamous epithelium, pigmented retinal epithelium, choroid
plexus, and fetal brain tissue and ganglia. Both of these tumors may be
referred to complex portions of the medullary plate.

Certain intracranial teratoids and teratomas arise in connection with
the hypophysis and the pineal gland (q.v.)

Teratoma of Pineal Gland. See Pineal Gland.

Peritoneal, Mesenteric, and Omental Cysts, Dermoids, and Terato-
mas.— A comprehensive resume of this subject was first contributed by Hahn
in 1887. A more minute analysis and history were given by Braquehaye
(1892), who recognized especially the dermoids and cysts derived from neigh-
boring organs. Dowd (1900) pointed out the probable identity and embryo-
nal origin of many glandular, serous and blood-cysts. A complete resume of
the entire subject with reference to 184 cases is presented by Niosi.

Four main varieties of cystic tumors appear in the peritoneum, (i)
Lymphatic or chylous cysts. (2) Enteric cysts. (3) Urogenital cysts. (4)
Dermoids and teratoids. Hydatid cysts and cysts of neighboring organs
complicate the clinical diagnosis.

(1) Chylous cysts form very large, single, usually multilocular tumors, or
very numerous small swellings of mesentery, omentum, intestinal wall, and
retroperitoneal regions (Klemm, Lit.). The contents are clear fluid, or
chyle, or more inspissated fatty material, and blood is often added. The
walls are of fibrous tissue in which are many round-cells or lymph-follicles,
and often dilated lymph-spaces. Bundles of smooth muscle-tissue may be
present, as in enteric cysts. The lining is of recognizable endothelium, which
may be hyperplastic (Tilger). Many giant-cells may form about fatty
detritus, or the cellular lining may be lost.

Klemm and Rittner interpret all mesenteric chylous cysts as cystic
lymphangiomas. That some represent merely dilated lymphatics is shown
by Kostlivy's study and by the cases of lymph-cysts arising after occlusion
of local lymphatics in cancer. In some cases the cyst appears to involve
chiefly certain lymph-nodes (Lion, Spaeth). Since enteric cysts may contain
chylous fluid a sharp distinction from chylous lymph-cysts is not always
possible.

The so-called serous cysts probably represent rare forms of other varieties
of this group. Tufner found clear fluid in one compartment 'and chylous
fluid in two other portions of a lymph-cyst. The presence of muscle-fibers in
the walls of serous cysts suggests an enteric origin.

Blood cysts usually arise from extravasation. Wagener has described a
true cystic hemangioma of the mesentery.

(2) Enteric cysts constitute a rather well-defined group of intraperitoneal
cysts. They form single or multiple large or small cysts lying usually along
the lower end of the ileum, in the wall of the intestine, at the point of Meckel's
diverticulum (Roth), in the mesentery, or near the navel (Wyss). When
originating within the muscular wall of the intestine they usually remain
connected with this organ and are enclosed by a muscular wall. Arising in the
subserosa they remain attached to the convex side or project into the mesen-
tery. There may be definite malformation of the intestine (Nasse). The
cavity is usually single and the contents are mucinous, colorless, yellowish or
brownish fluid. The wall resembles that of the intestine, and may contain
smooth muscle, mucosa, crypts, lymphoid tissue, and a lining of cylindrical
or cuboidal or stratified epithelium (Colmers). The epithelium may show
papillary proliferation. Secondary changes in the cyst may destroy much or
possibly all the epithelial lining, and many stages of the atrophy of muscle-

TERATOLOGY 953

tissue have been observed (Niosi). Both cylindrical and squamous-cells
may be found in the same cyst (Gfeller).

There are probably several modes of origin of enteric cysts. Many
originate from Meckel's diverticulum and are located at the lower ileum where
they may communicate with the bowel (Ruge, Roth). At the navel they
may be referred to the omphalomesenteric duct (Wyss). The term "ento-
dermoid" has been employed by Beneke to designate enteric cysts which
arise from definitely misplaced portions of intestine. Many of these lie
in the mesentery, and are multiple. Roth and Hennig found a large cyst
in mesentery and one in posterior mediastinum, both in infants. Sanger
and Klopp, in a newborn infant, found five cysts, in the walls of two of which
were portions of liver tissues. Honl has reported two remarkable cases of
multiple enteric cysts in which there were 37 and 89 small cysts lined by
intestinal mucosa.

(3) Intraperitoneal cysts of nephrogenic origin form a less definite and less
numerous group, of which Niosi collected five cases. Many other cases in
which the structure was obscure are held by Dowd and Niosi to belong in this
group. These cysts are of large size, single or multilocular, involving
mesentery and adjacent regions or extending into the pelvis, and occur
chiefly in adult \vomen. The contents are brownish serous fluid containing
pseudomucin. The wall is composed of fibrous tissue and the lining is of
high cylindrical or cuboidal glandular epithelium, which may be deficient
in some areas. In Niosi's case, the structure was complex and the wall
contained definite portions of adrenal cortex, and structures resembling the
embryonal kidney.

The origin of these cysts presents a difficult problem but it seems probable
that they are derived from aberrant remnants of the Wolffian body and that
the embryogenic disturbance occurs at various periods in the history of this
structure. Dowd regarded his case as arising from an ovarian rest, while
Niosi's case must have included more complex elements.

(4) Dermoid cysts of the mesentery and peritoneum are rare (Niosi,
Lit.). They are located in any portion of the mesentery from celiac axis
to pelvis and their dimensions may be considerable. In FraenkePs case the
cyst was attached to the diaphragm. The epithelial lining may be lost
(Marie). They are usually lined by squamous epithelium and contain hair
and sebaceous material. Ruysch and Martel observed in the omen turn large
cysts containing hair. Others are very complex and contain hair and teeth.
In a large cyst extending in mesentery from ribs to pelvis of an infant of
two years Dickinson found connective tissue, fat, bone and cartilage.

A few peritoneal teratoid tumors have been reported. Bonfigli describes
a cyst adherent to liver and stomach containing 19 loose teeth and two im-
bedded in well-formed bone. The wall was lined by hairy skin. A very
similar case is that of Schutzer.

Various sources appear to contribute to these tumors. Many simple
intraperitoneal dermoids are referred by Wilms to imperfect closure of the
abdominal plates. Others are commonly regarded as derived from the ovary,
by separation of an original ovarian tumor, or by development from a super-
numerary ovary, or by implantation from a ruptured ovarian dermoid.

The position of the complex dermoids strongly suggests that many of
them belong in the group of abdominal teratomas and that more complete
examination would have revealed a tridermal structure.

Abdominal Fetal Implantations and Teratomas.— Seventeen cases of
definite fetal implantation in the abdomen have been collected by Lexer.
They occurred in newborn infants or in subjects between the ages of a few

954 NEOPLAST1C DISEASES

months and 61 years. Their location in the transverse mesocolon or behind
liver in bursa epiploica indicates that they were originally celomic implanta-
tions. The vascular supply is from the aorta or the vessels of the colon.
Rudimentary limbs and organs and well-formed membranes and umbilical
cords have been recognized.

Several cases of tridermal teratomas of the peritoneum have been collected
by Lexer and by Askanazy, and to these may be added other bidermal growths
which are probably of similar origin. Their position has been behind the
liver and extending downward behind the kidney.

A sharp separation between peritoneal and retroperitoneal teratomas
cannot be made. The tumors occur in young or adult subjects and reach
large dimensions. The scope of structure includes solid portions composed
of bones with marrow cavity, cartilage, fat tissue, muscle, and connective,
and cystic portions with cavities containing hair or mucus, and lined by
epidermis or cylindrical or ciliated epithelium. Hosmer found a portion
of intestine with mesentery. Marchand observed intestine with calculi,
prostate gland, and rudimentary brain. Ahrens' case consisted chiefly of a
segment of gastro-intestinal canal, with lining of intestinal mucosa, or
squamous or ciliated cells. There was ulceration, and pepsin and acid
were demonstrated in the contents of the cyst. Whether this case was a
teratoma reduced to gastro-intestinal canal, or a derivative of misplaced
entoderm, it is difficult to determine. Yet Englander's case, containing in-
testine, cartilage and fat, furnishes a transition to genuine tridermal tera-
toma. Pilliet describes sarcomatous areas, and in Montgomery's case the
original sarcomatous and carcinomatous areas recurred. In GoebelPs
case adenosarcoma derived from the entoderm produced numerous metastases.
The peritoneum is occasionally the seat of malignant embryonal tumors
of carcinomatous or sarcomatous structure whose position suggests a
relation to the malignant forms of peritoneal teratoma. Fleischmann found
pure neuro-epithelioma in the metastases of a complex malignant tumor of the
omentum.

Primary abdominal chorioma in the male, located in the omentum, is
described by Bonney, and other abdominal tumors have been interpreted
as chorioma by Bostroem and Djewitsky.

Retroperitoneal Dermoids and Teratoids. — Three varieties of epidermal
tumors occur in retroperitoneal regions.

(1) Tridermal teratomas. These may be unattached teratomas, as in
Brouha's or Schonholzer's cases, or derived from the ovary, normal, displaced,
or supernumerary (Borst, Bolzano). Funke would derive all retroperitoneal
dermoids from germ epithelium, or from ovary, or from supernumerary
testes, of which Merkel has collected several cases.

(2) Epidermal rests derived from the Wolffian duct are probably the
source of certain dermoids of kidney (Schlegtendal, Wedeman), ligamentum
latum, spermatic cord and epididymis (Wilms, Lexer, R. Meyer). They
contain no dermal glands.

(3) True dermoids are derived from imperfect closure of abdominal folds.
Ruge describes a large cyst with two compartments, one lined by skin with
dermal glands and containing hair, the other reproducing intestinal mucosa,
which he would derive from a remnant of the vitelline duct. Of the abdom-
inal fetal implantations, Lexer finds two cases (Buhl. Phillips) in which the
location was retroperitoneal . The tumors lay. on the aorta behind pancreas,
and extended from diaphragm downward and behind kidney.

Dermoid cysts of the pelvic connective tissues are rare but well-recognized
conditions giving rise to pelvic symptoms (Germain, Lit.). They appear

TERATOLOGY 955

chiefly in women in the childbearing period, and are commonly situated
behind the rectum and above the levator ani muscle, and reach the size of a
hen's egg, or child's head, or larger. Six cases have occurred in male subjects.
Sanger collected n cases in which the tumors were found in various
positions, chiefly in contact with and behind the rectum. The presence of
hair in the stools has been the first symptom observed, or the bladder may be
reached and hair appear in the urine (Le Gendre). The occasional presence
of muscle-tissue and renal structures suggest a teratoid origin, but it is more
probable that they result from misplacement of portions of ectoderm and
mesoderm during the formation of the anus, rectum, and urinary passages
(proctodeal membrane and neurenteric canal). As a group they correspond
to the pharyngeal and cervical dermoids of the cephalic extremity. They
differ in location, origin and symptoms from the more superficial dermoids
which project externally and are usually present at birth. Some very exten-
sive pelvic and retroperitoneal dermoids probably belong in this group.
Zweifel removed a large cyst lined by hairy skin, which extended from dia-
phragm behind kidney and into pelvis, and' Bardenhauer's cystic tumor was
even more extensive in the same regions.

Ciliated Epithelial Cysts. Enterocystomas. — In many regions of the
body occur small or large cysts lined by ciliated epithelium, the origin of which
has given rise to much speculation. One group of these cysts is relatively
numerous along the gastro-intestinal canal, and since they are usually lined
by mucous membrane resembling that of the intestine they are commonly
named enteric cysts. Others, while of much the same structure, are widely
distributed in organs where an enteric origin is improbable, as in brain,
thorax, pharynx, lung, and genital organs, and in each situation they are
probably referable to local disorders of development. They seem to represent
an endodermal parallel of the dermoid cysts, but the presence of ciliated
cells does not necessarily indicate an end'odermal origin. In general their
structure may be explained by the fact that many embryonal canals are
originally lined by ciliated epithelium, as the neural, enteric, respiratory,
and genital, and that an early misplacement of cell groups from these struc-
tures would naturally have the lining cells in an embryonal state. In fact
all undifferentiated epithelium is generally ciliated. In the brain the cysts
occur in the region of the ventricles, with which they may be connected by
cell strands. Their origin is probably from the epithelium of the neural
canal (Eberth). In the regions of the branchial clefts, nasopharynx, mouth,
neck, tongue, and mediastinum, many cysts of this type are observed. ^ Their
origin may be traced to the same conditions that lead to branchiogenic
dermoids, with which they are often combined. In the skin Hess has described
a number -of cysts with ciliated lining, for which no explanation is apparent.

Along the 'esophagus in the fibrous or submucous coats the cysts have
frequently been observed and referred to misplacements of the embryonal
epithelial" lining which is originally ciliated (Wyss, Zahn, Trespe). In the
pleura, hilus of lung, arch of aorta (Stilling), and in mediastinum between
diaphragm and lung, simple or complex cysts occur, often associated with
mucous glands, muscle, or cartilage. They have been referred to misplaced
portions of the respiratory tract (Virchow, Zahn). In the liver the cysts
have appeared on the anterior surface, near the suspensory ligament and
along the inferior border. They lie between the peritoneum and capsule of
the organ (Zahn), and their origin is not readily explained.

About the female generative organs, internal and external, the cysts are
particularly frequent, and may be referred to the several embryonal struc-
tures connected with these organs.

956

N EOF LA STIC DISEASES

Sacrococcygeal Dermoids, Mixed Tumors and Teratomas. — The complex
embryonal processes occurring in the caudal extremity form the basis of a
series of fistulae, cysts, and tumors in this region. Very similar conditions
exist at the cephalic extremity with parallel results.

In the sacrococcygeal region the abnormalities resulting from embryonal
disorders include: (i) Simple dermoids, (2) complex dermoids, (3) teratoid
tumors, (4) teratomas, (5) fetal implantations. In many cases these condi-
tions are associated with various defects of the spinal cord and its membranes
and the spinal column (spina bifida).

While some of these conditions are simple and readily referable to par-
ticular embryonal structures, others are complex, difficult of interpretation
and seem to involve more than one embryonal structure. In dealing with
the more complex growths one encounters teratoid tumors which seem to

Mesonephros

Mesenterium dors.
Extremitas inf.

Intestine

Opening of Wolffian
duct

Aorta

Intestine

Colom

Duct, omphaloenteric
Duct, allantoideus

Membrana cloacae
Post-anal gut

Spinal column

Chorda
FIG. 477. — Model of caudal extremity of embryo. (After Kollmann.)

have a purely local origin and transitional cases which seem to belong to the
true bigeminal teratomas, among which are also pronounced forms of fetal
implantation. Thus the entire group is not only numerous but complex, and
a rigid classification is at present impossible (Borst, Lit.).

The embryonal structures which give rise to these growths are chiefly:
(i) The fovea coccygea and the coccygeal vestiges of the neural canal, (2)
the neurenteric canal, (3) the postanal gut, (4) the proctodeal membrane.
The location of these structures and the general conformation of the caudal
extremity is partially indicated in the accompanying sketch.

Fovea Coccygea. Coccygeal Vestiges of Neural Canal. — Up to the third
month the spinal cord reaches to the third coccygeal vertebra, beyond which
it is continued to the tip of coccyx and to the overlying skin as a fibrous cord
containing groups of epithelial cells. Up to the fifth month or later there
is further growth of the cells of this structure, producing irregular spaces
lined by polyhedral or pavement cells. The later development of the soft

TERATOLOGY 957

parts about the anus and the gradual atrophy of the remnant of cord often
produces a superficial depression over the coccyx — ihefovea coccygea (Tourneux,
Hermann, Mallory). Fistulas lined by pavement or polyhedral cells, der-
moids, and more complex tumors may develop from these structures. Tour-
neux has found remnants of gland tissue along with these coccygeal vestiges.
Perman describes a large tumor resembling a meningomyelocele which was
not connected with the spinal canal, but contained much neuroglia tissue
and cysts lined by cubical or stratified squamous epithelium. Nasse de-.
scribes a simple fistula lined with epidermis and many sweat-glands, and
Wendelstadt reports a case in which the tract contained skin and hair.
Wette observed a dermoid in the coccygeal canal, with a fistula leading to the
skin. Schmidt found a sacral dermoid with several fistulous openings,
associated with a complex mesodermal tumor in which were tubules lined by
cylindrical cells. Mallory has collected a series of cases of fistulous tracts,
cysts, dermoids, and a glioma, in this region, and demonstrated in several
fetuses the embryonal structures from which they spring. Bergmann
pointed out that the dermoid tumors in this locality show no free communica-
tion with the spinal canal, which is regularly present with meningocele. Yet
some spinal dermoids are connected with the canal by a narrow pedicle.

Xeurenteric Canal. — In the lower vertebrates there is constantly present a
short narrow canal connecting the lower end of the medullary groove with the
hind-gut. This neurenteric canal has been observed by Graf Spee in a human
embryo with still widely open medullary groove, and Eternod has repeated
this observation'. Although the canal is a very minute structure and there
is no evidence that it exists in any form in the adult (Keibel and Mall),
it has been drawn into the possible sources of certain tumors of the ventral
side of the coccyx, especially those which combine cysts lined by intestinal
wall with portions of nervous tissue.

Of these tumors Hildebrand's case may serve as an example. A female
infant of six months presented a tumor as large as its head, lying between rec-
tum and sacrum and protruding externally. It was composed of many cysts
lined by cuboidal or cylindrical or ciliated or hornifying squamous epithelium.
In some cysts the lining closely resembled the intestinal mucosa, and into
these cysts projected two papillary masses of neuroglia tissue. Other com-
plex cases which seem to belong in this group are reporetd by Jantreboff and
Ritchl. Bergmann described sarcomatous changes, and cases in which the
course is rapid and the tumor exhibits several types of sarcoma, but without
metastases (cystosarcoma).

Postanal Gut. — The proctodeal portion of the anal canal, formed by an
invagination of the ectoderm, does not meet the lower end of the intestine
but joins the intestinal wall at some distance anterior to its extremity.
The terminal portion of the intestine, lying on the ventral side of the coccyx,
becomes closed and atrophic, and this embryonal remnant appears to be
connected with many tumors lying between coccyx and rectum. It was
first employed by Middledorpf in explanation of a cystic tumor containing a
convoluted portion of intestine surrounded by much fat tissue.

These tumors are observed at birth. They form papillary external tumors
between anus and coccyx, displacing the genitals, and they extend upward
behind the rectum, and occasionally outward over the coccyx.

Simple tumors of this group are composed of segments and convoluted
folds of intestinal wall and mucosa. Middledorpf s tumor had an external
fistula and was adherent to rectum. Ganz found a segment of intestine 7
cm. long, and other similar cases are described by Freyer and Nasse. Wid-
ened sacral vessels coursing over the tumor may yield a bruit (Jordan).

958 NEOPLASTIC DISEASES

The well-developed muscular walls may yield spontaneous or electrically
excited peristaltic movements (Preuss, Bergmann, Stolper). Striated
muscle-fibers from the sacral region may be added to the capsules and con-
tribute to the movements (Ahlfeld).

Cloacal Membrane. — The various steps in the union of anus with gut,
the absorption of the cloacal membrane, and the formation of bladder and
external genitals, are concerned with tumors of these organs and may lead
to formation of dermoids. Some of these appear in the pelvic connective
tissue (Germain, Lit.). Small nodules along the raphe of penis and scrotum
composed of epithelial pearls, are referred to imperfect closure of the dermal
cleft at this point (Epstein).

A variety of cysts lined by epidermis or by cylindrical or mucous cells
and probably derived from cloacal remnants, have been collected by Mermet
and Marchadier.

A dermoid of the bladder with atresia ani et urethrae is described by
Martini.

There are thus four somewhat definite groups of tumors which may be
referred with considerable certainty to single embryonal structures in the
sacrococcygeal regions. Yet the majority of congenital tumors of this area
are most complex and seem to involve more than one of the embryonal
remnants or some additional anomalies of development.

Sacrococcygeal teratoid tumors constitute a somewhat heterogeneous group
in this field (Braune, Stolper, Lit.). These are solid and cystic large nodular
congenital tumors lying at the lower end of the spinal column in front of
sacrum and coccyx. They project below displacing the anus forward and
may extend over the dorsal surface of coccyx and sacrum. A definite con-
nection with the bones is occasionally seen (Kummel), and the sacrum may
be rudimentary (Pannwitz). The spinal dura is as a rule not involved. In
these features they differ from the tumors on the dorsal surface of the sa-
crum. The hypertrophied sacral arteries and the branches of the nerves of
the sacracoccygeal plexus course over the tumors. One-third of the subjects
are born dead, and 90 per cent, of the others die in the first few days.

The structure is very varied and comnl-x, a histological pot pourri
which is yet sufficiently restricted for a local origin, although three germ
layers are represented.

The solid portions contain cellular connective-tissue, fat, smooth and
striated muscle, bone and cartilage. Chorda rests were identified by Hen-
nig. Portions of central nervous system are often observed, in the form of
masses of glia-tissue or ganglia. The cysts are of numerous types, being
lined by cubical, cylindrical, ciliated epithelium, or with pavement cells,
or they resemble true dermoids with hornification, epithelial papillae, seba-
ceous material, hair, and sweat-glands (Nasse). The cyst walls are composed
of fibrous tissue or contain cartilage, bone, adenoid tissue with lymph-follicles
or nervous tissue. Areas of glia-tissue may contain small cysts lined by
neuro-epithelium (Perman, Stolper). Very large cysts lined by cuboidal cells
probably represent a distended neural canal simulating a cerebral ventricle.
Borst describes a cystic tumor which he interpreted as a rudimentary caudal
brain. Pigmentation of various tissues is frequent and certain pigmented
epithelial structures have been interpreted as rudimentary retinal vesicles
(Spondly, Kummel) . Well-defined retinal structures are described by Hennig,
and fully developed or rudimentary teeth by Port, Kronlein, and Danzel.
Fetal bones have also been identified by Kiderlen, Borst and Menzel.

Sacral Teratomas. — The presence of definite organs or their rudiments
which cannot well be referred to neighboring structures constitute the basis

TERATOLOGY

959

of classification in this group of tumors. This principle was first employed
by Nasse and its validity will be considered later.

The general relations of these growths are very similar to those of the
teratoid tumors. They are bulky masses, present at birth, lying on the dor-
sal surface of the sacrum and coccyx and adherent to or enclosed within the peri-
osteum or connected to the bone by a pedicle. Others lie anterior to the
sacrum and connected with this bone (Kauffmann), or with the rectum
(Feldmann), and projecting into the pelvis. The structure presents cystic
and solid portions similar to those of the teratoid tumors, including cysts
lined by various types of epithelium, dermoids, segments of intestinal mucosa,

•^ " * '"V*

TV3? **-.'-- T":

~.~ V-SIMSS

• -4&3^;~£ «"V' ' V, ';

'^®^fe^eiB^

'6:iX??5«

•^5?%£^

OV.^-;:

:"^<^^ *
•1@§&&^

',:• ^*^$^ - -'£S '*?.••:<£, ^%'^. •• ^

>.' 'i^*^.,^-' '*<-r - vX - ' ' / *\ - ^ ^r^*-*V- * ^ tf;

•fffiiil^^PrL#

FIG. 478. — Structure of a congenital sacral teratoma. a, b, c, Dermal layers; d, Smooth
muscle; e, Intestinal epithelium; g, Glia tissue. (After Slolper.)

gland structures, fat, muscle, cartilage, and bone, and, finally, portions of
nervous and -glia-tissue.

In addition a great variety of rudimentary organs are observed. These
include segments of intestine with mesentery, rudimentary esophagus,
stomach, and buccal ca*vity with salivary glands (Linser, Kleinwachter) ;
pulmonary parenchyma, bronchi with cartilaginous rings (Piper, Linser);
thvroid (Hagen thorn) , pancreas, spleen, adrenal (Stroh), kidney, brain with
ventricles and choroid plexus (Sperling, Stroh). The bones may reproduce
well-formed extremities, as forearm and hand (Bohm), tibia, femur, and
joint (Kaufmann), pelvis and extremities (Kleinwachter), toes (Feldmann),
eyes (Frank) (Depaul). In fact, Askanazy regards the sacral teratomas as
the most prolific in the production of rudimentary organs. An abortive

960 N EOF LA STIC DISEASES

fetus enclosed in amniotic membrane lay under the skin in a case of Jordan's.
Thus many transition stages up to definite fetal implantations are provided.
Secondary changes of importance occur in sacral teratomas, giving rise
to simple malignant tumors. Overgrowth of muscle-cells led Virchow to
speak of myosarcoma in these tumors. Bergmann described a variety of
sarcomatous changes. Nakayama observed infiltrating endothelioma and
myxoangiosarcoma, and a metastatic growth consisting of fetal brain tissue.
In a sacral tumor reported by Buzzi as angiosarcoma Perrier afterward
found teratoid structures. A recurring sarcomatous teratoma described
by Hinterstoisser gave extensive metastatic tumors "alveolar sarcoma,"
in lungs, liver, and lymph-nodes. Askanazy suggests that more thorough
examination of other simple tumors of the sacral region might disclose

FIG. 479. — A case of spina bifida, with meningocele.

teratoid elements. The sacral and ischiorectal region is a frequent seat of
angiosarcomas whose origin may thus be explained. The sacral neuroglio-
mas constitute a definite subdivision (Mallory, Keller, Scheuermann).

Tumors Associated with Spina Bifida. — While the common meningocele,
myelocele, myelocystocele, etc., have no neoplastic character, spina bifida
is often associated with tumor processes. The association with spina
bifida throws some light on the pathogenesis of the entire group of sacral
teratomas, since spina bifida signifies a lack of coherence of embryonal parts,
and a failure of growth momentum, which is favorable to spasmodic and
aberrant growth of the type of budding.

Sacral hygroma or cystic lymphangioma is the simplest tumor of this
class and arises from extensive cystic dilatation of the spinal subarachnoid
spaces. Such a cystic tumor may show extensive connection with the spinal
canal (Marchand, Kroner), or these connections may be lost and the tumor

TERATOLOGY 961

appear as an isolated lymphangioma lying on the dorsal or ventral side of the
spine. Marchand describes hernial protrusions of spinal meninges between
vertebrae, and Borst believes that many cervical and sacral hygromas arise
in this manner, referring to cases of Lotzbeck and Brauner, and to one of his
own observation in which the spinal connection was reduced to a narrow
canal.

Dilatation and overgrowth of lymph- and blood-vessels in the walls of
such cysts may lead to the growth of angioma and lymphangioma associated
with spina bifida (Hildebrand), and overgrowths of fibrous or fat tissue may
produce fibroma or lipoma. Such lipomas may contain cysts or a canal
leading to the spine.

^ Spina bifida occulta is a condition in which the original fissure in the
spinal column has become closed by a fibrous or bony membrane, while the
hernial sac and its accompanying tissues persist. This, condition has been
observed with a variety or malformations, sacral hyper trichosis, club-foot,
congenital luxation of hip, with atrophy of limbs, elephantiasis, syndactyly,
disturbances of innervation, mat perforant, and in a series of cases it has been
associated with sacral tumors (Recklinghausen). Most of these tumors
consist of fibrolipoma with areas of nerve-fibers and striated muscle, and are
connected by a fibrous or fatty tissue pedicle with the sacral fissure. The
so-called "false tail" is a pendulous lipoma which is often connected by a
strand of fibrous or muscular tissue with the sacral dura (Arnold, Bartels,
Hagenbach). The spinal cord may be extensively deformed (Bohnstadt).
The nerve plexus in the tumor may show myxomatous changes (Borst).
Muscatello described cases with extensive defects in sacral and dorsal
spine and cord, with a dermoid in the dorsal region and an epidermoid at the
sacrum.

On the convexity, at the base of the skull, and in the dorsal region,
hairy lipomas are described which probably have the same origin (Arnold,
Virchow, Bartels). That portions of brain and cord may be displaced with
the membranes in spina bifida is indicated in the reports of glioma with
meningocele (Hildebrand). Much more complex tumors and deformities
arising from spina bifida and imperfect development of the spinal cord are
described by Arnold and Borst.

Origin of Congenital Sacral Mixed Tumors. — The recent tendency has been
to regard the congenital mixed tumors of the sacral region as forms of true
teratoma, a view which is favored by many considerations. It has long been
recognized that many gradations exist between the comparatively simple
mixed tumors, teratoids, teratomas, and fetal implantations in this region,
and that there are no definite anatomical features on which they can readily
be separated. The resemblances to teratomas of the sex glands have often
been apointed out. Nakayama has recently reviewed the subject with the
conclusion that all or nearly all sacral mixed tumors are of tridermal structure
and arise from totipotent material and Askanazy accepts this conclusion.

Against the sweeping application of this view there stand, however,
the well-known embryogenic disturbances peculiar to the caudal and cephalic
extremities. It seems quite clear that certain complex growths must be
referred to the coccygeal vestiges of the neural canal, the postanal gut, prob-
ably also to the neurenteric canal, while the complex forms of spinal rhachis-
chisis doubtless account for other complex tumors. Many other special fac-
tors pertaining to the mechanics of development of the caudal extremity have
been adduced in support of the local origin of sacral tumors (Borst, Lit.).

Therefore, in view of the several important possible sources of complex
sacral tumors, it seems necessary to continue the attempt to analyze each

962 NEOPLASTIC DISEASES

case and place it in a proper category and not merge the group into one class
of teratomas. As previously pointed out, there are special reasons for
attributing many of the sacral growths as well as the cervical to budding
processes. In this aspect the sacral tumors differ from those of the sex glands,
which probably always arise from totipotent sex cells.

The difficulty of accomplishing this separation is illustrated in a case
described by Borst. A large congenital antesacral tumor, composed of solid
and cystic portions, was connected by a pedicle with the spinal column. It
appeared to represent an immature brain with gyri, bilateral ventricles,
choroid plexus, and pigmented ganglia. Small cysts were lined by cubodial
or flat epithelium. The solid parts contained much cellular connective,
fat tissue, and glandular alveoli, nerve-trunks, and ganglia. Borst refers
this tumor exclusively to derivatives of the medullary groove and its mesen-
chymal investments.

BIBLIOGRAPHY

KEY TO ABBREVIATIONS OF JOURNALS CITED

The common names of journals, rather than their official titles, are usually employed.

Articles are not entered more than once in the bibliography of one chapter, although
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A. G. Archiv f. Gynaecologie.

A. K. Archiv. f. Kinderheilkunde.

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Z. G. G. Zeitschrift f. Geburtshilfe u. Gynecologic.

Z. K. Zeitschrift f. Krebsforschung.

Z. M. Zeitschrift f. kl. Medezin.

Z. N. Deutsche Zeitschrift f. Nervenheilkunde.

Z. C. Deutsche Zeitschrift f. Chirurgie.

HISTORICAL

The author has made no research in the older literature of cancer. Most of the older
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963

964 BIBLIOGRAPHY

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CHONDROMA

180 Weber, Die Knockengeschwulste, Bonn, 1856; V. A., 35. Recklinghausen, D. P. G.,
i (Lit.). Mischaikoff, Diss., Zurich, 1888. 181 v. Recklinghausen, V. A., 118, 4.
Siegert, V. A., 129, 419. 182 Ranvier, Soc. d'Anat., 1865, 40. 183 Foerster, Wien. med.
W7., 8. Biesiadecki, Sitz. Wien. Akad. Wissen, 57. Ernst, Z. B., 28. 186 Xasse, Volk-
mann's Vort., 1895, X. F., 124 (Lit.). Hagen, L. A., 41, 420. Carman, Fisher, A. S., 61.
Ashhurst, A. S., 63. Lenormant, Revue d'Orthop., 16, 193. Deganello, V. A., 168 (Lit.).
Pfeiffer, Dis. Erlangen, 1890. Clark, Atwood, X. Y. M. J., 1907, 86, 97. 186 Bidder,
V. A., 720, 194. Recklinghausen, D. W., 1892, 339. Zahn, V. A., 115. 187 Deichert,
V. A., 141. Spisharny, D. W., 1892, 853. Boeckel, cit. by Spisharny. Kramer, V. A.,
156, 1 88. 188 Williams, Diseases of Breast, London, 1894. Williams, Uterine tumors,
London, 1901. R. Meyer, Y. A., 167, 81. Ewing, S. G. O., 1911, 230 (Lit.). Paget, Med.
chir. Trans., 1855, 38, 247. Ohkubo, Arch. f. Entwick, 1908, 26, 509 (Lit.). Kolliker,
Gewebelehre, 1889, j, 301, 317. H. Miiller, Zeit. f. rat. Med., 1858, 202. Ribbert,
Geschwulstlehre, 149; C. P., 5, 457 (Lit.). Grahl, I. D. Gottingen, 1903, cit. by Fischer.
Klebs, Allg. Path., 1889, 2, 693. Hassner, Y. A., 210, 385. 189 Xebelthau, I. D. Mar-
burg, 1897. Fischer, Z. B., 40, 109. Linck, Z. B., 46, 573- Feldmann, Z. B., 48. C.
Vecchi, L. A., 99, 575- Albert, S. G. O., 21, 766.

OSTEOMA

192 Sancerotte, cit. by Virchow, 1. c., II, 24. 193 Heymann, V. A., 104, 145. Reinecke,
B. B., 1891, 7. E. Miiller, Z. B., 57, 232 (Lit.). Hartmann,L. A., 35 (Lit.). Mischaikoff,

974 BIBLIOGRAPHY

1. D., Zurich, 1894. 194 Heymann, V. A., 116, 329 (Lit.). Kammerer, AnnaL Surg., 10.
Nakel, Z. C., 33, 308. Zimmerman, Z. C., 57 (Lit.). 195 Bornhaupt,L. A., 26, 589 (Lit.).
Tillmanns, Ibid, 32, 677. 196 Busse, Z. C., 1904, 73. Berndt, L. A., 1906, 79. Ropke,
L. A., 1907, 82. Luschka, V. A., 10, 500. Wagner, Arch. f. p. Heilk., 1859. Heschl,
Zeit. f. p. Heilk., 8. Forster, V. A., 13, 105. Bostrom, Sitz. Phys-med. Soc. Erlangen,
1875, 158. Picchini, Giorn. intern, d. Sci. med. Napoli, 1885. Triboulet, Bull. soc.
anatom., Paris, 1892, 340. Arnsperger, Z. B., 21 (Lit.). 197 Port, cit. by Virchow, Ges-
chwulste, II, 102. Cohn, V. A., 101, 156. Rullier, Arch, gen., 1824, V. Browning,
London Path. Soc., 1861, 13, 25. Le Diberder, L'Union med., 1867, 57. Krauss, cit. by
Arnsperger. Nusser, Zeit. f. p. Heilk., 1855. Gross, Amer. J. Med. Sci., 1879. Len-
hossek, V. A., 60, i. Konig, Lehrb. d. Chir., 2, 551. La Grange, Tumeurs de 1'Oeil,

2, 346. Panas, Mai. des Yeux, 1894. Lesser, Allg. Chir., 1905, 2, 288. A. Knapp,
Arch, of Ophth., 25, 353. Zanda, Z. B., 5 (Lit.). Meschede, V. A., 55. Ebstein, V. A.,
49. Bidder, V. A., 88. De Vecchi, Lo Sperimentale, 37. C. Cohn, V. A., 106. O
Klotz, Arteriosclerosis, 1911. Lexer, L. A., 50. Schultz, Schuler, B. B., 33. Munch-
mayer, Z. nat. Med., 1869, 24, 9. Elliott, J. A. M. A., 1911, 57, 873 (Lit.). De Witt,
Amer. J. M. S., 120, 295 (Lit.). 198 Mays, V. A., 74. Kaufmann, Lehrb. path. Anat.,
1909, 1191. Kroemer, Veit's. Handb. Gyn., 1908, 4.

MYOMA

201 Reich, Arb. path. Instit. Gottingen, 1893. Gottschalk, A. G., 43. 202 Krische,

I. D. Gottingen, 1869. Langerhans, Berl. W., 1893, 338. Beeston, Festschr. f. Orth,
1903. Schlagenhaufer, Wien. kl. W., 1902, 523. Ulesko-Stroganow, Mon. f. Geb., 18,
357. Hannsemann, Naturf. Vers., 95. Moser, D. W., 1903, 133. Eising, J. P. B., 1903,
233. Borrmann, M. G., 6. Williams, Zeit. f. Heilk, 1894, 15. Basso, M. G. G., 28.
Hansemann, Diag. bos. Geschwulste. Evelt, M. W., 1903, 1414. 203 Winter, Z. G. G., 57.
Hofmeier, Z. G. G., 5, 96. Flatau, Munch. W., 1901, 558. Cullen, J. A. M. A., 1903,
41, 1013. Kelly, Cullen, Myomata of Uterus, Phila., 1909. Ricker, V. A., 142. v.
Franque, Z. G. G., 40. Hansen, Nord. med. Arch., 1903. Cruveilhier, Anat. path. I,

II, 5. Stone, Amer. J. Obst, 1899, 519. 204 Fehling, Lehrb. d. Frauenk. Cullen,
J. H. B., 1896, 1898; Fest. Orth., 1903 (Lit.). Aschoff, M. G. G., 9, 25. Turner, Edin.
M. J., 1861, 698. Simpson, Dis. of Women., Edin., 1872. Leyden, Z. G. G., 26, 434.
Kustner, Ibid, 33, 338. Kelly, Operative Gyn. Hunter, cit. by Gebhard. Severanu,
cit. by Williams, 1. c., 67. Martin, C. G., 1888, 90. 205 Tillaux, Gaz. des Hop., 1867.
Bertelsmann, A. G., 50, 178. Lennander, C. G., 1895, 159. Wyder, A. G., 13, 35. Fab-
ricius, A. G., 50. Bulius, Z. G. G., 23, 358. Kuster, Beitr. z. Geb. u. Gyn., i, 7. Kots-
chau, C. G., 1887, 757. Hedren, A. G., 83. 206 Martin, A. G., 32, 470. Menge, C. G.,
1895, 453. Duncan, C. G., 1894, 222. Gusserow, Deutsche. Chir., 1885. 207 Stratz,
Z. G. G., 17. Henocque, Arch, de Phys., 1873. Everett, Amer. J. Obstet., 12. Payr,
Z. C., 81. Wylie, N. Y. J. Obstet and Gyn., 1894. Liebmann, V. A., 777. Schafer,
V. A., 129. Roily, V. A., 150, 555 (Lit.). Gebhard, Veit's Handb., 1897, 2, 409. Rosger,
Z. G. G., 18. Hertz, V. A., 46, 235. Freund, Beitr. z. G. u. G., 3, 150. Bennet, cit. by
Williams, 1. c. Kworostansky, Z. B., 32. 208 Amos, Z. G. G., 54. Klob, Path. anat. d.
weib. Sexualorgane, 1864. Bayle, Diet. d. sci. med., I, VIII. Tillaux, Ann. de. Gyn.,
26. 2Q3. Williams, Uterine Tumors, 1901. 210 Klein wachter, Z. G. G., 9, 68. Landau,
Berl. W:., 1901, 205. Pick, A. G., 60; M. G. G., 1897. Meyer, Z. G. G., 37, 38, 49.
Pick, A. G., 52, 54, 60; V. A., 156. Schroeder, Handb. Krank. weib. Geschl., 1881. Ruge,
Z. G. G., 17. v. Franque, C. G., 1900, 660. Babes, Wien. allg. med. Z., 1882. Reck-
linghausen, Die Adenomyome, d. Ut, 1896. Schroeder-Hofmeier, Handb. Krank. w.
Geschl., 1892. Pick, A. G., 54 (Lit.). Schickele, C. P., 1904. Ernst, A. G., 85 (Lit.).
211 Meyer, Z. G. G., 49 (Lit.). Grossmann, A. G., 54. v. Franque, Z. G. G., 47. Lock-
stadt, M. G. G., 7 (Lit.). Cohen, V. A., 158. Aschoff, M. G. G., 1899. Borst, Gesch-
wulste, I, 217. Klein, V. A., 154 (Lit.). Breus, Cystenbild. in Uterusmyomen, Wien,

BIBLIOGRAPHY 975

1894. Herpf, Deut. gyn. Gesell., 1897. Pfannenstiel, Deut. gyn. Gesell, 1897. R. Meyer,

A. G., 54. 212 Pichler, Prag. W., 1897. Illig, I. D. Giessen, 1894. Miodowski, V. A.,
173. Laboulbene, Traite anat. path., 1879, 120. Nazzari, Gas. med. ital., 1902. Steiner,

B. B., 22 (Lit.). Mercer, N. Y. Med. Rec., 36, 67. Trappe, Frankf. z. P., i, 109. Boet-
ticher, V, A., 104. Lode, Wien. Id. W., 1894, 381. Babes, Ziemsenn's Bandb., 14, 499.
Besnier, Annal. de. Dermat, 1885. Forster, Wien. med. W., 1858. Challard, Bull. Soc.
Anat., 1871. Axel, Key, V. H. Jahresb., 1877, i, 271. Czerny, L. A., 17. Chambard,
Gouilloud, Annal de Dermat., 1883. S. Pollitzer, J. Cut. Dis., 1894, 15, 367. Hess,
V. A., 120. Marc, V. A., 725, 543 (Lit.). Judassohn, V. A., 121. Walters, A. D., 25.
Sobotka, A. D., 8p, 323 (Lit.). Stein, Tumors of Bladder, N. Y., 1881. Terrier, Hart-
mann, Rev. de Chir., 1895 (Lit.). Volkmann, L. A., 18. Buttner, Z. G. G., 28. Becker,
V. A., 163. 213 H. Miiller, V. A., 145 (Lit.). Abramow, C. P., 12. Jacobaeus, Nord.
m. Arch., 1903, j. Larkin, J. Med. Res., 6.

RHABLX)MYOMA

Wolfensberger, Z. B., 15. Fujinami, V. A., 160, 203. Billroth, V. A., p. Zenker,
V. A., 120. Ribbert, V. A., 106, 130. Eberth, V. A., 55. Benenati, V. A., 171, 418
(Lit.). Marchand, V. A., 100. 214 Kasckewarowa, V. A., 54, 63. Arnold, Z. B., 8.
Girode, C. R. Soc. Biol., 1892. Nehrkorn, V. A., 151. Hauser, V. A., 88. Cattani,
Arch. sci. med., ip. Vincenzi, Riv. clin., Bologna, 1887. Stumpf, Z. B., 50. Pfan-
nenstiel, V. A., 127 (Lit-). Gow, St. Bart's Hosp. Rep., 27, 97. Pick, A. G., 46 (Lit.).
Demme, Ber. Jenner Kinderhosp., ip. Franque, M. W., 1898, 1301. Kalustow, A. G., 40.
Rosthorn, Wien. kl. W., 1889. 215 Kolisko, Wien. kl. W., 1889. Rein, A. G., 15. Pernici,
V. A.; 113. Ribbert, V. A., 130, 249. Neumann, V. A., 103, 497. Wood, N. Y. Path.
Soc., 1902. Ewing, S. G. O., 12, 230 (Lit.). Stoerk, Z. f. Heilk, 22. 216 Ponfick, D.
P. G., 1901, 4, 226. Cesaris-Demel, Arch. sci. med., ip, 139. Wolbach, J. Med. Res., 16,
495 (Lit.). Seiffert, Z. B., 27. Kolisko, Wien. m. Jahrb., 1887. Knox, Shorer, Arch.
Fed., N. Y., 1906. Bonome, Atti Instit. Veneto d. sci., 63. 217 Glinski, V. A., 167.
Brodowski, V. A., 67. Pende, Z. f. Heilk., 18. Prudden, Am. J. M. S., 85. Billroth,
V. A., 18. Kaufmann, Med. Gesell., Basel, 1902. Helbing, C. P., p. Buhl, Z. f. Biol.,
I, 263. Erdmann, V. A., 43. Kuttner, Deutsche Chir., 1913, I, 25a. H. R. Miiller,
J. Cancer Res., 1917.

ANGIOMA

220 Seifert, A. f. D., 59, 197 (Lit.). Fox, N. Y. Derm. Soc., 1895. Jackson, J. Cut.
Dis 1895. Unna, Histopath. d. Hautk., 1194. 221 Muscatello, V. A., 135 (Lit.).
Pupovac, L. A., 5* 555- Slitter, Z. C., 7*. 3*8 (Lit). Nauwerck, V. A., m, 211. 222
Lowenthal, L. A., 49. 223 Borrmann, Z. B., 40, 372. Gascoyen, London Path. Soc.,

1860 u, 267. Cruveilhier, Atlas d' Anat. Path., LXXX, pi. 5. Falkowski, Z. B., 57,
385 ' Hildebrand, Z. C., jo (Lit.). Esmarch, V. A., 6, 34. Schuh, Wien. med. Woch.,

1861 763 224 Shennan, J. Path, and Bact, ip (Lit.). 225 Recklinghausen, V. A.,
n8,\. 226 Albrecht, D. P. G., 1904, 7, 153- Reiche, Rust's Mag., 1836,46 Wegner,
L \ 20 641. Delbau, Union med., 1857, 478. Morton, Amer. J. M. S., 1865, 378.
di Ricci Dublin Quart. Jour., 1865, 33§. Quackenboss, Annal. Ophth. (St. Louis), 1908,
17 227 Schoene, Z. B., Sup., 7, 1905 (Lit). Gerhardt, Charite Annal., 20. Muthmann,
V ' \ 772 324 (Lit.). Veeder, Austin, Amer. J. M. S., 143, 102. Image, Hake, Med.
Chir 'Trans 1847, 30, 109. Dowd, Ann. Surg., 62. H. Albrecht, Z. f. fieiUc, 1902.
Ribbert V \ 151. Schmieden, V. A., 161. Orth, Spec. Path. Anat., Bd. II, 570. La
Villette,' These, Paris, 1906. 228 Luschka, V. A., 6, 458. Lafora, N. Y. M. £1912,
nfi TOO? Enders M. m. W., 1908, 1646. Wergman, Lancet, 1914, I, I74&. Orbison,
J 'A. M.' A., 1915 *4, '575- Deetz, V. A., M, 341 (Lit-). Schuck, L D Berlin 1885.
Heine, Prag. Vierteljahrs., 1869. Lable6, Gaz. d. Hop., 1872. Kretschmann, I. D.,

976 BIBLIOGRAPHY

Halle, 1881. Emanuel, D. Z. f. Nervenheil, 14. Ritschl, B. B,, 15. Langhans, V. A.,
75. 229 Wegner, B. B., 1894. Nasse, L. A., 44, 233. Sutter, Z. C., 77, 368. Novack,
L. A., 86, 873 (Lit.). Kuttner, B. B., 18. Ribbert, V. A., 151. 231 Haug, cit. by Borst.
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Krauss, V. A., 125. Schmidt, D. P. G., 1898. Ritter, Zeit. f. Heilk., 1900, 21. Blatteis,
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Frobenius, Z. B., 6. Takano, Z. B., 53 (Lit.). Sick, V. A., 770, 9. Smoler, B. B., 32.
Schwarzenburg, B. B., 77. Lion, V. A., 167. 233 Hedinger, V. A., 164. Ranvier, C. R.
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Z. f. Heilk., 24. Kroemer, Veit's Handb., 1908, 4.

SARCOMA

235 Malherbe, Rech. s. 1. sarcome., Paris, 1904. 238 Wakabayashi, V. A., 205, 54.
Howard, Fetsch. f. R. Hertwig. 239 Virchow, Geschwulste, 2, 214. Favre, Regaud,
C. R. Soc. Biol., 74, 608, 688. Brault, Arch. gen. de. Med., 1899. 240 W. C. White,
J. H. Bull., 1900, 209. Seelig, S. G. O., 4, 319. 241 Ricker, L. A., 50, 573. Miiller,

1. D., Zurich, 1894. Ewing, Jour. Med. Res., 1913, 28, i. 242 v. Hansemann, Diag.
bos Geschw. Berndt, L. A., 65. 243 Kolisko, Wien. kl. Woch., 1906, 1429. Heukelom,
V. A., 707. Ackermann, Volkmann's Vort., 233-4.

SPINDLE-CELL SARCOMA; FIBROBLASTIC SARCOMA

244 Walter, I. D., Wurzburg, 1896. 245 Goldmann, B. B., 18. Hedinger, V. A.,
164. Heukelom, V. A., 707. Lubarsch, Erg. Path., 1894. Stroebe, Z. B., 77. 246
Babes, Cent. m. Wis., 1883. Ackermann, Volk. Vort., 233. 247 Paltauf, Mracek's Handb.
Boeck, A. D., 73. Spiegler, A. D., 27. Joseph, A. D., 46. Pollard, A. D., 104. Fano,
A. D., 73. Kaposi, A. D., 1872. Mariani, A. D., 98. De Amicis, Mon. D., 25. Phil-
lipsohn, V. A., 767. 248 W. Pick, A. D., 87. Justus, A. D., 99, 446. 249 Linser, B. B.,
26. Moldovan, Prag. W., 1905, 403. Perret, London P. S., 1902, 360. 250 Johnston,
J. Cut. D., 1901, 1903. 251 Lowenstein, B. B., 48. Gross, Soc. de Chir., 1878, 284.
Paquet, Ibid., 705. Reverdin, Rev. Med. Suisse. Rom., 1885, 671. Heurteaux, Arch.
Gen., 1891, 40. Spiess, Frankf. Z. P., ij, i. 253 Fleissig, Z. C., 122. Chambe, These,
Paris, 1895. Pasteau, Soc. Anat., 1895. Bodenstein, M. W., 1892, 4. Sokalow, V. A.,
57, 321. Guitton, These, Paris, 1894. Peters, Med. News, 42, 279. W. Schaffer, I. D.,
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Wolfensberger, Z. B., 75. Glinsky, V. A., 767. Lippmann, Z. K., 3. Baur, I. D., Tub-
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2, 1535. Dreyer, I. D., Gottingen, 1894. Leube, Spec. Diag. Cammidge, B. M. J.,
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SARCOMAS OF BONE AND BONE-MARROW

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45. Richardson, J. A. M. A., 191 1, 56, 315.

CANCER OF UTERUS

623 Welch, Pepper's System Med., 1885, II, 533. R. Williams, Natural History of
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524 Cullen, Cancer of uterus, Phila., 190. Engelhorn, Beitr. G. G., 13, 278. Glockner,
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527 Abel, Landau, A. G., 35, 214. Krauss, Z. G. G.. 54, 383. 528 Frankel, Beitr. G. G.,
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Hauser, A. G., 99, 339. Sitzenfrey, Z. G. G., jp, 385. Hoffmeier, Z. G. G., 32, 171.
Ruge, Veit, Z. G. G., 2, 415; 5, 232; 8, 405. Meyer, Z. G. G., 65, 218; A. G., pi, 579.
Adair, S. G. O., 10, 337. Schottlander, Mon. G. G., 26, i. 529 Fischel, A. G., 75, 76.
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A. G., pi, 579. Heurlin, C. G., 1898, 38. Oeri, Z. G. G., 57, 384. Winter, Die Bekamp-
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B. W., 1889, 701. Bumm, Z. G. G., 55, 173. Fromme, A. G., 79, 197. Sappey, Traite
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BIBLIOGRAPHY 987

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VULVA

Gurlt, L. A., 25, 446. Dittrich, Amer. J. M. S., 1905, 130 (Lit.). Arnot, London P.
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VAGINA

Schwarz, U. d. Erfolg. d. Oper. Vul. u. Vag., Berlin, 1893. Wille, I. D., Erlangen,
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Hoehne, Z. G. G., 67. Hirsch, Z. G. G., 67.

CHORIOMA (CHORIONEPITHELIOMA)

546 R. Volkmann, V. A., 61. Sanger, A. G., 44. Pestalozza, II Morgagni, 1891, 33.
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CYSTS AND EPITHELIAL TUMORS OF THE OVARY

562 Felix, Embryology (Keibel & Mall). Bulius, Hegar's Festschr., 1889. Xagel,
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988 BIBLIOGRAPHY

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THE OVARIAN TERATOMA

593 Kroemer, Veit's Handb. Gyn., 1908, 4 (Lit.); A. G., 57, 322. Hohn, D. Ges. f.
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CARCINOMA OF STOMACH

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EPIDERMOID CARCINOMA OF SKIN, LIP, TONGUE, AND LARYNX

Selberg, V. A., 145. 797 Krompecher, Z. B., 28; Die Basalzellenkrebs, Jena, 1903; Z.
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1000 BIBLIOGRAPH Y

Clubbe, cit. by Juracz. Simon, Cent. f. Laryng., 1888-9; Lancet, 1904, 2, 1263. J. Solis-
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Butlin, Malig. Dis. Lar., 1883.

CARCINOMA OF ESOPHAGUS

835 Kraus, Nothnagel's Handb., 1902, 16. Heimann, L. A., 57. Mehnert. Heller,
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Herxheimer, Z. B., 44 (Lit.). Donath, V. A., 194.

EPITHELIAL TUMORS OF BLADDER

838 Albarran, Les tumeurs de la vessie, Paris, 1891. Fenwick, Tumors of Bladder,
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843 Montfort, These, Paris, 1902. Kuster, L. A., 42, 864. Voelcker, London P. S., 46,
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1904.

TUMORS OF PENIS

845 Creite, Z. C., 79. C. Kaufmann, Deut. Chir., 50 a., 163. Barney, Mass. Gen.
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MELANOMA

849 Demieville, V. A., 82. Recklinghausen, Fibrome d. Haut, 1882. Unna, Berl.
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TUMORS OF THE THYROID

869 Wolfler, L. A., 29. Gudernatsch, Am. J. Anat. 870 Bircher, Med. Klinik., Bei-
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THE THYMUS AND ITS TUMORS

889 Hammar, Erg. Anat., 19; Anat. Hefte, 43. 890 Erdheim, Z. B., 35. Sharp,
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TUMORS OF THE HYPOPHYSIS

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INDEX

ABDOMINAL fetal implanta-
tions, 953
teratoma, 953
Hodgkin's granuloma, 356
Abortive mitosis in tumors,

38
Acanthoma, 457

adenoides cysticum, 813
of skin, 797

Demodex folliculorum

in, 80 1
etiology, 799
secondary changes, 799
structure, 798
tubular, 798
Acidemic coma in gastric

cancer, 635
Acidosis of cancer, 74
Acinar carcinoma, 454
of breast, 502

following fibro-ade-

noma, 504

Acoustic neuro fibroma, 416
Acromegaly, 919
diabetes with, 920
glycosuria with, 920
Adamantinoma, 688
clinical features, 693
glandular, 692
of tibia, 694
structure, 691
Adeno-acanthoma of uterus,

527

Adenocarcinoma, 439, 453
dental, 692
of adrenal gland, 748
of breast, 492
forms, 494
histogenesis, 495
small cystic, 499
structure, 494
of cervix uteri, 527

mucous, 529
of corpus uteri, papillary,

534

squamous cell, 534
of kidney, alveolar, 727
embryonal, in adults,

729

in infants, 728
multiple, in sclerosis,

725
papillary, 721

histogenesis, 725

structure, 727

with granular cells,

725
tubular, 729

Adenocarcinoma of kidney,
tubular structure, 731

of large intestine, gelati-
nous, 649

of ovary, cystic, 577
pseudomucinous, 575
serous, papillary, 569

of pituitary gland, 909
metastases, 909
structure, 910

of prostate, 765

of salivary glands, 705

of stomach, 607
occurrence, 636

of thyroid gland, 876
small alveolar large-
cell, 879

papillary, of c h o r o i d

plexus, 402
Adenofibroma, 149

edematodes, 163

of breast, 478

of ovary, 577
Adenoid carcinoma, 447

epithelioma of skin, 813
cystic, 813
simple, 814
Adenoma, 28, 435

alveolare a cellules claires
of kidney, 724

clinical characteristics, 436

destruens of large intes-
tine, 648

functional capacity, 437

gelatinosum, 871

gross appearance, 436

in gastritis polyposa, 441

in hypertrophic endome-
tritis, 441

in prostatic hypertrophy,
442

malignum, 436, 438
of adrenal gland, 748

mode of growth, 438

of adrenal gland, 747

of bile-ducts, cystic, 668
multiple, 669

of bladder, 842

of cervix uteri, simple, 529

of corpus uteri, 533

of kidney, 718
alveolar, 719
histogenesis, 719
papillary, 718
tubular, 719

of large intestine, 650

of larynx, 828

of liver, multiple, 665
1007

Adenoma of liver, solitary,

660

of mucous membranes, 440
of ovary, 566

everted papillary, 577
solid, 576

superficial papillary, 577
testicular, 590
of pancreas, 681
of prostate, 764
of salivary glands, 704
of stomach, simple, 609

structure, 609
of testis, 780

of thyroid gland, fetal, 873
interacinous, 872
malignant, 876
papillary cystic, 438
physiological conception,

440

sebaceum, 444
structure, 438
tubular, 438
Adenomatoid hyperplasia,

functional, 442
inflammatory hyperplasia,

440

Adenomyoma, 207
mesonephric, 210
of ovary, 590
of uterus, 207
psammopapillare, 211
Adenomyomatosis of corpus

uteri, diffuse, 536
Adenomyosarcoma of kid-
ney, 214, 939
anatomy, 732
embryonal, 732
histogenesis, 733
structure, 732

Adenosarcoma of breast, 484
Adiposogenital dystrophy,

theories, 923
Adrenal gland, adenocar-

cinoma of, 748
adenoma of, 747
cancer of, 747

fully developed, 748
hyperplasia of, 746
melanoma of, 756
neurocytoma of, 750
clinical types, 753
sarcoma of, in infants,
congenital (Pep-
per type), 753
with cranial metas-
tases (Hutchin-
son type), 753 ,

1008

INDEX

Adrenal gland, tumors of,

746

classification, 746
medullary, 749
chromaffme cell, 754
with adrenalin con-
tent and nephritic
symptoms, 754
melanoma, 868
rests, extrarenal, tumors

of, 740

occurrence, 735
tumors of, 734

carcinomatous, 738
gross appearance, 736
lateral retroperiton-

eal, 741
occurrence, 735
peritheliomatous, 738
renal tumors and, dif-
ferentiation, 739
sarcomatous, 738
structure, 737
trabecular, 738
tumors of female genital

organs, 741
of ovary, 590
of testis, 781
Adult tumors, 26, 49
Albuminuria in cancer, 75
Albumosuria in myeloma of

bone, 285
Aleukemic systemic lymph-

omatosis, 362
Alkalescence of blood in

cancer, 40

Altruism of cells, TOO
Alveolar adenocarcinoma of

kidney, 727
of thyroid gland, small,

large-cell, 879
adenoma of kidney, 719
cancer of corpus uteri, 534
of renal pelvis and

ureter, 744
small, 454
endothelioma, 296
Amitosis in tumors, 39
Amphipyrenin in tumor-cells,

46
Ampulla of Vater, cancer of,

679
Anaplasia in tumors, 39

of tumor-cells, 101
Anemia from Hodgkin's

granuloma, 353
secondary, in cancer of

stomach, 635

Anemic type of cancer, 67
Angiocholitis proliferans, 658
Angiochondroma, 181
Angio-endothelioma of skin,

316

Angiofibroma, 28, 149
Angioma, 27, 218

arteriale racemosum, 228
cavernous, clinical fea-
tures, 226

Angioma, cavernous, course,
224

cutaneous, 226

histogenesis, 225

neoplastic nature, 226

of liver, 227

of ovary, 227

of tongue, 226

structure, 225

submucous, 226
fissural, 220
histogenesis, 221
of brain, 227
of breast, 488
of bones, 226
of larynx, 828
of muscles, 220
of orbit, 226
of spinal cord, 424
plexiform, 219
Angioplastic endothelioma,

31.9

Angiosarcoma of liver, 672
of pituitary gland, 911

Antigen, autogenous tumor,
complement deviation
with, 91

Antitryptic power of blood
in cancer, 92

Antra, osteoma of, 194

Antrum, maxillary. See
also Maxillary antrum.

Aplastic leukemia, 346

Aponeuroses, giant-cell sar-
coma of, 251

Appendix, cancer of, 644
anatomy, 644

Arachnitis serosa circum-
scripta, 426

Astrocytes, 386

Astrocytoma, 384

Astromas, 386

Asymmetric mitosis in tu-
mors, 39

Ateliosis, 919

Atheromatous cysts of skin,
942

Atrophic bidermal teratoma
of ovary, 599

Autochthonous teratomas, j

949

Autogenous tumor antigen,
complement deviation
with, 91

BACTERIA in cancer, 116
Bartholin's gland, tumors of,

544
Basal-cell carcinoma, 457

epithelioma of skin, 808
Bathing-trunk type of nevus,

851
Bidermal atrophic teratoma

of ovary, 599
Bile-ducts, adenoma of, i

cystic, 668
multiple, 669

Bile-ducts, cancer of, surgi-
cal results in, 681
cysts of, 667

intrahepatic, multiple can-
cer of, 669

larger, cancer of, 677
anatomy, 678
etiology, 678
location, 678
structure, 679
tumors of, 667, 668
Bird's-eye inclusion in can-
cer, 116

in cancer-cells, 47
Bladder, adenoma of, 842
cancer of, etiology, 843
glandular, 842
secondary invasion in,

843

myoma of, 212
papilloma of, 838

allantoid type, 842

anatomy, 839

course, 839

structure, 841
sarcoma of, 844
tumors of, 844

epithelial, 838
Blastema theory of cancer,

Blastomycetes in cancer, 118
Blood, alkalescence of, in

cancer, 70
antitryptic power of, in

cancer, 92

changes in leukemia, 345
cysts, 952
in cancer, 67
in chloroma, 349
in stools in cancer, 72
in true pseudoleukemia,

362
regeneration of, in cancer,

Blood-vessels in dissemina-
tion of cancer, 81
of breast, 511
in fibroma, 151
in glioma, 390
relation of, to tumors, 56
Bones, angioma of, 226
endothelioma of, 298, 312

classification, 312
fibroma of, 160
formation, heteroplastic,

196

myxoma of, 1.70
perithelioma of, 330
sarcoma of, 264. See also

Sarcoma of bone.
Bone-marrow lesions in
Hodgkin's disease, 356
myeloma of, multiple, 283
sarcoma of, 264

primary multiple, 283
Brain, angioma of, 227
cholesteatoma of, 951
melanoma of, 863

IXDEX

1009

Brain, sarcoma of, 408
diffuse, 408
malignancy, 410
structure, 409
tumors of, 378. See also |

Tumors of brain.
Branchiogenic cancer, 945

chondroma, 186
Breast, acute carcinosis of,

5i3

adenocarcinoma of, 492
adenofibroma of, 478
adenosarcoma of, 484
angioma of, 488
cancer of, 489. See also I

Cancer of breast.
chondroma of, 187
cystadenocarcinomaof,5i3 i
cystadenoma of, 479
cystosarcoma phyllodes of,

480
cysts of, dermoid, 488

sebaceous, 488
epithelioma of, 488
fibro-adenoma of, 478, 482

papillary intracystic,

479
fibrocarcinoma of, 499, j

5i5

fibroma of, 161
hydatid disease of, 468
hypertrophy of, 467

diffuse, of adults, 467

infantile, 467
leiomyoma of, 488
lipoma of, 488
lymphatics of, involved in

cancer, 508
melanoma of, 488
myxoma of, intracanal-

icular, 480

osteochondromyx o sar-
coma of, 487
papilloma of, 488
perithelioma of, 330
sarcoma of, pure, 485

round-cell, 486

spindle-cell, pure, 487
senle involution of, 470
tumors of, 488

epithelial, 467

ectodermal mixed, 483

mesodermal, 482

mixed, 477

teratoid, 482

Broad ligament, adrenal tu-
mors of, 741

Bronchial cancer arising
from mucous glands, !
789

of lining epithelium, 787

structure, 789
papilloma, 791
Byzantine period, cancer in,
18

CACHEXIA in uterine cancer,
54i

Cancer, 28, 444
a deux, 115
acidosis of, 74
acinar, 454
adenoid, 447
adult, 455

growth, 63
albuminuria in, 75
alkalescence of, in cancer,

alveolar, small, 454
anaplastic growths, 63
anemic type, 67
antitryptic power of blood

in, 92

bacteria in, 116
basal-cell, 457
bird's-eye inclusion in, 1 16
blastema theory of, 21
blastomycetes in, 118
blood in, 67

in stools, 72
braiichiogenic, 945
bronchial, of lining epi-
thelium, 787
structure, 789

arising from mucous

glands, 789
structure, 790
cachexia of, demineraliza-

tion in, 75
cell autonomy, theory of,

cellular overgrowth in, 449

changes in urine in, 72

character of affected tissue
in, 464

chimney sweep's, 847

chronic inflammation as
cause, 103

cicatricial character, 446

classification, 445

coccidia in, 116

Cohnheim's theory, limita-
tions, 97

collateral hyperplasia in,
464

coma, 74

connective tissue theory
of, 22

constitutional predisposi-
tion to, 104

contact infection from, 85

contagiousness of, 115

cystic, 454 _

desmoplastic properties,
45i

diagnosis of malignancy,

diffuse, 455
dissemination of, by

blood-vessels, 81
distribution of nutriment

in, 99

districts, 114
emaciation from, 65
embryonal, 455

growth, 63

Cancer, embryonal, theory,

limitations, 97
en cuirasse, 507, 515
epidermoid, 28, 457, 797

glandular, 458
epiphanin reaction in, 93
epithelial theory, 23
experimental study, 119,

127

families, 105

fatty degeneration in, 446
following intestinal poly-

posis, 641

from chronic inflamma-
tion, 459

from physiologic involu-
tion of organs, 460
from regenerative hyper-
trophy, 461

from transformation of
benign into malignant
tumors, 461
fully developed, 454
general intoxication from,

genius loci in, 86
gross anatomy, 446
hemorrhage in, 68
heredity theory of, 105
heterotopia in, 450
histological period, 20
historic study of, 17
houses, 114
in ancient times, 17
incidence of, 114
induration in, 446
infiltrative growth in, 62
inflammatory reaction in,

influence of intestinal di-
gestion on, 72
of mechanical pressure

in, 98

of mode of origin, 463
on gastric digestion, 70
organization on, 100
specialized functions on,

99
intermittent quiescence in,

invasion of thoracic duct
T by, 79
Kangn, 800
leukocytosis in, 68
local extension, 50

invasion in, 464

invasive and destruc-
tive properties, 450

predisposition to, 103
localities, 114
loss of polarity in, 452
lupus, 802
lymph theory of, 18
lymphocytosis in, 68
marantic type, 67
mechanical separation of

epithelial cells, 102

1010

INDEX

Cancer, meiostagmin reac-
tion in, 92
metastases, 62, 452
microorganisms in, 116
microscopic structure, 448
mode of extension, 463
modern era in study of,

mycetozoa in, 117
of adrenal gland, 747

fully developed, 748
of ampulla of Vater, 679
of appendix, 644
anatomy, 644
structure, 644
of bile-ducts, surgical re-
sults in, 680
of bladder, etiology, 843

glandular, 842
of breast, 489
acinar, 502
fibrous, 505
following fibre -

adenoma, 504
primary, 504
age incidence, 489
blood-vessels in dis-
semination, 511
cerebral metastases in,

5ii

clinical varieties, 513
development of surgical

treatment, 517
developmental anoma-
lies in, 490
dissemination, 507
duct, 497

gross anatomy, 497

histogenesis, 500
effective causation, 490
encephaloid, 513
etiology, 489
extension in breast, 505

to lungs in, 510
general prognosis, 518
generalization, 509
hepatic lesions in, 511
heredity in, 489
in males, 517

incidence, 489
invasion of skin in, 506
involvement of pleura

in, 510

lactation in, 489
lymphatic invasion in,

507

medullary, 513
modes of extension, 505
mucoid, 495, 515
operative mortality, 521
pathological anatomy,

491
peritoneal invasion in,

S.1?
position of, 519

previous exudative in-
flammation in, 490
recurrence, 519

j Cancer, regressive phenom-
ena in, 512
scirrhus, 514
secondary invasion in,

843

small cystic duct, 499
tubular, 497
of cervix uteri, 524

atypical forms, 529
erosion in cause, 528
sarcomatoid struc-
tures in, 530
scirrhus, 529
of corpus uteri, 531
alveolar, 534
anatomy, 531
histogenesis, 535
structure, 533
of duodenum, 640
of esophagus, 835
anatomy, 836
etiology, 836
structure, 837
of Fallopian tube, 590
etiology, 590
structure, 591
of gall-bladder, 672
anatomy, 673
squamous-cell, 676

clinical features, 676
structure, 674
surgical results in, 680
of hypophyseal duct, epi-

dermoid, 913
of ileum, 641
of intestine, 640
of intrahepatic bile-ducts,
multiple, 669

anatomy, 669
incidence, 669
structure, 670
of jejunum, 641
of kidney, 721

metastases in, 723
papillary with clear cells,

722
tubular, 729

structure, 731
of large intestine, 646

anatomical varieties,

648

anatomy, 647
developing from soli-
tary polyps, 650
etiology, 646
histogenesis, 648
lymphatics involved

in, 647

squamous-cell, 652
statistics, 646
of larger bile-ducts, 677
anatomy, 678
etiology, 678
location, 678
structure, 679
of larynx, 828
anatomy, 830
course, 833

Cancer of larynx, larval, 831
lymphatic extension, 833
structure, 832
of lip, 816

of liver with cirrhosis, 665
of liver-cells, multiple, 663

primary massive, 66 1
of lung, 785

arising from pulmonary

alveoli, 790
classification, 787
etiology, 786
metastases, 791
symptomatology, 793
of maxillary antrum, 700
clinical course, 702
deformation stage,.

702

invasion stage, 703
latent stage, 702
of ovary, 577

clinical course, 585
granulosa cell, 583
solid, 577
structure, 579
of pancreas, 681
anatomy, 682
etiology, 682
origin, 684
structure, 683
symptoms, 685
of pituitary gland, atypi-
cal, 911
of prostate, 759

age of incidence, 760
clinical course, 763
etiology, 760
gross anatomy, 761
heredity in, 760
lymphatic extensions,.

761

scirrhus, 766
skeletal osteoplastic

metastases in, 762
structure, 764
variations in structure,.

766
of renal pelvis and ureter

alveolar, 744
of salivary glands, 704

round-cell, 706
of scrotum, 847
paraffin, 848
of skin, epidermoid, 797
of stomach, 605

acidemic coma in, 635
age in etiology, 605
alcoholism in, 606
anatomy, 607
cachexia in, 634
curability, 639
cylindrocellulare micro-

cysticum, 609
diffuse, 615

scirrhus, 616
enlarged supraclavicu-
lar lymph-nodes in,
628

INDEX

1011

Cancer of stomach, etiology,

605

experimental, in rat, 133
extensions of, 625
following, anatomy,

610, 614
clinical features,

637
following peptic ulcer,

610

gastric mucosa in, 624
gelatinous, 609

clinical features, 637
structure, 610
heredity in etiology, 696
histogenesis, 629
idiosyncrasy in, 606
location, 606, 633
lymphatic invasion in,

627

medullary, 615
metastases in ovary in,

629

onset, 631
operability, 638
operative mortality, 639
pathogenesis, 632
relation of lymphatics in ,

626
to anatomic varieties,

636

scirrhus, clinical fea-
tures, 638

secondary anemia in, 635
simple, 615

clinical features, 637
statistics, 605
surgical treatment, 638
symptomatology, 631
telangiectatic, 615
trauma in etiology, 696
of testis, embryonal, with
lymphoid stroma, 777
of thymus, 897
of thyroid gland, 879
duration, 879
histogenesis, 884
metastases, 880
structure, 883
of tongue and mouth, epi-

dermoid, 819
clinical course, 824
embryonal forms,

824

etiology, 819
gross anatomy, 821
lymph-node in-
volvement in,
822

metastases in, 822
prognosis, 824
structure, 823
tobacco in etiology, '

820

of ureter, primary, 843
of urethra, 847
of uterus, 523, 537
cachexia in, 541

Cancer of uterus, classifi-
cation, 523

clinical course, 541

effect of pregnancy on,
540

etiology, 523

evertens, 526

histogenesis, 525

invertens, 526

lymphatic invasion in,

539 .

mortality, 541
structure, 525
termination, 541
visceral metastases in,

54i

of vagina, epidermoid, 544
histogenesis, 545
prognosis, 545
structure, 545
of vulva, epidermoid, 542
course, 543
pruritus in, 543
structure, 544
papillary, 447, 453
parasitic theory of, 114
theoretic objections,

121

percentage of urea in, 72
potential malignancy, clin-
ical course and, differ-
entiation, 64
protozoa in, 116
Ransohoff's test in, 93
rapidity of growth, 62, 463
recurrence, 86
regeneration of blood in, 69
sarcomatodes, 940
scope of relation of para-
sites to, 123
specific degenerative

changes in, 447
spirochetae in, 117
squamous cell, of choroid

plexus, 403
of renal pelvis and

ureter, 743

Stammler's reaction in, 93
structure, 449

primary versus second

ary, 449

theories of nature of, 94
tissue tension theory of, 98
ulcerative lesions in, 448
uric acid increase in, 72
urobilin in, 74
varia, 455
Wassermann reaction in,

x-ray dermatitis and, 802
Cancer-cells, atypical quali-
ties, 449

bird's-eye inclusion in, 47
Capsular lipoma, 176

sarcoma of bone, 270
Carcinoid tumors of intes-
tine, multiple benign em-
bryonal, 642

Carcinoma, 444. See also

Cancer.

Carcinomatous cirrhosis of
liver, 665

structure in cystic tumors,

447

Carcinome villeux, 492
Carcinosarcoma of esopha-
gus, 837
of uterus, 262
Carcinosis, acute, of breast,

513

miliary, 447
Cardiac lipoma, 179
Carotid gland, peritheli-

oma of, 331

Cavernous angioma, 222
clinical features, 226
course, 224
cutaneous, 226
histogenesis, 225
neoplastic nature, 226
of liver, 227
of ovary, 227
of tongue, 226
submucous, 226
structure, 225
Cell autonomy theory of

cancer, 97

division in tumors, 38
| Cells, altruism of, 100

endothelial, origin and

functions, 290
pathology of, 292
physiology, 291
syncytial wandering, 548
Cellular nevus, 315
Cephalic tumors of pituitary

gland, 917
Cerebral glioma, 394

metastases in cancer of

breast, 511
Cervical dermoid cysts, 943

structure, 944
erosion as cause of cancer,

528

teratoids, 945
teratomas, 945
j Cervix uteri, adenocarci-

noma of, 527
mucous, 529
adenoma of, simple, 529
cancer of. See Cancer

of cervix uteri.
cystadenoma of, 529
endothelioma of, 530
perithelioma of, 530
precancerous changes in,

53°

Cheloid, 158

Chemistry of tumors, 89
Chimney-sweeps' c a n c e r ,

847

Chloroma, 348
blood in, 349
form, 349

gross anatomy, 348
occurrence, 348

1012

INDEX

Ghloroma, structure, 349

symptoms, 348
Choanal polyp, 163
Choked disc in brain tumors,

383

Cholangioma, 667
Cholesteatoma of brain, 951
Chondroma, 27, 180
branchiogenic, 186
clinical types, 185
cystic papillary, 182
etiology, 184
heredity in, 184
matrix, 182

multiple character, 181
myxomatodes, 166
of breast, 187
of larynx, 828
of ovary, 602
of respiratory tract, 187
of salivary glands, 188
of testis, 479
of uterus, 188
ossification, 182
osteoid, 185
Ranvier's classification,

182

rickets in etiology, 184
skeletal, 185

location, 181
structure, 182
subperiosteal, 181
teratoid, 188

trauma in, etiology, 185
Chondromyxoma, 171
Chondrosarcoma, 28, 182

of ovary, 257
Chordoma, 27, 188

malignant, 189
Chorio-adenoma destruens,

.547

clinical course, 557
differential diagnosis,

549

metastases in, 549
structure, 548
uterine contents in, 548
Choriocarcinoma, 551
metastases, 555
structure, 553
Chorioma, 546

clinical course, 557
deportation of normal cho- j
rionic elements in, 559 i
etiology, 547
gross anatomy, 547
historical note, 546
of Marchand, atypical, 555 !
ovarian changes in, 560
ovarii, 60 1
recovery after curettage or ,

partial removal, 558
structure, 547
testis, 775

Chorionepithelioma, 546
Choroid plexus, papillary i
adenocarcinoma o f,
402

Choroid plexus, squamous-
cell carcinoma of, 403
tumors of, 398
Chromatophores, origin and

function of, 865
Chylangioma, 232
Chylous cysts, 952
Ciliated epithelial cysts, 955
Cirrhosis mammas, 469
of liver, cancer with, 665
carcinomatous, 65
relation of primary epi-
thelial tumors to, 657
Coccidia in cancer, 116
Cohnheim's theory of can-
cer, limitations, 97
Colitis, polyposa, 652
adenoma in, 441
Collateral hyperplasia in

cancer, 464

hypertrophy in tumors, 37
Colloid degeneration in

tumors, 49
goiter, 869
anatomy, 871
metastasizing, 881
structure, 871
struma, 443
Collonema, 175
Coma in cancer, 74

of stomach, acidemic,

635

Complement deviation with
autogenous tumor anti-
gen, 91

Complex dermoids, 938
Condyloma acuminatum,

433

latum, 434
Congenital hypertrophy of

thyroid, 442
rhabdomyoma of heart,

215

tumors, 26

Connective tissue tumors, 27
Contact infection in cancer,

Cornu cutaneum, 433
Coronodental cysts, 695
Corpus adiposum mala?, 177
cavernosum penis, endo-

thelioma of, 316
luteum cysts, 564
uteri, adenocarcinoma of,

papillary, 534
squamous cell, 534
adenoma of, 533
cancer of. See Cancer

of corpus uteri.
precancerous changes

in, S36

Cranial lipoma, 178
Crateriform rodent ulcer, 840
Cutaneous cavernous an-

gioma, 226
fibromas, 152
horns, 433
lyrnphosarcoma, 373

Cutaneous warts, 431
Cylindroma, 294

of salivary glands, 705
Cystadenocarcinoma of

breast, 513
Cystadenoma of breast, 479,

prognosis, 481
structure, 480
of cervix uteri, 529
of kidney, malignant

transformation, 727
of ovary, pseudomuci-

nous, 571
course, 573
structure, 573
serous, 566
course, 568
implantation metas-
tases in, 568
structure, 568
of pancreas, 681
Schimmelbusch's multi-
ple, 469

Cystes epidermiques, 942
Cystic adenocarcinoma of

breast, small, 499
of ovary, 577
adenoma of bile-ducts, 668

papillary, 438
cancer, 454
duct cancer of breast,

small, 499
mastitis, 472
tumors of carcinomatous

structure, 447
Cystoma of ovary, serous,

563
with dermoids or tera-

toma, 594
Cystosarcoma phylloides, 32

of breast, 480
Cysts, blood, 952
chylous, 952
coronodental, 695
corpus luteum, 564
dentigerous, 695, 696
dermoid. See Dermoid

cysts

enteric, 952
entodermoid, 953
epidermoid, 942
epithelial, ciliated, 955

special forms, 942
implantation dermoid, 942
in lipomas, 175
in tumors, 31
intraperitoneal, of nephro-

genic origin, 953
mesenteric, 952
of bile-ducts, 667
of breast, dermoid, 488
of maxillary antrum, 700
of ovary, 562

simple follicular, 562
small multiple, 562
of parathyroid gland, 887
of pineal gland, 926

INDEX

1013

Cysts of skin, atheromatous,

042

epithelial, 942
of thymus gland, 892
of thyroid gland, 887
peritoneal, 952
radiculodental, 694
sebaceous, of breast, 488
serous, 952
tubo-ovarian, 564

DEBRIS epitheliaux paraden-

taires, 686

Deciduoma malignum, 546
Demineralization in cancer

cachexia, 75
Demodex folliculorum in

acanthoma of skin, 801
Dentigerou? cysts, 695, 696
Dermatitis, x-r&y, cancer

and, 802

clinical course, 802
structure, 803
Dermato myoma, 212
Dermoid cysts, cervical, 943

structure, 944
complex, 938
from first branchial cleft,

944

hypophyseal, 950
implantation, 942
intracranial, 950
mediastinal, 946
mesobranchial, 944
of breast, 488
of mesentery, 953
of orbitonasal fissures,

947
of ovary, 593

anatomy, 593

atypical forms, 599

clinical course, 593

contents, 595

etiology, 603

malignant characters
in, 600

mesodermal elements
in, 598

metastases, 598

multiple, 599

prognosis, 593

secondary changes in,
600

teratoma and, differ-
entiation, 595

with cystoma, 594
of pelvic connective tis-
sue, 954

of peritoneum, 953
of thyroglossal duct, 946
pharyngeal, 947
presternal, 947
retroperitoneal, 954
sacrococcygeal, 956
simple, 941
special forms, 942
sublingual, 944
true, 943*

Desmoplastic tumor-cells, 54
Diabetes with acromegaly,

920

Diffuse carcinoma, 455
hypertrophy of breasts in

adult, 467

Districts, cancer, 114
Double monsters, 932
symmetrical, '932
Duct carcinoma of breast,

497

small cystic, 499
Duodenum, cancer of, 640
Dystrophia adiposogenita-

lis, 921

Dystrophic tumors of pitui-
tary gland, 917
Dystrophy, adiposogenital,
theories, 923

ECCHOXDROSIS, 1 80
physalifora, 188
spheno-occipitalis, 188
Ectodermal mixed tumors of

breast, 483
Elephantiasis, 155
angiomatosa, 156
arabum, 157
durum, 156, 469
fibrosarcomatosa, 262
graecorum, 157
hemangiomatosa, 220
lymphangiectatica, 156,

232

molle, 156
telangiectatica, 156
Emaciation from tumors, 65
Embolism, pulmonary met-

astatic, 84
paradoxic, 84
secondary, 84
tertiary, 84
Embryologic classification of

tumors, 28
Embryoma, 28

of testis, adult, 768
Embryonal adenomyosar-
coma of kidney, 732
anatomy, 732
histogenesis, 733
in adults, 729
structure, 732
carcinoid tumors of intes-
tine, multiple benign,
642
cancer, 455

of testis with lymphoid

stroma, 773
theory of cancer, 94

limitations, 97
tumors, 26, 49
of testis, 772
Embryos, post-generation

of, 934

Enamel pearls, 697
Encephaloid cancer of breast,

5i3
Enchondroma, 180, 181

: Endometritis, hypertrophic,

adenoma in, 441
syncytial, 555
Endophlebitis carcinoma-

tosa, 83

Endothelial cells, origin and
functions, 290

pathology of, 292

physiology, 291
psammoma, 315
sarcoma of spleen, 376
tumors, 27
Endothelioma, 290
alveolar, 296
angioplastic,_3i9
calcification in, 301
classification, 296
clinical types, 304
combined with sarcoma,

302

diagnosis, differential, 302
diffuse, 296
etiology, 303
gross anatomy, 300
growth, 297
histological types, 296
history, 293
hyaline degeneration in,

301

interfascicular, 294, 296
intravasculare, 317
mucinous degeneration in,

301

nomenclature, 296
of bones, 299, 312

classification, 312
of cervix uteri, 530
of corpus cavernosum pe-
nis, 316
of ganglia, 309
of lymph-nodes, 321

clinical types, 321

etiology, 325

frequency, 321

gross anatomy, 322

histogenesis, 324

localized, 321

metastases in, 322

structure, 322

systemic form, 321
of meninges, 305

course, 308

forms, 305

location, 306

structure, 306
of nerve trunks, 309
of orbit, 309
of ovary, 317

appearance, 318

clinical course, 318

diagnosis, 318

structure, 319
of serous membranes, 309
of skin, 314
of stomach, 320
of testis, 298
of uterus, 320
origin, 297

1014

INDEX

Endothelioma, peritoneal, j

310

classification, 312
structure, 311
perivascular, 296, 323
pleural, 309
classification, 312
clinical course, 310
origin, 310
structure, 310
plexiform, 296, 323
structure, 300
Endothelium, pathology, |

292
tumor-like hyperplasia of,

3°4.

Enostosis, 193
Enteric cysts, 952
Entodermoid cysts, 953
Ependyma, tumors of, 398

infundibular, 405
Ependymal glioma, 385, 404

of pineal gland, 927
gliomatosis, 393
neuroglioma of p i n e a 1

gland, 928

Ependymitis granularis, 399
Epidermoid cancer, 28, 457,

797, 435
glandular, 458
of hypophysealduct, 913
of skin, 797
of tongue and mouth,

819

of vagina, 544
of vulva, 542
cysts, 942
Epidermoids, 941
Epignathi, 948
Epiphanin reaction in can-
cer, 93

Epithelial cells, mechanical
separation of, in cancer,
102

cysts, ciliated, 955
of skin, 942
special forms, 942
hyperplasia of liver, 654
papilloma of maxillary

antrum, 700

pearls in acanthoma, 457
proliferation, influence of
lipoid solvents on, 129
theory of cancer, 23
tumors, 27

of bladder, 838
of breast, 467
of kidney, 717

classification, 718
of liver, primary, 657
of renal pelvis and

ureter, 742

of salivary glands, 704
of submaxillary gland,

716

of thyroid gland, papil-
lary, 877
structure, 878

Epithelial tumors, of vulva,

542

Epithelioma, 21, 28, 457
chorio-ectodermale, 602
of breast, 488
of lip, 816
papillary, 816
ulcerative infiltrating,

816

of penis, 844
course, 846

established disease, 845
extension, 845
initial lesion, 845
structure, 847
of prostate, squamous, 766
of skin, adenoid, 813
cystic, 813
simple, 814
basal cell, 808
reticulated, 808
papillary, of renal pelvis
and ureter, 742
metastases, 743
structure, 743
petrified, 799
plexiform, 458
secondary, 328
Epitheliome intracanalicu-

laire, 492
kystique intra-a c i n e u x,

469

Epithelium, tumors of, gen-
eral pathology, 429
Epoophoron, tumors of, 589
Epulis, 690

type of sarcoma, 271
Erosion as cause of cancer

of cervix uteri, 528
Esophagus, cancerof, 835,837
leiomyoma of, 212
sarcoma of, 253
Exophthalmic goiter, 874

stages, 875
Exostosis, 192
bursata, 193
cartilaginea, 193
clavata, 192
clinical groups, 193
de croissance, 193
eburnea, 192
medullaris, 192
of trachea, 193
parosteal, 193
spongiosa, 192
traumatic, 193
Extramedullary plasma-cell

lymphosarcoma, 374
tumors of spinal cord, 427
Extrarenal adrenal rests,

tumors of, 740
Eye, lymphangioma of, 231
osteoma of, 197

FACIAL bones, osteoma of,

194

Fallopian tubes, adrenal tu-
mors of, 741

Fallopian tubes, cancer of,

etiology, 590
structure, 591
tumors of, 592
False tail, 961
Family incidence of cancer,

105

Fasciae, fibroma of, 160
sarcoma of, 244, 253
Fats in tumors, 90
Fatty degeneration in tu-
mors, 43

Febiger's experimental gas-
tric cancer in rat, 133
Ferments, tumor, 67, 90

heterolytic action, 67
Fetal adenoma of thyroid

gland, 873
fibro-adenoma of breast,

482
implantations, abdominal,

953

special forms, 942
teratomas, abdominal, 953
Fetus, parasitic, 935
Fibro-adenoma of breast,

478

fetal, 482
papillary intracystic,

479

of large intestine, 651
Fibro-angioma, 28
Fibroblastic sarcoma, 244
Fibrocarcinoma, 456
of breast, 499, 515
of large intestine, stenos-

ing, 649

of stomach, diffuse, 619
sclerosing, 619

clinical features, 638
Fibrochondroma, 149
Fibrolipoma, 149, 175, 178

of spermatic cord, 779
Fibroma, 27, 149
blood-vessels in, 151
clinical types, 152
cutaneous, 152
edematodes cysticum, 163

simplex, 163
etiology, 157
gross appearance, 149
juvenile nasopharyngeal,

164

course, 165
lipomatodes, 160
lymph vessels in, 151
matrix, 150
molluscum, 150, 152

typical, 153
natural history, 151
of bones, 160
of fasciae, 160
of glandular organs, 161
of kidney, 161
of larynx, 827
of nares, 162
of ovary, 162
of periosteifm, 160

INDEX

1015

Fibroma of testis, 779

origin of, 151

papillary, 149

pendulum, 153

plexiform, of spermatic
cord, 779

structure, 150
Fibromatosis diffuse, 155,

157

uteri, 262

Fibromyoma, uterine, 203
Fibroneuroma, true, 411
Fibrosarcoma, 28, 150, 246
mucocellulare carcinoma-
todes of ovary, 257,

5.83
ovarii mucocellulare carci-

nomatodes, 317
Fibrous acinar carcinoma of

breast, 505

Fissural angioma, 220
Folliculoma malignum, 583 |

ovarii, 582
Frontal sinus, osteoma of,

T, 195-

Functional activity in

tumors, 53
adenomatoid hyperplasia,

442
Fungosites radiculoden-

taires, 687
Fungus hematodes, 19, 30

GALEN'S theory of cancer, 17
Gall-bladder, cancer of, 672
anatomy, 673
clinical features, 676
squamous cell, 676
structure, 674
surgical results in, 680
myosarcoma of, 676
Gametoid mitosis in tumors,

39
Ganglia, endothelioma of, 309

Gasserian, tumors of, 418
Ganglionic neuroma, 411,

414

etiology, 416
Gasserian ganglion, tumors

of, 418

Gastric cancer, 605. See
also Cancer of stomach.
digestion, influence of can-
cer on, 70
Gastritis polyposa, adenoma

in, 441
Gastro-iritestinal Hodgkin's

granuloma, 354
lipoma, 179
pseudoleukemia, 363
tract, lymphosarcoma of,

372

Gaucher's type of spleno-
megaly, 304
Gelatinous adenocarcinoma

of large intestine, 649
cancer of stomach, 609
structure, 610

Genius loci in cancer, 86
Geotropism in tumors, 53
Giant-cell sarcoma of bone,

273

benign, 271
prognosis, 278
of tendon-sheaths and

aponeuroses, 251
Giantism, 917
Glandular adamantinoma,

692

cancer of bladder, 842
chronic mastitis, 469
epidermoid carcinoma,

45?.

mastitis, chronic, 472

organs, fibroma of, 161
Glans penis, melanoma of,

847
Glioma, 27, 384

blood-vessels in, 390

cerebral, 394

clinical types, 394

durum, 384

ependymal, 385, 404

etiology, 392

gangliocellulare, 384

ganglionare, 384

growth, 391

intracranial, histological
classification, 395

molle, 384

nasal, 395

of pineal gland, ependy-
mal, 927

of posterior lobe of pitui-
tary, 916

of retina, 405
etiology, 407
structure, 406

of spinal cord, 395

pial, 397

sarcoma and, differentia-
tion, 392

secondary degeneration in,

385

structural forms, 384
structure, 386
telangiectaticum, 385
teratomatous, 398
Gliomatosis, ependymal, 393
Gliosarcoma, 384
Gliosis, syringomyelia asso-
ciated with, 397
Glycogenic degeneration of

tumors, 44
Glycosuria with acromeg-

aly, 920

Goiter, colloid, 869
anatomy, 871
metastasizing, 881
structure, 871
congenital, 872
exophthalmic, 874

stages, 875
parenchymatous, 872

acquired, 873
simple, 869

Goiter, simple, adenomatoid

hyperplasia in, 443
Granulation tissue, hyper-
trophic, 219
Granuloma, Hodgkin's 352,

426

abdominal, 356
anemia from, 353
change to sarcoma, 359
clinical course, 353

types, 354
etiology, 360
gastro-intestinal, 354
mediastinal, 355
structure, 357
tuberculous lesions in,

361
with chronic generalized

lesions, 354

Graves' disease, adenoma-
toid hyperplasia in, 443
Gynecomastism, 468

HAMARTOMA, 226
Heart, myxoma of, 1 70
rhabdomyoma of, con-
genital, 215
Hemangio-endothelioma,

221, 2p8

Hemangioma, 218
hypertrophicum, 221
of parotid gland, 715
simplex, 219

Hemorrhage in cancer, 68

Hemorrhagic sarcoma, mul-
tiple, 247

histologic structure,
248

Hepatic hypernephroma, 741

Hepatoma, 660
multiple, 663
solitary, 663

Hereditary tumors, 26
theory of cancer, 105

Heterochthonous teratomas,

949
Heterologous lipoma, 177

tumors, 28, 49
Heteroplastic bone forma-
tion, 196

clinical forms, 196
deposits in leukemia, 340
osteoma, 192

Heterotopia in cancer, 450
Heterotypic tumors, 49
Hidrocystoma tuberosum

multiplex, 315

Highmore, antrum of, tu-
mors of, 699

Hilus, reral, lipoma of, 745
myoma of, 745
myxoma of, 745
myxosarcoma of, 745
sarcoma of, diffuse, 745
tumors of, 745
Hippocrates' theory of can-
cer, 17
, Histioid tumors, 28, 48

1016

INDEX

Hodgkin's disease, 353

bone-marrow lesions in, I

356

granuloma and, 360
mediastinal tumors in, !

355

skin lesions in, 356
splenic, 354

gr-anuloma, 352, 426. See
also Granuloma, Hodg-
kin's.

sarcoma, 359
Homologous lipoma, 177

tumors, 28, 49
Homotypic tumors, 49
Horns, cutaneous, 433
Houses, cancer, 114
Hunter's theory of cancer, 19
Hutchinson's type of sar-
coma of adrenal gland in
infants, with cranial met-
astases, 753
Hyaline changes in tumors,

45
Hydatid disease of breasts,

468
Hydropic degeneration in

tumors, 43
Hydrops follicularis of ovary,

562
Hygroma cysticum, 156

colli, 232
sacral, 233, 960
Hylomata, 29
Hypernephroma, 717, 723,

734

hepatic, 741
of spermatic cord and

testis, 742
Hyperostosis, 192
Hyperplasia, collateral, in

cancer, 464
functional adenomatoid,

442

neoplastic, versus inflam-
matory hyperplasia, 40
of adrenal gland, 746
of interstitial cells of testis,

781
of liver, epithelial, 654

multiple nodular, 656
of pituitary gland, diffuse,

907

natural course, 923
tumor-like of endothe-

lium, 304

Hyperplastic lymphaden-
itis, 336
osteoma, 192
Hypertrophic endometritis,

adenoma in, 441
"^ granulation tissue, 219
Hypertrophy, collateral, in

tumors, 37
of breasts, 467

diffuse of adults, 467
infantile, 467
of prostate, 757

Hypertrophy of prostrate
adenomatous, 442, 758
etiology, 758
carcinomatous, 758
productive inflamma-
tion in, 757
structure, 757
of thyroid, congenital, 442
regenerative, cancer from,

461
Hypophyseal dermoid cysts,

95°
duct, carcinoma of, epi-

dermoid, 913
teratoids of, 912
tumors of, 912
Hypophysis cerebri. See
Pituitary gland.

ILEUM, cancer of, 641
Implantation dermoid cysts,

942
Induration chronique en

masse, 469
Infantile hypertrophy of

breasts, 467
Infantilism, 918
reversif, 919
tardif, 919
Infants, adenocarcinoma of

kidney in, 728
sarcoma of adrenal gland
and liver in, con-
genital (Pepper
type), 753
with cranial metas-
tases (Hutchin-
son type), 753
Infiltrative growth in malig-
nancy, 62
Inflammatory hyperplasia,

adeiiOmatoid, 440
morphology, 41
versus neoplastic hyper-
plasia, JO

reaction in cancer, 50
Infundibular ependyma, tu-
mors of, 405
Interacinous adenoma of

thyroid gland, 872
Interfascicular endothelioma,

294, 296

Intermuscular lipoma, 177
Interstitial cells of testis,

hyperplasia of, 781
mastitis, chronic, 469, 471
Intestinal digestion, influ-
ence of cancer on, 72
polyposis, 652

cancer following, 641
Intestine, adenoma of, large,

650

destruens of, large, 648
cancer of, 640
large, cancer of, 646.
See also Cancer of
large intestine.
fibre-adenoma of, 651

Intestine, large, fibrocarci-
noma of, stenosing,
649

gelatinous adenocarci-
noma of, 649

solitary polyps of, can-
cer from, 650

villous papilloma of,

651

leiomyoma of, 212
lymphomatous tumors of,

255

lymphosarcoma of, 372
melanoma of, 864
sarcoma of, 255

spindle-cell, 255
tumors of, multiple benign
embryonal carcinoid,
642
Intracanalicular myxoma of

breast, 480
Intracranial dermoid cysts,

950

glioma, histological classi-
fication, 395
teratoids, 951
teratomas, 951
Intracystic fibre-adenoma of

breast, papillary, 479
Intrahepatic bile-ducts, car-
cinoma of, multiple, 669
Intramedullary tumors of

spinal cord, 427
Intraperitoneal cysts of neph-

rogenic origin, 953
Involution, senile, of breasts,

470

Irritation group of tumors,
458

JEJUNUM, cancer of, 641
Juvenile nasopharyngeal fi-
broma, 164
course, 165

KANGRI cancer, 800
Keloid, 158

from trauma, 158
in negro race, 158
neoplastic properties, 159
spontaneous, 158
Kidney, adenocarcinoma of,

alveolar, 727
embryonal, in adults,

729

in infants, 728
multiple, in sclerosis,

725
papillary, 721

histogenesis, 725

structure, 727
tubular, 729

structure, 731
with granular tells, 725
adenoma of, 718
alveolar, 719
histogenesis, 719
papillary, 718

IXDEX

1017

Kidney, adenoma of tubular,

719
adenomatoid focal hyper-

plasia in, 444
adenomyosarcoma of, 214,

939

embryonal, 732
anatomy, 732
histogenesis, 733
structure, 732
cancer of, 721

metastases in, 723
papillary, with clear

cells, 722
tubular, 729

structure, 731
cystadenoma of, malignant

transformation, 727
fibroma of, 161
leukemic infiltrations in,

340

lymphosarcoma of, 374
myolipoma of, 213
myoma of, 213
perithelioma of, 330
spotted, 720
tumors of, 717

adrenal tumors and,

differentiation, 739
classification, 718
epithelial, 717
of adrenal tissue, 734
Krunkenberg's fibrosarcoma
mucocellulare carcinoma-
todes of ovary, 583

LACHRYMAL gland, tumors

0^309, 704

Lactic acid in tumors, 89
Langenbeck's theory of can-
cer, 22

Larval cancer of larynx, 831
Larynx, adenoma of, 828
angioma of, 828
cancer of, 828
anatomy, 830
course, 833
larval, 831
lymphatic extension,

833

structure, 832
chondroma of, 828
fibroma of, 827
leukoplakia of, 830
lipoma of, 828
papilloma of, 825

structure, 826
sarcoma of, 834
tumors of, 825

benign, 827
Leather-bottle stomach in

linitis plastica, 624
Leiomyoma, 27, 199
cavernosum, 200
clinical types, 203
course, 2or
durum, 200
molle, 200

Leiomyoma of breast, 488
of esophagus, 212
of intestine, 212
regressive changes, 201
structure, 200

Lentigo maligna juvenilis,
80 1

Leontiasis ossea, 192

Lepidomata, 28

Lesions, precancerous, 458

Leukanemia, 346

Leukemia, aplastic, 346
atypical, 346
blood changes in, 345
cutaneous lesions in, 341
heteroplastic deposits in,

340
infiltrations in kidney in,

340

lymph-nodes in, 339
lymphoid-cell, 348
mixed-cell, 346
nature, 350
plasma-cell, 350
splenic lesions in, 340
Leukemic lymphoma, 337
Leukocytosis in cancer, 68
Leukoplakia of larynx, 830

of uterus, 537
Leukosarcomatosis, 347
Linin in tumor-cells, 46
Linitis plastica, 320, 619
clinical features, 638
leather-bottle stomach

in, 624

Lip, cancer of, 816
epithelioma of, 816
papillary, 816
ulcerative infiltrating,

816

Lipoid solvents, influence of,
on epithelial proliferation,

T-129

Lipoma, 27, 173

annulare colli, 177

arborescens, 177

capsular, 176

cavernosum, 174

clinical course, 175
types, 177

combined with myxoma,
172

congenital tissue predis-
position in, 176

connection with blood-
vessels, 174

cranial, 178

cysts in, 175

etiology, 175

gastro-intestinal, 179

heterologous, 177

homologous, 177

intermuscular, 177

mediastinal, 179

microscopic structure, 1 74

molle, 173

multiple, 176

symmetrical, 176

Lipoma, myelogenous, 179
of breast, 488
of heart, 179
of larynx, 828
of posterior lobe of pitui-
tary, 916

of renal hilus, 745
of spinal cord, 424
of uterus, 179
pelvic, 179
perirenal, 179
petrificum ossificans, 175
renal, 178
subcutaneous, 177
sy no vial, 177
telangiectaticum, 174
trauma as cause, 176
Lipomatosis, replacement,

177

Liposarcoma, 178
Liquefaction cysts in tumors,

32
Liver, adenoma of, multiple

665

solitary, 660

angioma of, cavernous, 227
angiosarcoma of, 672
cirrhosis of, cancer with,
v 665

relation of primary epi-
thelial tumors to, 657
hyperplasia of, fojal ade-
nomatoid, 444
epithelial, 654
multiple nodular, 656
melanoma of, 672
regenerative powers of, 655
sarcoma of, 671

in infants, congenital

(Pepper type), 753
tumors of, 654. See also

Tumors of liver.
Liver-cell cancer, multiple,

663

primary massive, 661
Localities, cancer, 114
Lung, cancer of, 785. See

also Cancer of lung.
extension to, in cancer of

breast, 510

lymphosarcoma of, 796
reticulated osteoma of,

196
sarcoma of, 794. See also

Sarcoma of lung.
tumors of, 785
Lupus cancer, 802
Lusitanus' theory of cancer,

Lutein-cell tumors, 565
Lymph theory of cancer, 18

vessels in fibroma, 151
Lymphadenia ossium, 363
Lymphadenitis, chronic, 304

hyperplastic, 336
Lymphadenoma, 336, 352
Lymphangiofibroma, 149
1 Lymphangioma, 228

1018

INDEX

Lymphangioma caverno-

sum, 229, 232
clinical forms, 230
cutis circumscripta, 231
cysticum, 232
cystoides, 229
development, 229
histological structure, 229
mesenteric, 232
of ovary, 234
of salivary glands, 715
origin, 230
retropefitoneal, 232
sacral cystic, 960
simple, 229, 230
tuberosum, 294

multiplex, 231, 314
Lymphangitis carcinoma-

tosa, 297
prolifera, 297

Lymphatic invasion in can-
cer of uterus, 539

in sarcoma, 80
permeation, metastasis

from, 76
tuberculosis, 352
Lymphatics involved in can-
cer of large intestine, 647
of breast involved in can- !

cer, 508
Lymphemia, lymph-nodes

l in, 339

lymphoplastic, 339
Lymph-nodes enJothelioma

of, 321

clinical types, 321
etiology, 325
frequency, 321
gross anatomy, 322
histogenesis, 324
localized, 321
metastases in, 322
structure, 322
systemic form, 321
in leukemia, 339
in lymphemia, 339
metastasis in, 77
Lymphocytoma, malignant,

368
Lymphocytosis in cancer,

Lymphogranuloma, 352.
See also Granuloma, Hodg-
kin's.

Lymphogranulomatosis cu-
tis, 356
Lymphoid tissue, tumors of, |

334

classification, 334
Lymphoid-cell leukemia, 348
Lymphoma, 27, 334
leukemic, 337
simple, 336
Lymphomatosis, aleukemic

systemic, 362
Lymphomatous tumors of

intestines, 255
tumors of stomach, 255

Lymphoplastic lymphemia,

339

Lymphosarcoma, 366
agressive qualities, 368
anatomic features, 366
clinical features, 366

subvarieties, 369
congenital, 375
cutaneous, 373
duration, 367
etiology, 374
extension, 367
extramedullary plasma-

. cell, 374

histologic character, 369
metastases in, 372
of gastro-intestinal tract,

372

of intestine, 372
of kidney, 374
of lung, 796
of prostate, 767
of spleen, primary, 377
of stomach, 372
of testis, 373, 782
of thymus gland, 894

structure, 895
of tongue, 373
origin, 368
primary pharyngeal, 371

lesions, 368

regressive changes in, 368
relation of syphilis to, 241

of tuberculosis to, 241
retroperitoneal, 373
round- cell, large, 368
structure, 367, 372
tuberculosis in, 375
types, 368

MACROCHEILIA, 232
Macroglossia, 232
Macro melia, 232
Maladie de Reclus, 472
kystique, 468
noveuse, 472

Malignancy, diagnosis, 63
infiltrative growth in, 62
potential, clinical course
and, differentiation, 64
significance of, 62
Malignant adenoma of thy-
roid gland, 876
chordoma, 189
lymphocytoma, 368
neuroma, 415
tumors. See Cancer.
Marantic type of cancer, 67
Marchand's atypical chori-

oma, 555
Mastitis, chronic glandular,

472

cyst contents in, 472
development, 472
of benign or malig-
nant process in,
474

Mastitis, chronic glandular,
predisposition t o
cancer in, 476
progress, 472
structure, 473
treatment, 476
interstitial, 471
productive, 468
etiology, 469
glandular, 469
interstitial, 469
senile, 469
cystic, 472

Maxillae, osteoma of, 194
Maxillary antrum, cancer of,

700

clinical course, 702
deformation stage,

702

invasion stage, 703
latent stage, 702
cysts of, 700
epithelial papilloma of,

700

tumors of, 699
tumors of dental origin, 686
Mediastinal dermoid cysts,
. 946

lipoma, 179

tumors in Hodgkin's dis-
ease, 355
Medullary cancer of breast,

5i3

of stomach, 615
tumors of adrenal gland,

749
chromafline cell,

.754

with adrenalin con-
tent and nephri-
tic symptoms,

754

Medullocelles, 264
Meiostagmin reaction in

cancer, 92

Melanin in melanoma, 859
Melanoma, 849

clinical characters, 849
course, 851

extensions, 855

histogenesis, 865

histology, 852

history, 849

malignant change in, 855

melanin in, 859

modes of origin, 854

of adrenal gland, 756, 868

of brain and cord, 863

of breast, 488

of glans penis, 847

of intestine, 864

of liver, 672

of meninges, diffuse, 422

of nares, 702

of rectum, 652

of uncertain origin, 865

orbital, 860
etiology, 863

INDEX

1019

Melanoma, orbital, structure,
862

pigmentation in, 857
Melanotic whitlow, 851
Meningeal pseudoneo-

plasms, 426
Meninges, endothelioma of,

305

melanoma of, diffuse, 422
sarcoma of, 408, 420
diffuse, 408, 422
structure, 409
sarcomatosis of, diffuse,

421

multiple, 421
Meningitis arenosa, 306

serosa circumscripta, 426
Mesenteric cysts, 952
lymphangioma, 232
Mesobranchial d e r m o i d

cysts, 944
Mesodermal t u m o r s of

breast, 482
Mesentery, dermoid cysts of,

953
Mesonephric adenomyoma,

210

tumors, 590
Metastasis, 76
formation of, 62
from lymphatic permea-
tion, 76

lymph-node, 77
of benign tumors, 84
preservation of structural

type in, 86
pulmonary embolism from,

paradoxic, 84
secondary, 84
tertiary, 84
susceptibility of tissue to,

86
Metastatic sarcoma of spinal

cord, 425
Microorganisms in cancer,

116

Mikulicz's disease, 356
Miliary carcinosis, 447
Mitosis in tumors, 38
Mixed tumors, 938

special forms, 942
Mixed-cell leukemia, 346
Mole, congenital, 852

nbromatous regression in,

854

pigmented, of adults, 853
Mollities ossium, 283
Molluscum contagiosum, 434
Monsters, double, 932
symmetrical, 932
Mouth, cancer of, epider-

moid, 819
Mucoid cancer of breast,

495, 5i5
Mucous adenocarcinoma of

cervix uteri, 529
degeneration in tumors, 44

Mulberry cells in tumors, 45
Muller's tailed corpuscles, 21
Multicentric growth of tu-
mors, 36
Multiple lipoma, 176

symmetrical lipomas, 176
Mural sarcoma of uterus,

258

Muscle tissue tumors, 27
Muscles, angioma of, 220

sarcoma of, 253
Mycetozoa in cancer, 117
Myelogenous lipoma, 179

pseudoleukemia, 283
Myeloid pseudoleukemia,

365

Myeloma of bone, 283
albumosuria in, 285
classification, 289
clinical course, 285
erythroblastic origin,

289

etiology, 289
gross anatomy, 284
histogenesis, 287
structure, 285
of bone-marrow, multiple,

283

Myeloplacques, 264
Myofibroma, 178
Myolipoma of kidney, 213
Myoliposarcoma, 178
Myoma, 27, 199
malignum, 201
of alimentary tract, 212
of bladder, 212
of kidney, 213
of renal hilus, 745
of skin, 212
of stomach, 212
of testes, 212, 780
of urinary organs, 212
of uterus, 203

degenerative changes in,

206

etiology, 208
form, 204

gross appearance, 206
microscopic structure,

207

recurrent, 260
| Myosarcoma, 27

of gall-bladder, 676

of stomach, spindle-cell,

254

! Myositis ossificans, 197
Myxochondrocarcinoma of

salivary glands, 714
Myxo-endothelioma, 168
Myxofibroma, 166
Myxoglioma, 386
Myxolipoma, 166
, Myxoma, 27, 166

anatomical characters, 167
clinical forms, 169

course, 168

combined with lipoma,
172

Myxoma, congenital, of
navel, 170

etioiogy, 172

fibromatosum of kidney,
161

intiacanalicular, of breast,
480

location, 169

matrix, 167

of bones, 170

of heart, 170

of nervous system, 169

of renal hilus, 745

origin, 171

primary, 166

structure, 167, 171
Myxosarcoma, 168

of ovary, 257

of renal hilus, 745

NARES, fibroma of, 162

melanoma of, 702
Nasal glioma, 395
polyp, 162

sinuses, tumors of, 699
Nayopharyngeal fibroma, ju-
venile, 164
course, 165
Navel, congenital myxoma

of, T7o
| Necrotic tissue, osteoma of,

197
Negroes, predisposition to

keloid, 158

Neoplastic hyperplasia, mor-
phology, 41
versus inflammatory

hyperplasia, 40
Nerve nevus, 157
Nerve-trunks, endothelioma

of, 309

tumors of, 411
Nervous system, myxoma of,

169

osteoma in, 196
tumors, 27
Neurinoma, 155
Neurocytoma, 398
of adrenal gland, 750

clinical types, 753
Neuro-epithelioma, 27, 384,

390

retinae, 406
Neurofibroma, 149
acoustic, 416
cirsoides, 154
of spinal cord, multiple,

424

optic, 418
plexiform, 154
Netirofibro matosis, pig-
mented, 153
visceral, 154
Neuroglioma of pineal gland,

ependymal, 928
Neuroma, 27, 411
amyelinicum, 411
gangliona, 27, 749

1020

INDEX

Neuroma, ganglionic, 411,

414

etiology, 416
malignant, 415
myelinicum, 411
plexiform, 411
traumatic, 411
Neuropathic papilloma, 157
Nevus, bathing-trunk type,

r 851-

Imeans, 157

nerve, 157

results of study of, 866

unius lateris, 157

vascular, 219

vasculosus mollusciformis,
220

vinosus, 219
Nipple, Paget's disease of,

805

Nodes, singer's, 826
Nuclear fluid in tumor-cells,

Nuclein in tumor-cells, 46
Nucleus, cystic degeneration
of, in tumors, 47

fragmentation of, in tu-
mors, 47

ODONTOMA, 696, 697

etiology, 698

modes of origin, 699

soft, 698

Omental cysts, 952
Oncology, general, 17

special, 149

Oophoroma folliculare, 583
Optic neurofibroma, 418
Orbit, angioma of, 226

endothelioma of, 309

melanoma of, 860
etiology, 863
structure, 862

osteoma of, 194

teratomas of, 947
Orbitonasal fissures, dermoid

cysts of, 947
Organization, influence of,

on cancer, 100
Organoid tumors, 48
Osteitis fibrosa, 282
Osteochondroma, multiple,

185
Osteochondromyxosarcoma

of breast, 487
Osteochondrosarcoma, 183
Osteodystrophia juvenilis,

282

Osteo-endothelioma, 296

Osteogenic sarcoma, 265

course, 270

sclerosing, 270

Osteoma, 27, 191

heteroplastic, 192

hyperplastic, 192

in nervous system, 196

of antra, 194

of eye, 197

Osteoma of facial bones,

194

of frontal sinus, 195
of lung, reticulated, 196
of maxillae, 194
of necrotic tissue, 197
of orbit, 194
of penis, 197
of skin, 197
secondary, 195
terminology, 191
true, 194

Osteomalacia, senile, 283
Osteophyte, 192
Osteosarcoma, 28
Ovarium gyratum, 162
Ovary, adenocarcinoma of,

cystic, 577
papillary serous, 569
pseudomucinous, 575
adenofibroma of, 577
adenoma of, 566

everted papillary, 577

solid, 576

superficial papillary,

577

testicular, 590
adenomyoma of, 590
adrenal tumors of, 741
angioma of, cavernous,

227
cancer of, 577. See also

Cancer of ovary,
chondroma of, 602
chondrosarcoma of, 257
chorioma of, changes in,

560

cystadenoma of, pseudo-
mucinous, 571
serous, 566

cystoma of, serous, 563
cysts of, 562. See also

Cysts of ovary.
dermoids of, 593. See
also Dermoid cysts 'of
ovary.

endothelioma of, 317
appearance, 318
clinical course, 318
diagnosis, 318
structure, 319
fibroma of, 162
fibrosarcoma mucocellu-
lare carcinomatodes of,
583

lymphangioma of, 234
metastases in, in gastric

cancer, 629
myxosarcoma of, 257
sarcoma of, 256

round-cell, 256
teratoma of, 593. See

also Teratoma.
tumors of, adrenal, 590
age in etiology, 586
etiology, 586
histogenesis, 586
origin, 588

PACHYDERMATOCELE, 156
Pachydermia, 156

laryngis, 830
Pachy meningitis cervicalis

hypertrophica, 426
interna sarcomatosa, 409
Paget's disease of nipple, 805
origin, 807
structure, 805

Pancreas, adenoma of, 68 1
cancer of, 68 1. See also

Cancer of pancreas.
cystadenoma of, 681
sarcoma of, 685
tumors of, 681
Papillary adenocarcinoma of

choroid plexus, 402
of corpus uteri, 534
of kidney, histogenesis,

725

structure, 727
with granular cells,

725

of ovary, serous, 569
adenoma, cystic, 438

of kidney, 718

of ovary, everted, 577

superficial, 577
cancer, 447, 453 _

of kidney with clear

cells, 722

epithelial tumors of thy-
roid gland, 877
structure, 878
epithelioma of lip, 816
epithelioma of renal pelvis

and ureter, 742
fibroma, 149
intracystic fibro-adenoma

of breast, 479
Papilloma, 27, 429
bronchial, 791
clinical course, 430
development of malig-
nancy in, 431
form, 430
neuropathic, 157
of bladder, 838

allantoid type, 842

anatomy, 839

course, 839

structure, 841
of breast, 488
of large intestine, villous,

651
of larynx, 825

structure, 826
of maxillary antrum, epi-
thelial, 700
of renal pelvis and ureter,

742

of tongue, 435
Paraffin cancer of scrotum,

848
Paranuclein in tumor-cells,

Parasites, scope of relation
to cancer, 123

INDEX

1021

Parasitic fetus, 935
theory of cancer, 114

classification by, 126
theoretic objections,

121
Parathyroid gland, cysts of,

887

tumors of, 886
Parenchymatous goiter, 872

acquired, 873
Parosteal exostosis, 193

sarcoma, 270
Parotid gland, hemangioma

of, 7i5

Parovarium, tumors of, 589
Pars intermedia of pituitary,

tumors of, 915
Pearls, enamel, 697

epithelial, in acanthoma,

457

Peau d'orange, 471
Pelvis, connective tissue of

dermoid cysts of, 954
lipoma of, 179
renal, sarcoma of, diffuse,

745

spinosa, 180

Penis epithelioma of, 844
course, 846

established disease, 845
extension, 845
initial lesion, 845
structure, 847
osteoma of, 197
tumors of, 844
Pentose in tumors, 89
Pepper's type of congenital
sarcoma of adrenal gland
and liver in infants, 753
Peptic ulcer, cancer follow-
ing, 610
Peribronchial sarcoma of

lung, 795
Periosteum, fibroma of, 160

sarcoma of, 265
Perirenal lipoma, 179
Perithelioma, 219, 295, 307,

.327

clinical types, 330
gross appearance, 328
of bones, 330
of breast, 330
of cervix uteri, 530
of kidney, 330
ofparotid gland, 331
of pia mater, 330
structure, 329

Peritoneum, cysts of, 952

dermoid, 953
endothelioma of, 310
invasion of, in cancer of

breast, 511
teratoid tumors of, 953

Perivascular endothelioma,

323

Petrified epithelioma, 799
Phagocytosis by tumor-cells,

Pharynx, dermoid cysts of,

947

lymphosarcoma of, pri-
mary, 371

teratomas of, 948
Phosphorus in tumors, 89
Physaliden of Virchow, 44,

182
Pia mater, perithelioma of,

330

Pial glioma, 397
Pigmented mole of adults,

853

neurofibromatosis, 153
Pineal gland, 925

cysts of, 926

glioma of, ependymal,
927

general pathology, 925

histology, 925

neuroglioma of, ependy-
mal, 928

teratoma of, 926

tumors of, 925
classification, 926
clinical features, 929
occurrence, 926
structure, 928
symptomatology, 928 ,
Pituitary gland, adenocarci-

noma of, 909
metastases, 909
structure, 910

anatomy of, 902

angiosarcoma of, 911

cancer of, atypical, 911

functional changes in,

.905

histology of, 904
hyperplasia of, diffuse,

907

natural course, 923
posterior lobe, glioma of,

916

lipoma of, 916
tumors of, 901, 907, 916
anatomy, 906
cephalic, 916
dystrophic, 917
etiology, 901
relation of type with
symptom complex,
922

symptomatology, 916
glandules, accessory, anat-
omy of, 904

Plasma-cell leukemia, 350
lymphosarcoma, extrame-

dullary, 374

Plastin in tumor-cells, 46
Pleura, endothelioma of, 309
involvement of, in cancer

of breast, 510
Plexiform angioma, 219
endothelioma, 296, 323
epithelioma, 458
neurofibroma, 154
neuroma, 411

Polarity, loss of, in cancer,

452
Polyp, choanal, 163

nasal, 162

Polyposis, intestinal, 652
cancer following, 641
Porphyry spleen, 354
Port- wine stain, 219
Posterior lobe of pituitary,

glioma of, 916
lipoma of, 916
Post-generation of embryos,

934

Postnatal tumors, 26
Precancerous changes in cer-
vix uteri, 530
in corpus uteri, 536
lesions, 458
stage of tumor growth,

34
Pregnancy, effect of, on

uterine cancer, 540
Presarcomatous lesions, 241
Presternal dermoid cysts,

947
Prostate, adenocarcinoma

of, 765

adenoma of, 764
cancer of, 759. See also

Cancer of prostate.
epithelioma of, squamous,

766

hypertrophy of, 757
adenomatous, 442, 758
carcinomatous, 758
etiology, 758
productive inflamma-
tion in, 757
structure, 757
lymphosarcoma of, 767
rhabdomyosarcoma of , 767
sarcoma of, 766

spindle-cell, 767
tumors of, 757
Proteins, tumor, constitution

of, 89

febrile destruction of,'66
toxic destruction of, 66
Protozoa in cancer, 116
Psammoma, 296
endothelial, 315
of spinal cord, 423
Pseudo-adiposis in tumors,

47
Pseudoleukemia, 351

gastro-intestinal, 363

myelogenous, 283

myeloid, 365

true, 362

blood in, 362
clinical features, 362
general features, 362
histology, 362

Pseudomucinous adenocarci-
noma of ovary, 575

adenoma of ovary, 566

cystadenoma of ^ovary,
57i

1022

INDEX

Pseudomyxoma p e r i t o n e i,

447, 575
Pseudoneoplasms, m e n i n-

geal, 426

Psoriasis preputialis, 845
Pulmonary embolism, meta-

static, 84
paradoxic, 84
secondary, 84
tertiary, 84
Pulp tumors, 29
Pylorus, sclerosing fibrocar-
cinoma of, 619

RADICULODENTAL cysts, 694
Rankenneurome, 154
Ransohoff's test in cancer,

93
Rat, experimental cancer of

stomach in, 133
Rectum, melanoma of, 652
Recurrent myoma of uterus,

260
Regenerative hypertrophy,

cancer from, 461
Regressive changes in tu-
mor-cells, 43
Renaissance period, cancer

in, 18

Renal hilus, lipoma of, 745
myoma of, 745
myxoma of, 745
myxosarcoma of, 745
sarcoma of, diffuse, 745
tumors of, 745
lipoma, 178
pelvis, alveolar cancer of,

744 .

epithelial tumors of, 742
papillary epithelioma of,

742

papilloma of, 742
sarcoma of, diffuse, 745
squamous-cell cancer of,

743
Replacement lipomatosis,

177
Respiratory tract, chon-

droma of, 187
Reticulated epithelioma of

skin, 808

osteoma of lung, 196
Reticulosplenome nodulaire,

377
Reticulum-cell sarcoma, 325,

368

Retina, glioma of, 405
etiology, 407
structure, 406
neuro-epithelioma of, 406
Retroperitoneal d e r m o i d

cysts, 954

lymphangioma, 232
lymphosarcoma, 373
teratoids, 954
tumors of adrenal rests,
lateral, 741

Rhabdomyoma, 27, 199, 213,

217

appearance, 213
clinical forms, 214
course, 214

of heart, congenital, 215
of testis, 216
of urinary bladder, 214
of uterus, 214
structure, 213

Rhabdomyosarcoma of pros-
tate, 767
Rickets in etiology of chon-

droma, 184
Riga's disease, 435
Rodent ulcer, 808
crateriform, 840
histogenesis, 8n
structure, 840
Round-cell cancer of salivary

glands, 706

lymphosarcoma, large, 368
sarcoma, 238
of bone, 276
of breast, 486
of lung, 795
of ovary, 256

SABER-SHEATH veins in tu-
mors, 57
Sacral cystic lymphangioma,

960

hygroma, 233, 960
mixed tumors, congenital, I

origin, 961
teratomas, 958
Sacrococcygeal d e r m o i d j

cysts, 956
mixed tumors, 956
teratoids, 958
teratomas, 956
Salivary glands, adenocarci-

noma of, 705
adenoma of, 704
cancer of, 704

round cell, 706
chondroma of, 188
cylindroma of, 705
epithelial tumors of, 704
lymphangioma of, 715
myxochondro c a r c i-

noma of, 714
tumors of, mixed, 706
Sand tumors, 30, 296
Sarcoma, 27, 235

alveolare epit helioides,

321

anatomy, 235
botryoides, 214
characters of growth, 236
clinical types, 244
combined with endothe-

lioma, 302

deciduocellulare, 546
epithelioides, 294
etiology, 240
fasciculatum, 245
fibrd'blastic, 244

Sarcoma, general character,

235

glioma and, differentia-
tion, 392
Hodgkin's, 359
lamellosum, 245
lymphatic invasion by, 80
multiple hemorrhagic, 247
histologic structure,

248
of adrenal gland, in infants

with cranial metastases

(Hutchinson type), 753
of bladder, 844
of bone, 264

capsular, 270

classification, 265

duration, 277
of life in, 277

etiology, 280

giant-cell, 273
benign, 271
prognosis, 278

histologic varieties, 268

historical notes, 264

prognosis, 276

rapidity of growth, 277

round-cell, 276

spindle-cell, 272
prognosis, 279

structures, 272

telangiectatic, 268
prognosis, 278

trauma in, 280
of bone-marrow, 264

primary multiple, 283
of brain, malignancy, 410

and meninges, 408
diffuse, 408
gross anatomy, 408
structure, 409
of breast, pure, 485

round-cell, 486

spindle-cell, pure, 487
of esophagus, 253
of fascia, 244, 253
of gall-bladder, 676
of intestine, 255

spindle-cell, 255
of larynx, 834
of liver, 671

and adrenal in infants,
congenital (Pepper's
type), 753
of lung, 794

classification, 795

diffuse spindle-cell, 795

peribronchial, 795

round-cell, 795
of meninges, clinical

course, 422
of muscles, 253
of ovary, 256

round-cell, 256
of pancreas, 685
of prostate, 766
of renal hilus and pelvis,

diffuse, 745

INDEX

1023

Sarcoma of, skin, 247

of spinal cord, central, 423
and meninges, 420
metastatic, 425
solitary, 421
of spleen, 376
endothelial, 376
spindle-cell, 376
of stomach, 254, 255
of tendon-sheaths and
aponeuroses, giant-cell,
251

of testis, 773, 780
of thymus, 898
of thyroid gland, 884
of uterine mucosa, 261
of uterus, 258
etiology, 261
histogenesis, 261
metastases in, 259
mural, 258
structure, 258, 259
osteogenic, 265

course, 270
parosteal, 270
periosteal, 265
radiare, 245

reticulum-cell, 325, 368
round-cell, 238
sclerosing osteogenic, 270
spindle-cell, 244. See also

Spindle-cell sarcoma.
structure, 237
telangiectatic, 219
trabeculare, 245
Sarcomatoid structures in
cancer of cervix uteri, 530
Sarcomatosis of meninges,

diffuse, 421
multiple, 421

Sarcomatous struma, 911
Sarcome angiolithique, 424
angioplastique of testis,

775
Schimmelbusch's disease,

4/2

multiple cystadenoma, 469
Scirrhus cancer of breast,

of cervix uteri, 529
of prostate, 766
of stomach, clinical fea-
tures, 638
diffuse, 616

Eustuleux, 515
jrosing fibrocarcinoma of
stomach, clinical fea- |
tures, 638

osteogenic sarcoma, 270
pyloric fibrocarcinoma,

619
Scrotum, cancer of, 847

paraffin, 848
Sebaceous cysts of breast,

488
Secondary epithelioma, 328

osteoma, 195
Seminome, 773

Senile chronic mastitis, 469
involution of breasts, 470
osteomalacia, 283
Sennert's theory of cancer,

Serology of tumors, 89
Serous adenoma of ovary,

566
cavities, invasion of, by

cancer, 80

cystadenoma of ovary, 566
cystoma of ovary, 563
cysts, 952
membranes, endothelioma

of, 309

Singer's nodes, 826
Skeletal chondroma, 185

location, 181

Skin, acanthoma of, 797.
See also Acanthoma of
skin.
angio-endothelioma of,

316
cysts of, atheromatous,

942

epithelial, 942
endothelioma of, 314
epithelioma of, adenoid,

813

adenoid simple, 814
basal-cell, 808
reticulated, 808
invasion in cancer of

breast, 506

lesions in Hodgkin's dis-
ease, 356
myoma of, 212
osteoma of, 197
sarcoma of, 247
spindle-cell sarcoma of,

249

etiology, 251
histogenesis, 250
structure, 249

Skull changes in brain tu-
mor, 383
Spermatic cord, fibrolipoma

of, 779
fibroma of, plexiform,

779

hypernephroma of, 742
Spina bifida occulta, 961

tumors associated with,

960
Spinal cord, angioma of, 424

degeneration of, in brain
tumors, 383

glioma of, 395

lipoma of, 424

melanoma of, 863

neurofibroma of, mul-
tiple, 424

psammoma of, 423

relation of tumors to, j

• 427

sarcoma of, 420

central, 423

metastatic, 425

Spinal cord, sarcoma, of, soli-
tary, 421

tuberculosis of, 426
tumors of, 419. See
also Tumors of
spinal cord.
secondary changes in,

425

symptomatology, 426

xanthochromia in, 425

membranes, relation of

tumors to, 427
Spindle-cell myosarcoma of

stomach, 254
sarcoma, 244

blood-vessels of, 245
diagnosis, 245
histogenesis, 246
of bone, 272

prognosis, 279
of breast, pure, 487
of intestine, 255
of lung, diffuse, 795
of ovary, 256
of prostate, 767
of skin, 249
etiology, 251
histogenesis, 250
structure, 249
of spleen, 376
rate of growth, 244
secondary changes, 245
structure, 244
Spirochetas in cancer, 117
Spleen, lesions in, in leuke-
mia, 340

lymphosarcoma of, pri-
mary, 377
porphyry, 354
sarcoma of, 376
endothelial, 376
spindle-cell, 376
Splenic Hodgkin's disease,

354

Splenoma, 377
Splenomegaly, primary

(Gaucher type), 304
Spontaneous cure in tumors,

Spotted kidney, 720
Squamous epithelioma of

prostate, 766

Squamous-cell adenocarci-
noma of corpus uteri,
534
cancer of choroid plexus,

403

of gall-bladder, 676
of large intestine, 652
of renal pelvis and

ureter, 743
Stain, port- wine, 219
Stammler's reaction in can-
cer, 93
Stenosing fibrocarcinoma of

large intestine, 649
Stomach, adenocarcinoma
of, 607

1024

INDEX

Stomach, adenocarcinoma of ,

occurrence, 636
structure, 609
adenoma of, simple, 609
cancer of, 605. See also

Cancer of stomach.
endothelioma of, 320
fibrocarcinoma of, diffuse,

619

sclerosing, clinical fea-
tures, 638
leather-bottle, in, linitis

plastica, 624
lymphosarcoma of, 372
mucosa of, in cancer, 624
myoma of, 212
myosarcoma of, spindle-
cell, 254
relation of lymphatics in

cancer, 626
sarcoma of, 254, 255
tumors of, lymphomatous,

255

ulcerocancer of, 637
Stools, blood in, in cancer, 72
Stroma of tumors, 54

regressive changes in, 55
Struma adrenalis, 444

colloid, 444

hypophysis, 444

ovarii, 595, 601

postbranchialis, 879

sarcomatous, 911

suprarenalis, 178
Subcutaneous lipoma, 177
Sublingual dermoid cysts,

Q44

Submaxillary gland, epithe-
lial tumors of, 716
Submucous cavernoma, 226
Subperiosteal chondroma,

181

Sweat-glands, tumors of, 814
Symmetrical double mon-
sters, 933
Syncytial endometritis, 555

wandering cells, 548
Syncytioma, 555

clinical course, 558

metastases in, 556
Synovial lipoma, 177
Syphilis, relation of, to

lymphosarcoma, 241
Syringomyelia associated

with gliosis, 397
Systemic aleukemic lympho-

matosis, 362

TAIL, false, 961
Telangiectasis, 219
Telangiectatic sarcoma, 219
of bone, 268

prognosis, 278
Tendon-sheaths, giant-cell

sarcoma of, 251
Teratoblastomas, 939^
Teratoid chondroma, 188
Teratoids, cervical, 945

' Teratoids, intrarranial, 951
of breast, mixed, 482
of hypophyseal duct, 912
ol testis, 772
peritoneal, 953
retroperitoneal, 954
sacrococcygeal, 958
Teratology, 931
Teratoma, 28, 936
abdominal fetal, 953
autochthonous, 949
causes, 938
cervical, 945
classification, 938
intracranial, 951
morphogenesis, 937
of orbit, 947
of ovary, 593

anatomy, 593

atrophic bidermal, 599

clinical course, 593

contents, 595

dermoids and, differen-
tiation, 595

etiobgy, 603

mesodermal elements in,
598

metastases, 598

prognosis, 593

relation to simple
tumors, 602

with cystoma, 594
of pineal gland, 926
of testis, 768

adult, clinical course,
772

derivatives, 768

etiology, 782

historical note, 768

metastases, 778

relation to miscellane-
ous tumors, 779

structure, 775

varieties, 768
pharyngeal, 948
sacral, 958
sacrococcygeal, 956
source, 937
special forms, 942
Teratomatous glioma, 398
Testicular adenoma of

ovary, 590

Testis, adenoma of, 780
chondroma of, 779
embryoma of, adult, 768
endothelioma of, 298
fibroma of, 162, 779
hypernephroma of, 742
interstitial cells of, hyper-

plasia of, 781
lymphosarcoma of, 373,

782

myoma of, 212, 780
rhabdomyoma of, 215
sarcoma of, 780
teratoma of, 768. See

also Teratoma of testis.
tumors of, 768

Testis, tumors of, adrenal,

781

embryoid, 772
embryonal, 773
miscellaneous, relation

to teratoma, 779
mixed, 772'
teratoid, 772
Thiersch's theory of cancer,

23
Thoracic duct, invasion of,

by cancer, 79
Thymoma, 894

interpretation of, 898
structure, 895
Thymus gland, anatomy,

889

anlage of, 889
cancer of, 897
cysts of, 892
general pathology, 891
hypertrophy of, simple,

891
lymphosarcoma of, 894

structure, 895
sarcoma of, 898
tumors of, 889
classification, 894
clinical course, 900
primary, 893
Thyroglossal duct, dermoid

cysts of, 946

Thyroid gland, adenocarci-
noma of, 876
small alveolar large-
cell, 879

adenoma of, fetal, 873
interacinous, 872
malignant, 876
cancer of, 879. See also
Cancer of thyroid
gland.

cysts of, 887
hypertrophy of, con-
genital, 442
normal, metastases

from, 882
sarcoma of, 884
tumors of, 869

papillary epithelial,

877

structure, 878
Tibia, adamantinoma of,

694
Tissue tension theory of

cancer, 98

Tongue, angioma of, caver-
nous, 226

cancer of, epidermoid, 819
lymphosarcoma of, 373
papilloma of, 435
Trachea, exostosis of, 193
Transplantable tumors, 136
adaptation of, 140
fate of, 139
nature and origin, 136
Transplantation of tumors,
127, 134

INDEX

1025

Transplantation of tumors,
acquired resistance to,
144

between animals of dif-
ferent species, 134

between lower animals
of same species, 135

between man and man,

between related species

of lower animals, 135

hypersusceptibility to,

147
influence of variations

in soil, 141
natural resistance to,

144
nature of factors in

resistance, 145
passive resistance to, 145
Transplanted tumors, in- j
fluence of diet on, 141 |
resistance to, 143
spontaneous absorption, \

141
structural changes in, ,

142
Trauma in etiology of tu- |

mors, 109, no
frequency, 112
medicolegal aspects,

112

mechanism, in
Traumatic exostoses, 193
neuroma, 411
tumors, 26

Tryptophan in tumors, 90
Tuberculosis, Hodgkin's dis-
ease and, 360
in lymphosarcoma, 375
lymphatic, 352
of spinal cord, 426
relation of, to lympho-
sarcoma, 241
Tubo-ovarian cysts, 564
Tubular acanthoma of skin,

798

adenocarcinoma of kid-
ney, 729, 73i
adenoma, 438

of kidney, 719
cancer of kidney, 729

structure, 731

Tumeur a medullocelles, 264 '
Tumeur a myeloplacques,

264
Tumor-cells amphipyrenin

in, 46

anaplasia of, 101
desmoplastic, 54
fertilized, 102
linin in, 46
nuclear fluid in, 46
nuclein in, 46
paranuclein in, 46
peculiarities of, 46
phagocytosis by, 47
plastin in, 46
65

Tumor-cells, rapid and pro-
gressive multiplication
of, 59

regressive changes in, 43
relation to sex-cells, 102
Tumors, 25

adrenal, of female genital

organs, 741
adrenal rest, 734

carcinomatous, 738
gross appearance, 736
lateral retroperito-

neal, 741
occurrence, 735
peritheliomatous, 738
renal tumors and, dif-
ferentiation, 739
sarcomatous, 738
structure, 737
trabecular, 738
adult, 26, 49
amitosis in, 39
anaplasia in, 39
associated with spina bi-

fida, 960

asymmetric mitosis in, 39
autogenous antigen, com-
plement deviation with,

9T
benign, metastasis of, 84

malignant transforma-
tion in, 461

blood-vessel lesions in, 57
cell division in, 38
central growth in, 3 1
chemistry of, 8,9
classification, 26
collateral hypertrophy in,

colloid degeneration in, 46
color of tissue, 29
complex tissue type, 28
congenital sacral mixed,

origin, 961

connective tissue type, 27
consistence, 30-
course, 59

cystic degeneration o f
nucleus in, 47

of carcinomatous struc-
ture, 447
cysts in, 34
definition, 25
effects on body, 65
emaciation from, 65
embryologic classification,

embryonal, 26, 49
endothelial type, 27
epithelial type, 27
etiological classification,

expansive growth, 25
experimental production

of, 127
by .v-ray, 132
chronic inflammation
in, 131

Tumors, experimental study,

119

extensive growth, 25
fats in, 90

fatty degeneration in, 43
febrile destruction of pro-
tein in, 66
ferments in, 67, 90

heterolytic action, 67
fragmentation of nucleus

in, 47

from chemical agents, 120
functional activity in, 53
gametoid mitosis in, 39
general morphology, 29
geotropism in, 53
glycogenic degeneration

of, 44

growth, 31, 48
hereditary, 26
heterologous, 28, 49
heterotypic, 49
histioid, 28, 48
histological classification,

histopathology, 34
homologous, 28, 49
homotypic, 49
human, effects of injection

of extract into animals,

132

hyaline changes in, 45
hydropic degeneration in,

infiltrative growth, 25, 31
influence of mechanical

pressure in, 98
irritation group, 458
lactic acid in, 89
liquefaction cysts in, 32
local circumscription of,

lutein-cell, 565
malignant change in, 461
malignancy in, significance

of, 62
maxillary, of dental 'oririn,

686

mesonephric, 590
mitosis in, 38
mixed, 739

special forms, 942
modes of origin, 36
mucous degeneration in,

mulberry cells in, 45
multicentric growth of, 36
muscle tissue type, 27
natural limitations of
growth in, 40

limits to, 59

nervous system type, 27
nomenclature, 26
of adrenal gland, 746
classification, 746
medullary, 749

chromaffine cell,
754

1026

INDEX

Tumors of adrenal gland,
medullary, with adre-
nalin content and ne-
phritic symptoms, 754
tissue of kidney, 734
of antrum of Highmore,

699

of Bartholin's gland, 544
of bile-ducts, 667, 668
of bladder, 844

epithelial, 838
of brain, 378

age incidence, 378
anatomical classifica-
tion, 383

choked disc in, 383
circulatory disturbances

in, 383
destruction of tissue in,

382

duration, 381
edema in, 382
general distribution, 380
meningeal complica-
tions, 383
occurrence, 378
operability, 380
relative frequency, 379
secondary effects, 381
sex in, 378

skull changes in, 383
spinal cord degenera-
tion in, 383
trauma in etiology, 378
of breast, 488

ectodermal mixed, 483
epithelial, 467
mesodermal, 482
mixed, 477
teratoid mixed, 482
of choroid plexus and

ependyma, 400
etiology, 400
gross appearance,

401

structure, 402
of congenital origin, 26
of epithelium, general pa-
thology, 429
of epoophoron, 589
of extrarenal adrenal rests,

740

of Fallopian tube, 592
of Gasserian ganglion,

418

of hypophyseal duct, 912
of infundibular ependyma,

405

of intestine, lymphoma-
tous, 255

multiple, benign, em-
bryonal, carcinoid,
642
of kidney, 717

adrenal tumors and, dif-
ferentiation, 739

epithelial, 717

classification, 718

Tumors of lachrymal gland,

309, 704
of larynx, 825
benign, 827
of liver, 654

classification, 654
primary epithelial, 657
anatomical varie-
ties, 660
clinical course, 659

varieties, 660
etiology, 657
histogenesis, 658
metastases, 659
relation to cirrho-
sis, 657
of lung, 785
of lymphoid tissue, 334

classification, 334
of maxillary and nasal

sinuses, 699
of ovary, adrenal, 590
age in etiology, 586
etiology, 586
histogenesis, 586
origin, 588
simple, relation to tera-

toma, 602
of pancreas, 68 1
of parathyroid gland, 886
of parovarium, 589
of pars intermedia, of

pituitary, 915
of penis, 844
of pineal gland, 925
classification, 926
clinical features, 929
occurrence, 926
structure, 928
symptomatology, 928
of pituitary gland, 901,

907, 916
anatomy, 906
cephalic, 916
dystrophic, 917
etiology, 901
relation of type with
symptom -complex,
922

symptomatology, 916
of postnatal origin, 26
of prostate, 757
of renal hilus, 745

pelvis and ureter, epi-
thelial, 442

of salivary glands, epi-
thelial, 704
etiology, 712
mixed, 706

clinical course, 712
gross anatomy, 713
theories of origin,

706

structure, 714
of spinal cord and mem-
branes, 419
age incidence, 420
classification, 420

Tumors of spinal cord and
membranes, etiol-
ogy, 419
duration, 428
extramedullary, 427
intramedullary, 427
level of, 426
relation of, to cord,
membranes, and
vertebras, 427
secondary changes in,

425

symptomatology, 426
vertebral, 427
xanthochromia in,

425
of stomach, lymphoma-

tous, 255

of submaxillary gland, epi-
thelial, 716
of sweat-glands, 814
of testis, 768
adrenal, 781
embryoid, 772
embryonal, 772
miscellaneous, relation

to teratoma, 779
mixed, 772
teratoid, 772
of thymus gland, 889
classification, 894
clinical course, 900
primary, 893
of thyroid gland, 869

epithelial papillary,

877

structure, 878
of vulva, epithelial, 542
organoid, 48

parasitic theory of, classi-
fication by, 126
pentose in, 89
peripheral growth in, 31
phosphorus in, 89
precancerous stage, 34
progressive growth, 25
proteins of, constitution,

pseudo-adipose in, 47
pulp, 29

rate of growth, 59
recurrence, 86
regional classification, 26
relation of blood-vessels

to, 56

retrograde transport of, 83
saber-sheath veins in, 57
sacrococcygeal, mixed, 956
sand, 30, 296
serology of, 89
simple mixed, 28
special etiology, 109
specific causes, 26
spontaneous cure in, 60

regression in, 40
stroma of, 54
reactions in, 55
regressive changes in, 55

INDEX

1027

Tumors, structure, 48

teratoid. See Teratoids.

toxic destruction of pro-
teins in, 66

transplantable, 136
adaptation of, 140
fate of, 139 ]
nature and origin, 136

transplantation of, 127,

134

acquired resistance to,
144

between animals of dif-
ferent species, 134

between lower animals
of same species, 135

between man and man,

135
between related species

of lower animals, 135
hypersusceptibility to,

147
influence of variations

in soil, 141

natural resistance, 144
nature of factors in

resistance, 145
passive resistance to,

145
transplanted, influence of

diet on, 141
resistance to, 143
spontaneous absorption,

141
structural changes in,

142
trauma in etiology, 26,

109, no
frequency, 112
mechanism, in
medicolegal aspects,

112

tryptophan in, 90
typical mitosis in, 38
ulceration in, 33
unicentric growth of, 36

ULCER, peptic, cancer fol-
lowing, 610
rodent, 808

crateriform, 840

Ulcer, rodent, histogenesis,

structure, 840
Ulceration in tumors, 33
Ulcerative infiltrating epi-

thelioma of lip, 816
Ulcerocancer of stomach, 63 7
Unicentric growth of tumors,

36
Urea, percentage of, in

cancer, 72
Ureter, cancer of, alveolar,

744

primary, 843
squamous cell, 743
epithelioma of, papillary,

742

papilloma of, 742
tumors of, epithelial, 742
Urethra, cancer of, 847
Uric acid increase in cancer,

72
Urinary bladder, rhabdomy-

oma of, 214
organs, myoma of, 212
Urine, changes in, in cancer,

Urobilin in cancer, 74
Uterus, adeno-acanthoma of,

527

adenomyoma of, 207
adrenal tumors of, 741
cancer of, 523. See also j

Cancer of uterus,
carcinosarcoma of, 262
chondroma of, 188
endothelioma of, 320
fibromyoma of, 203
lipoma of, 179
mucosa of, sarcoma of, 261
myoma of, degenerative
changes in, 206

etiology, 208

form, 204

gross appearance, 206

microscopic structure,
207

recurrent, 260
rhabdomyoma of, 214
sarcoma of, 258. See also

Sarcoma of uterus.

VAGINA, epidermoid cancer

of, 544

Varicosities, chronic, 219
Vascular nevus, 219
Vater, ampulla of, cancer of,

679
Verruca plana juvenilis, 431

vulgaris, 431
Vertebrae, relation of spinal

tumors to, 427
Vertebral tumors of spinal

cord, 427
Villous papilloma of large

intestine, 651

Virchow's physaliden, 44,
182

theory of cancer, 22
Visceral neurofibromatosis,

Vulva, epidermoid cancer of,

542
epithelial tumors of, 642

WANDERING cells, syncytial,
548

Warts, cutaneous, 431

Wassermann reaction in can-
cer, 91

Whitlow, melanotic, 851

XANTHELASMA, 159
Xanthochromia in spinal

cord tumors, 425
Xanthoma, 159

diabeticorum, 159

generalized, 159

multiplex, 159

palpebrarum, 159

planum, 159

structure, 160

tuberosum, 159

vulgare, 159
Xanthomatosis, 160
Xeroderma pigmentosum,

80 1
X-ra,y dermatitis, cancer and,

802

clinical course, 802
structure, 803

experimental production
of tumors by, 132

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