THE MERICAN
JOURNAL OF CANCER
A Continuation of The Journal of Cancer Research
VOLUMEXXXIII
JULY,
1938
NUMBER
3
CARCINOSARCOMA
OTTO SAPHIR, M.D.,
AND
ALOYSIUS VASS, M.D.l
(From the Pathology Departmeizt of the Nelson Morris Institute, Michael Reese Haspitel,
Chicago)
The histologic classification of malignant tumors is important not only
from an academic (histogenetic) standpoint, but also from that of prognosis
and treatment. Thus the application and dosage of irradiation are primarily
and principally dependent upon histologic detail, as is also the grading of
malignant tumors. While ordinarily it is fairly well within the power of the
pathologist to classify a malignant tumor, occasional growths are encountered
which, despite obvious malignant features, cannot, because of their peculiar
histologic detail, easily be classed as the descendants of one particular cell
type. These tumors present features which may lead to the belief that they
are the result of atypical growth of more than one cell type.
Interest in these tumors is as old as histopathology itself. All early
pathologists considered their origin to be of dual nature. Thus, Virchow
labeled them carcinosarcoma. He believed that within the primary carcinomatous or sarcomatous elements, the stromal or epithelial portions respectively were subsequently or simultaneously stimulated to malignant growth.
Herxheimer and others believed this occurrence to be more frequent in primary
carcinomas. They held that a carcinoma could stimulate an excessive growth
of the stroma; that when the stroma-proliferation reached the stage of malignancy, the resulting tumor would be a carcinosarcoma. Perhaps, also, the
secondary malignancy might supersede the primary one.. This opinion was
corroborated by Ehrlich and Apolant, and others, who observed that transplanted mouse carcinomas changed their histologic appearance, first to carcinosarcoma and eventually to sarcoma.
With the acceptance of the existence of these dual tumors, various attempts at classification were undertaken. Saltykow called tumors resembling
carcinoma in some portions and sarcoma in others “ carcinoma sarcomatodes,”
a term first employed by Herxheimer. Those growths which were the product
1 Aided
by a grant from the A. B. Kuppenheimer Fund.
33 1
---_
.
.&-A
FIG. 11. PRIMARY
DUCTCARCINOMA
OF BREAST. HEMATOXYLIN-EOSIN.
X 85
FIGS.12
13. METASTASTS
IN OVARY
OF PRIMARY
DUCTCARCIXOMA
OF BREAST(FIG. 11)
Note the round tumor cells. Hematoxylin-eosin. X 75 and X 160
AND
FIGS.14 AND 15. Two AREAS IN PRIMARY
CARC~NOMA
OF THYROID
Note the spindle shape of the carcinoma cells in Fig. 15. Hematoxylin-eosin. X 75
FIG. 16. PRIMARY
CARCINOMA
OF ESOPHAGCS
Note the presence of many connective-tissue cells which in some instances have been interpreted
as sarcoma cells. Hematoxylin-eosin. X 100
345
CARCINOSARCOMA
333
of carcinoma cells and recommended the use of the term “ pseudosarcomatous
carcinoma ” or “ pseudocarcinosarcoma ” for carcinomas with sarcoma-like
appearance. Semb, in describing tumors of the breast, mentioned the possible misinterpretation of morphologically transformed carcinomas as sarcomas. Krompecher doubted the true dual nature of these tumors and
conceived of them as originating from an embryonal cell, the “ transitional
cell,” which supposedly possesses the potentialities of both epithelial and connective-tissue cells. Cohn stressed the fact that it is next to impossible to
diagnose correctly immature tumors, and pointed out that scme of these, because of the variability of tumor cells, may be interpreted as carcinosarcomas.
Ewing’s point of view has been mentioned above.
Harvey and Hamilton, on the other hand, maintain that there is a double
tumor which is a mixture of carcinoma and sarcoma and that this may be
denominated carcinosarcoma. The sarcomatous development is probably an
exaggeration of stroma reaction to invasion by carcinoma. They further
point out that it is generally believed that the carcinoma cells exert a stimulating influence on the stroma cells, which in transplanted tumors in course of
the transfers yield a tumor of fibroblastic origin. The current interpretation
of the carcinosarcomatous structures in man and the lower animals, however,
is, as these authors point out, a matter of much difficulty, and probably no
single explanation will apply to all cases. The chief source may be the transformation of epithelial cells into spindle cells. These writers state, however,
that there are tumors of both epidermic and glandular carcinoma type which
may show, in part, aggregations of spindle-shaped epithelial cells, having
much the appearance of a sarcoma, which may be denominated spurious
carcinosarcoma or carcinoma sarcomatoides.
Kettle pointed out that, although it is possible that many of the carcinosarcomas recorded are true mixed tumors, it is certain that others are merely
examples of extreme polymorphism of carcinoma cells.
Willis stated that in human pathology no acceptable example of sarcomatous change in the stroma of a tumor has been described. All alleged instances of this occurrence are clearly traceable to the structural versatility
of carcinomas as described by Kettle.
The discrepancy of opinion indicated by this brief review justifies a
re-investigation of the tumors reported as carcinosarcomas.
In a previous study one of us (Saphir) has shown that in a series of carefully studied tumors, principally epithelial, more than one type of apparently
epithelial element was often present. In some tumors, particularly those referred to as squamous-cell carcinomas with transitional-cell features, the latter
often assumed spindle forms which upon cursory examination might easily
be mistaken for sarcomatous elements. Only a large number of sections revealed the true nature of some of these tumors through observation of the
change from transitional and basal cells to the spindle-shaped sarcoma-like
elements. Upon superficial examination these tumors could have been interpreted as carcinosarcomas. Since a re-study of our very meager material
on carcinosarcomas almost invariably revealed that these tumors could be
interpreted as carcinomas of various types showing so-called morphologic
variations, we decided to collect these tumors and to determine whether or
3 34
OTTO SAPHIR AND ALOYSIUS VASS
TABLE
I: Location of 153 Carcinosarcomas Reported in the Literature
-
Uterus. . . . . . . . . . . . . .
. . . . . 36
Tube . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
................... 7
Breast . . . . . . . . . . . . . . . . . . . . . . .
Thyroid gland, . . . . . . . . . . . . . . . . . . . . . . . .
32
17
............ 1
Esophagus . . . . . . . . . . . . . . . . . . . . . . .
14
5
........ 1
Gallbladder. . . . . . . . . . . . . . . . . . . . . . . . . . . .
.........................
Larynx. . . . . . . . . . .
Hypopharynx . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1
6
1
Lung . . . . . . . . .
................. 7
Kidney . . . . . . . . . . . . . . . . . . .
Urinary bla
. . . . . . . . . . . . .1
Ureter.. . . . . . . . . . . .
Prostate. . . . . . . . . . . . . . . . . . . . . . . .
Skin.. . . . .
.......................
5
Middle e a r . . . . . . . . . . . . .
Salivary gland. . . . . . . . . . . . . . . . . . . .
Labium m a j u s . .
................ 1
Maxillary sinus. . . . . . . . . . . . .
Nasal cavity
......................
1
Ciliary body. . . . . .
.............. 1
not they were single tumors. I t was also considered wise to re-study those
instances of carcinosarcoma reported in the literature which were available to
us, and to see if such an interpretation was indisputable.
In the following pages the carcinosarcomas reported in the literature are
cited, our interpretation of these tumors is given, and similar tumors which
have come to our observation are reported in view of the possibility of a
diagnosis of carcinosarcoma. For the sake of coherence, these observations
are given after the review of the literature on carcinosarcomas of individual
organs or systems of organs.
REVIEWOF
4
“*
THE
LITERATURE
AND PERSONAL
OBSERVATIONS
This review is by no means complete, but it covers most of the publications in the American, English, French, German, and Italian literature. I n
the study of the reported tumors, we were concerned only with those which,
although presenting apparently mixed characteristics, were obviously not
teratomas. The terms most commonly used by the various authors in their
diagnoses were “ carcinosarcoma ” and, less frequently, “ carcinoma sarcomatodes.” Our study was based upon the descriptions and the illustrations
accompanying the case reports. Our analysis concerned itself with the following possibly complicating factors in the alteration of the fundamental histologic appearance of the tumor: (1) growth of a carcinoma into a benign
tumor; ( 2 ) inclusion of benign epithelial cell formations within a malignant
tumor of connective-tissue origin; ( 3 ) chronic productive inflammation in the
vicinity of the tumor; ( 4 ) marked anaplasia; ( 5 ) morphologic variations in
tumor cells, as described by one of us (Saphir); ( 6 ) history and histologic
evidence of x-ray irradiation. I n our interpretation of the fundamental character of the tumor, the nature of the metastases was given due consideration.
The material for our investigation consisted of 153 reported carcinosarcomas, the distribution of which in various organs is presented in Table I.
Uterus: Table I1 lists the reported tumors and the nature of metastases
of 36 uterine carcinosarcomas.’ In 19 instances pedunculated tumors projected either from the endometrium into the uterine cavity or from the cervix
*The report of Kubinyi of carcinosarcomas of the uterus, as quoted by Bczza, could not he
verified.
335
CARCINOSAkCOMA
TABLE
11; Chrcinosarcomas of the Uterus
No.
Date of
Publicat ion
Author
Carcinoma
Sarcoma
1893
1896
1896
1901
1904
1904
1908
1909
1909
1909
1912
1914
1914
1915
1922
1922
1922
1922
1923
1925
1925
1925
1925
1925
1925
1925
1925
1926
1928
1931
1932
1935
1935
1935
1936
1936
Sehrt
Iwanoff
Niebergall
Fraen kel
Nebesky
Nebesky
Lindemann
Forssner
Forssner
Albrecht
Stein
Saltykow
Saltykow
Benthin
Klee
Rrun
Kleinsch mid t
Kleinschmidt
JaffC
Frankl
Frankl
Frankl
Frankl
Frankl
Frankl
Frankl
Frankl
Raltzer
Schiffmann
Leroux and Perrot
Bosenberg
Daniel and Lazaresco
Harvey and Hamilton
Harvey and Hamilton
Goldstine
Schwarz
-
-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Metastasis
-
+-
-
+-
-
+
-
-
-
+-
--
-
-
+
+-
Mixed
--
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
into the vagina. Microscopically they consisted of large spindle-shaped or
elongated cells, similar to smooth muscle cells, among which many atypical
anaplastic cells of varying size and multinucleated giant cells were also seen.
Ulceration of the surface of the tumor was present in most instances, and inflammatory changes were regularly evident within the stroma. The tissue
around the base of the pedunculated mass was purely carcinomatous and was
so interpreted by the author. In one case the pedunculated tumor did not
consis; of spindle-shaped muscle cells, but of connective tissue enclosing
uterine glands of somewhat irregular arrangement composed of cells with no
anaplastic features. The stroma of this apparently polypoid growth contained a great number of inflammatory cells and many anaplastic tumor cells.
Here, too, the tissue surrounding the tumor presented typical carcinomatous
features and was so interpreted by the author.
In 8 instances parts of the tumors were distinctly carcinomatous. In
other regions, however, chronic productive inflammatory changes were present.
FIG. 1, SQUAMOUS-CELL CARCINOMA O F UTERUS WlTH MANYLYMPHOCYTIC CELLS
The tumor was irradiated. Tumors presenting similar pictures have been recorded in the
literature as carcinolymphosarcoma. Hematoxylin-eosin. X 60
FIG. 2. SQUAMOCS-CELL CARCINOMA O F CERVIX WITH TRANSITIONAL-CELL FEATURES
Note the transitional cells simulating connective-tissue cells which surround islets of squamous
cells. Hematoxylin-eosin. X 50
[ L q e r t d cont. at f o o l ul 9 . 3371
336
CARCINOSARCOMA
3 37
In these areas, besides typical carcinoma cell groups, there were tumor cells
showing anaplasia with bizarre pleomorphism. These pleomorphic cells were
interpreted by the authors as sarcoma cells. Tumors No. 20 and 23 belonging to this group were treated with x-ray irradiation and multiple curettages.
In tumor No. 31 there were found, beneath and partly among the cells of a
typical transitional-cell carcinoma of the cervix, many closely packed small
round cells of uniform size and shape. These cells were interpreted by the
author as those of a round-cell sarcoma.
In Case No. 11, a polypoid structure arising in the endometrium was
present in an adenomyomatous uterus. Microscopically this polypoid structure consisted of spindle cells enclosing endothelial-lined cavities containing
blood; only a scanty stroma was present. Among the spindle cells were cells
with large cytoplasms and irregularly outlined nuclei. Some of the cells contained multiple nuclei. Enclosed within the tumor tissue were irregularly
formed glandular structures lined by partly stratified squamous cells differing
somewhat in size and shape. Metastases occurring one year later did not
contain these glandular structures.
Tumor No. 16 may be interpreted as a metastatic carcinoma within a
myofibroma. The primary tumor was apparently a cystadenocarcinoma of
an ovary which had been removed previously. Also in Kleinschmidt’s tumors
it seems that a primary carcinoma had invaded a myofibroma. The metastasis in one of these was carcinomatous. Because of absence of sufficient
description and illustrations case No. 1 cannot be discussed.
Nineteen tumors were characterized, as stated before, by a more or less
pedunculated myomatous growth. The tissue surrounding the base of the
myoma was in all instances purely carcinomatous, as admitted by the authors.
I t is known that carcinoma cells invading connective or muscle tissue may
become morphologically altered by the mechanical pressure of the invaded
tissue. It seems, therefore, that this group of tumors should be considered
as primary carcinomas invading myofibromas which may be undergoing
various progressive and regressive changes, rather than that they should be
interpreted as carcinosarcomas. That this interpretation is the more probable one for this group is demonstrated by the carcinomatous nature of the
metastases in the few instances where these were present.
In the second large group of 8 cases, anaplastic tumors were encountered
which showed in some parts distinct carcinomatous features, while in others
they presented marked pleomorphism, which led to the diagnosis of carcinosarcoma. I n all of these tumors the pleomorphism was present in areas of
chronic productive inflammation. I n tumors No. 2 1 and 23 a long history
corroborates the chronicity of the inflammatory process. I t seems that the
pleomorphism of the tumor cells is more likely the result of the chronic inFIG. 3. ADENOCARCINOMA
METASTASIS
IN MYOFIBROMA
Instances of this type were reported as carcinosarcoma. Iron hematoxylin-eosin.
X 90
FIG.4. PAPILLLFEROUS
CYSTADENOCARCINOMA
OF OVARY
Note the transitional type of cells in the left lower field. These are occasionally regarded as
connective-tissue cells. Iron hematoxylin-eosin. X 110
FIGS,5 AND 6. Two INSTANCES
OF PAPILLARY
CYSTADENOCARCINOMA
ARISING
IN A MAMMARY
DUCT
Note the spindle shape of some of the tumor cells. Hematoxylin-eosin. X 210 and X 90
338
OTTO SAPHIR AND ALOYSIUS VASS
flammation than due to a true duality of origin. X-ray therapy and multiple
curettages may have been partly responsible for the marked anaplasia in the
two tumors just mentioned.
In tumor No, 10 we do not believe from the illustrations accompanying the
report that a complicating carcinoma was present. There seems to have been
a sarcoma within an adenomyomatous uterus. A possible confirmation of
this is seen in the nature of the metastases occurring one year later, which
showed no evidence of carcinoma.
In those instances in wh‘ch the diagnosis of squamous-cell carcinoma and
spindle-cell sarcoma was mdde, it is clear that what were considered to be the
spindle-shaped elements of the sarcoma were “ transitional-cell-carcinomatous
features ” as stated previously. This is clearly seen, particularly in the pictures accompanying the report of tumor No. 30. The histologic structures
of tumors Nos. 32 and 33 may also be explained on the basis of morphologic
variations.
From the analysis, therefore, of 36 instances of so-called (‘carcinosarcoma” of the uterus reported in the literature it is apparent not only that
sufficient evidence for such a diagnosis is lacking, but that factors were
present which may very well account for the increased anaplasia leading to
the dual diagnosis of these tumors.
We have encountered a number of tumors which at first glance might have
been interpreted as adenosarcomas or carcinosarcomas of the uterus. I n one
instance it could be shown clearly that the tumor in question was a myofibroma of the uterus into which a primary carcinoma of the ovary had metastasized. In several instances the primary carcinoma was a transitional-cell
carcinoma of the cervix with squamous-cell features. I n these cases the
transitional cells were elongated and spindle-shaped and were, on cursory
examination, confused with the cells of a spindle-cell sarcoma. Cells of this
type are by no means rare in squamous-cell carcinomas and have been discussed in full in a previous communication.
In another case which came to our observation the tumor apparently arose
from the epithelial elements of an endometrioma. The stroma showed interlacing fibers which compressed the glandular structures, but there was no
evidence of malignancy in the stromal structures. In another instance a
primary carcinoma of the cervix uteri had been treated with radium. The
tumor recurred and the recurrence revealed, in addition to squamous and
transitional cells, many round cells which could easily be confused with
malignant lymphocytes, thus suggesting a carcinolymphosarcoma. I n a
number of sections, however, the round cells could be traced to a variety of
transitional cells which had similar nuclei. Thus, the final diagnosis was
anaplastic transitional carcinoma.
Pallopian Tube: One of the two tumors considered of possible complex
origin in this series is that of v. Franque, diagnosed as carcinosarcoendothelioma. Throughout the mucosa the tumor presented adenocarcinomatous
features, while in the metastases there were only anaplastic celIs, apparently
sarcomatous, but no adenomatous structures. The presence of vascular
channels in the tube close to and within the tumor, in some areas lined by
endothelial cells, produced an appearance which was interpreted by the author
3 39
CARCINOSARCOMA
TABLE
111: Carcinosarcomas of Ovary *
No.
1
2
3
4
5
6
7
Metastases
Year of
Publication
Author
Carcinoma
1901
1905
1913
1916
1916
1922
1929
Haacke
Lippmann
Rothacker
Harbitz
Harbitz
Kleinschmidt
Quin
-
+
-.
Sarcoma
?
-
-
Mixed
-
++(?)
-
+-
* Vecchi’s report (Vecchi, G.: Arch. per le sc. med. 48: 135, 1926) was not available to US.
as endotheliomatous. The absence of adenomatous structures in metastases
of primary adenocarcinomas is not rare and the presence of anaplastic cells in
the metastases does not signify that the primary tumor contained sarcomatous
elements. I t seems, therefore, assuming the validity of morphologic variations of tumor cells, that this case was a primary adenocarcinoma of the fallopian tube with secondary anaplasia, rather than a simultaneous occurrence
of tumors of different origin.
The second carcinosarcoma of the fallopian tube, in a fourteen-year-old
girl, was reported by Motta. It was described as adenocarcinoma with pavement cells and spindle-cell sarcoma. The metastases were supposedly sarcomatous. The photomicrographs accompanying the report are of poor
quality and do not show the presence of two tumors.
We have observed one instance of primary papilliferous adenocarcinoma
in the tube, where the carcinoma cells assumed transitional forms which, as
is pointed out later (pp. 343 and 356) resembled the cells of a spindle-cell
sarcoma. A similar explanation may hold for Motta’s tumor.
Ovary: In the literature reviewed there were 7 carcinosarcomas of the
ovary (Table 111). Unfortunately only a few microscopic illustrations are
available and the descriptions are not sufficiently ample to warrant detailed
accounting. From the authors’ meager descriptions these tumors appear to
have been mainly cystadenocarcinomas with closely packed groups of pleomorphic and spindle-shaped cells growing between partly hyalinized connective-tissue fibers. In our interpretation the latter areas represent carcinoma
cells morphologically altered by growth into the restricted special environment
of the fibrous wall of a fibrocystoma. The tumors described by Harbitz are
in his own opinion questionable carcinosarcomas. One is seemingly a primary
sarcoma and the other very likely a carcinoma with carcinomatous metastases.
There are a number of papilliferous cystadenocarcinomas in which the
lining cells of the papillae are not cuboidal but either approach or actually
are of transitional type. In these latter instances, when the transitional cells
invade the core and the ovarian structures, they often assume spindle shapes,
and the tumors may be confused with spindle-cell sarcomas and lead to the
erroneous diagnosis of carcinosarcoma.
Breast: ‘ Thirty-two cases reported in the literature as carcinosarcoma of
According to Helwig, the first carcinosarcoma of the breast was reported by Kerbiriou and
Danel. This report was not available to us.
3 40
OTTO SAPHIR AND ALOYSIUS VASS
TABLE
IV: Carcinosarcomas of the Breast
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
.
16
17
18
19
20
21
22
23
24
25
26
21
28
29
Year of
Publication
Author
1896
1906
1910
1910
1912
1912
1913
1913
1914
1915
1916
1920
1920
1922
1925
1925
1925
1928
1928
1931
1931
1932
1933
1933
1935
1935
1936
1936
1937
Uorsch
Schlagenhaufer
Coenen
Orth
Kettle
Perrier
Takano
Waelle t
Wehner
HedrGn
Harbitz (4 tumors)
Kunsemuller
Bergeret and Rotelho
Jessup
Kreibig
Kreibig
Kreibig
Helwig
Kuckens
Sussi
DeGaetani
Stropeni
Greenblatt
Nowicki
Harvey and Hamilton
Harvey and Hamilton
Pasternack and Wirth
Mondor et al
Sailer
*
Known duration Of process Carcinoma
Metastases
_______..-
Sarconm
Mixed
* Not included are those tumors showing a large amount of cartilage or bone, which may
rather be interpreted as mixed tumors. Also not included is Melnichenko's report (Melnichenko,
V. D.: Med. zhur. 5: 361, 1935), which was not available t o us.
t Tumor also shows some cartilage.
the breast are presented in Table IV." They are morphologically very similar.
In 2 1 instances parts of the tumor revealed the characteristics of a carcinoma
simplex arising from the ducts. In other regions, however, spindle and bizarre
shaped anaplastic tumor cells were observed. The latter were found in areas
which showed chronic productive inflammatory changes of variable extent.
There were fat necrosis, granulation tissue with ( foreign-body) giant cells,
marked fibrosis, calcification, and formation of osteoid tissue. One tumor
consisted of a so-called adenoacanthoma which in some regions also revealed,
within a very cellular stroma, seemingly anaplastic tumor cells with hyperchromatic nuclei, some of which showed mitotic figures. In adjacent areas
there was typical granulation tissue with foreign-body giant cells (fat necrosis). The entire tumor was enclosed in a firm, fibrous capsule. Tumor
16 consisted of bundles of elongated spindle-shaped cells throughout, among
which were glandular structures lined by high cuboidal epithelial cells mani4 A tumor of the breast demonstrated by Schmincke is often referred to as carcinosarcoma.
This tumor, however, is a sarcoma with benign epithelial structures which are constituents of an
adenoma.
FIG. 7. PAPILLARY
CYSTADENOCARCIXOMA
OF BREAST,
SAMEAS FIG. 6. HEMATOXYLIN-EOSIN.
x 180
FIG.8. SPINDLE-SHAPED
CARCINOMA
CELLSOF A PRIMARY
DUCTCARCINOMA
OF THE BREAST
Note the likeness of these cells to spindle cells of a sarcoma. Hematoxylin-eosin. X 100
FIG.9. DUCTCARCINOMA
OF BREAST
Note the transition from polygonal carcinoma cells to spindle cells. Hematoxylin-eosin.
X 75
FIG. 10. SQUAMOUS-CELL
CARCINOMA
OF CERVIX
WITH TRANSITIONAL-CELL
FEATURES,
SAMEAS
FIG. 2
.The spindle-shaped cells resemble sarcoma cells. Note the likeness to the spindle-shaped cells
of Figs. 6 t o 8. Hematoxylin-eosin. X 100
34 1
342
OTTO SAPHIR AND ALOYSIUS VASS
festing no gross anaplastic features. Recurrence of this tumor after excision
consisted only of the spindle-shaped cells.
In other instances chronic productive inflammatory changes were present
in the areas manifesting the “ sarcomatous ” features. In some instances
where the history was available, this bore out the chronicity of the lesion.
I t is possible that, as Ewing stated, the chronic inflammatory changes produce
morphologic alterations of the carcinoma cells which to some degree may have
been responsible for the diagnosis of sarcoma. As far as the tumor cells are
concerned which are reproduced in the illustrations, they can be interpreted as
carcinomatous in nature.
In tumor No. 2 7 , the questionable “ sarcomatous ” cells lie in a stroma
which reveals chronic productive inflammatory changes. These cells, distinctly anaplastic in appearance, are evidently carcinomatous. Tumor No.
16 was presented by the author in a discussion of carcinosarcoma, with the
implication that the tumor in question was of that nature. Obviously, however, it was an adenofibrosarcoma, perhaps a sarcoma arising in a fibroadenoma.
Helwig’s case was interpreted as a carcinoma showing sarcomatoid metaplasia. A similar tumor was found in the axillary lymph nodes and in recurrent mammary nodules. From the pictures accompanying the report this
tumor may perhaps be interpreted as a primary sarcoma of the breast. Kunsemuller’s tumor is also probably a simple sarcoma. That author stated that
the nuclei of the sarcoma cells were similar to those cells which were interpreted as carcinoma. Jessup reported before the New York Pathological
Society a giant-cell sarcoma and a carcinoma in the same breast. Martland,
in discussing this case, stated that he did not believe that this tumor was a
carcinosarcoma but rather a simple carcinoma. Wood, however, held to the
sarcomatous and carcinomatous nature of the tumor. Harbitz stressed the
presence in his tumors of lymphocyte-like sarcoma cells, which were interpreted as sarcomatous cells. From the description, however, it seems that
these were rather anaplastic carcinoma cells. Harvey and Hamilton’s first
case, and Bergeret and Botelho’s, seem to be primary carcinomas with a
marked overgrowth of connective-tissue cells.
A large number of tumors reported, particularly Kuckens’, showed, in
addition to the neoplasm, marked fibrotic changes, with or without the presence of cysts. It may be interesting at this time to mention Kuckens’ conception of the origin of carcinosarcoma of the breast. He assumed that there
is a primary fibrosis of the breast. Either a primary carcinoma arises which
secondarily causes the development of sarcoma of the fibrotic portions, or a
sarcoma occurs primarily in the fibrotic breast which leads secondarily to the
development of carcinoma. He postulated, however, that it might also be
possible that a carcinoma or sarcoma of the breast occurs primarily and that
the fibrosis is a secondary phenomenon, giving rise, in turn, to the sarcomatous
or carcinomatous component respectively.
Kidner’s tumor is interesting but apparently does not belong to the carcinosarcoma group. This author reported a primary carcinoma of the breast
which was removed surgically. The recurrent tumor showed what was interpreted as sarcoma. In this connection we may quote an instance which came
CARCINOSARCOMA
343
to our observation. A primary duct carcinoma was removed from a fifty-twoyear-old woman, who died several years later. At autopsy several large
masses were found in both ovaries, which histologically showed a large number
of round cells, at first interpreted as sarcomatous in nature, until many sections were examined and it was found that occasionally there was a tendency
toward the arrangement of tumor cells in the form of plaques similar to those
seen in primary duct carcinomas of the breast. This indicated that the
ovarian neoplasm was a metastatic tumor of the Krukenberg type, the primary
lesion being located in the breast.
Six out of nine metastases of these breast tumors showed carcinoma. In
two instances (cases Nos. 12 and 23) the metastatic tumor consisted of interlacing bundles of malignant spindle cells which were considered sarcomatous
because of a fine reticulum network as demonstrated by reticulum stain.
Even with these special stains, however, it seems hazardous to base the differential diagnosis of carcinoma and sarcoma in these instances upon the
presence or absence of reticulum fibers, in view of the evidence of marked
chronic inflammatory changes with fibrosis. Though one of these tumors
(case 23) may be considered from the accompanying photomicrographs as
purely carcinomatous in nature, the possibility of a carcinosarcoma cannot
be ruled out.
I t is interesting that in 2 1 out of the 29 breast tumors reported in the
literature, the carcinomatous portions were duct carcinomas. We have observed a number of papilliferous duct carcinomas of the breast where, as in
the tumors of the ovaries, the papillae were covered by transitional cells.
These cells, when invading the breast aside from the ducts, assumed spindleshaped forms and in some fields could not be differentiated from the cells of
a transitional-cell carcinoma arising in the urinary bladder. As in these tumors, the malignant transitional cells of the papillary carcinomas of the breast
are often thin with elongated spindle-shaped nuclei, and may easily be confused, therefore, with connective-tissue (sarcoma) cells. They are obviously
malignant, as seen by the atypical mitotic figures and the relative anaplasia.
But the fact that on the one hand typical adenocarcinomatous structures with
papilliferous excrescences are present, and on the other hand cells which resemble those seen in spindle-cell sarcomas, may lead to the erroneous diagnosis
of carcinosarcoma.
I t thus seems that a number of the tumors reported in the literature as
carcinosarcomas of the breast can be reconstructed as primary Carcinomas
arising from the ducts, with papilliferous excrescences lined by epithelial cells
of the transitional type which had invaded the adjacent breast tissue. These
transitional cells have been interpreted as sarcoma cells.
One interesting tumor which at first was misdiagnosed may be described
in more detail, since it seemed to have all the characteristics of a carcinosarcoma of the breast, but finally was recognized as a papilliferous adenocarcinoma arising in the ducts with secondary invasion of the breast. This
tumor, clinically a benign lesion, removed from a young woman, was firm,
grossly more or less well circumscribed, and revealed a grayish-pink, slightly
opaque cut surface, interspersed with firm whitish strands and small minute
cystic structures. Histologically there were many spindle-shaped cells with
344
OTTO SAPHIR AND ALOYSIUS VASS
TABLE
V: Carcinosarcomas of Thyroid Gland *
_
I
I
_
_
_
_
No.
Date of
Publication
Author
Geographic
Location
Metastases
___I.-__
Carcinoma Sarcoma
Mixed
* Wells, and also Slye et al, have reported carcinosarcoma of the thyroid in animals.
report was not available.
Milone’s
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1878
1898
1905
1907
1909
1909
1909
1909
1909
1913
1913
1916
1921
1929
1930
1930
1932
Kaufmann
Kummer
Salt ykow
Herrenschmidt
Nassetti
Waechter
Waech ter
Waechter
Waechter
Simmonds
Rassal & Rigaud
Harbitz
Giavotto
Ziillner
Oesterlin
liolando
Dal I’ozzo
Switzerland
Switzerland
Switzerland
France
Bologna
Freiburg
Freiburg
Freiburg
Freiburg
Hamburg
Toulouse
Oslo
Genoa
Alps
Great Lakes region
Northern Italy
Northern Italy
hardly any recognizable cytoplasm and with oval nuclei which showed some
variations in size and shape, and a number of atypical mitotic figures. These
cells were arranged in rows and bands, and large groups of them were separated by scant connective tissue. In other fields a number of glandular
structures were found which in part were compressed by the surrounding
tumor cells and were lined by several layers of low cuboidal cells which showed
no evidence of malignancy. The original diagnosis was carcinosarcoma of
the breast. Only after many more sections had been studied carefully was
the true nature of this tumor recognized, In serial sections a few obviously
dilated glandular structures were noted with lining cells extending in fingerlike projections into the lumen. In these regions the lining cells had assumed
a spindle-shaped form, were apparently transitional in character and similar
to those seen in the urinary bladder or in certain papilliferous cystadenocarcinomas of the ovaries. At several points these cells extended into the surrounding parenchyma and stroma of the breast and formed large areas of
spindle-shaped tumor cells, In the sections which were examined first, only
these transitional tumor cells were seen surrounding some of the ducts, and
they were interpreted as of connective-tissue origin. In short, what seemed
to be a carcinosarcoma of the breast proved to be a primary carcinoma arising
in the ducts. Tumor cells of the transitional type had secondarily invaded
surrounding portions of the breast, giving the impression of sarcoma cells.
Thyroid Gland: Table V presents the 17 carcinosarcomas of the thyroid
gland. I t is questionable whether Nassetti’s tumor (no. 5 ) belongs in this
group, since it was apparently a primary carcinoma of the thyroid which was
removed. The tumor recurred and the subsequent diagnosis was sarcoma.
The others present more or less similar pictures. In some areas a typical
carcinoma was encountered. In others, groups of anaplastic spindle-shaped
or pleomorphic tumor cells with little intercellular substance were noted, In
---_
.
.&-A
FIG. 11. PRIMARY
DUCTCARCINOMA
OF BREAST. HEMATOXYLIN-EOSIN.
X 85
FIGS.12
13. METASTASTS
IN OVARY
OF PRIMARY
DUCTCARCIXOMA
OF BREAST(FIG. 11)
Note the round tumor cells. Hematoxylin-eosin. X 75 and X 160
AND
FIGS.14 AND 15. Two AREAS IN PRIMARY
CARC~NOMA
OF THYROID
Note the spindle shape of the carcinoma cells in Fig. 15. Hematoxylin-eosin. X 75
FIG. 16. PRIMARY
CARCINOMA
OF ESOPHAGCS
Note the presence of many connective-tissue cells which in some instances have been interpreted
as sarcoma cells. Hematoxylin-eosin. X 100
345
346
OTTO SAPHIR AND ALOYSIUS VASS
all instances these cells were present in regions of thyroid tissue which showed
marked secondary changes ranging from necrosis to fibrosis, calcification, and
formation of cartilage and osteoid tissue. The anaplastic tumor cells in these
areas were considered sarcomatous. Because the " sarcomatous " features
were found principally in those regions of the thyroid gland which showed
the degenerative changes, it seems that perhaps these changes secondarily
altered the morphology of the tumor cells (Ewing). It may be of interest in
this connection to point out that a number of these tumors are reported to
have occurred in goiter regions and to have originated in long-standing goiters
in elderly persons. Carcinosarcomas of the thyroid gland have also been reported as occurring spontaneously in the dog and rat.
The metastases of these reported tumors were considered definitely carcinomatous in 2 instances and possibly sarcomatous in 1, definitely sarcomatous in 3 and questionable in 1. The diagnosis in the latter cases was
based mainly on the spindle-shape of the cells. I t must be pointed out, however, that, as Ewing emphasized, in the growth of carcinoma the relationship
between epithelium and stroma may be such that the epithelial cells become
elongated and of spindle form. Spindle-cell sarcoma of the thyroid, however,
is a well known entity (Kaufmann).
We have encountered three tumors of the thyroid which were diagnosed
as carcinoma simplex, but which have some earmarks of sarcoma, at least of
those described in the older literature as round-cell sarcomas. Karsner states
that it is difficult to 'distinguish between the large round-cell sarcoma and an
epithelial tumor. I n our tumors there was a new formation of many round
cells with hardly any recognizable cytoplasm. The nuclei were round or
oval and densely stained, and there was no intercellular stroma. Because of
the fact that in an occasional section it seemed that the tumor cells were derived from the lining cells of the very few recognizable follicles, because in
many instances the nuclei were of outspoken vesicular type, and finally because
of the absence of an intercellular stroma, it seems evident that these tumors
were epithelial in nature.
Tongue: There is only one carcinosarcoma of the tongue in this series
(Schwarz). This tumor was in its superficial areas a typical squamous-cell
carcinoma. In its deeper layers were found, besides squamous cells, small
groups of spindle-shaped and pleomorphic anaplastic tumor cells apparently
inseparable from the stroma. The stroma in the deeper layers showed chronic
inflammatory changes. The anaplastic pleomorphic cells in the deeper layers
were considered by the author to be sarcomatous in nature. This tumor
obviously must be classified as squamous-cell carcinoma with transitional-cell
features (Saphir).
Pharynx: Harvey and Hamilton reported one instance of carcinosarcoma
occurring in the hypopharynx. Though no definite objections against such
a diagnosis can be stated, it seems very likely that this tumor may also be interpreted as a primary squamous-cell carcinoma with transitional-cell features,
Esophagus: Fourteen carcinosarcomas of the esophagus are shown in
Table VI. Eight of these present essentially similar characteristics. Here,
as in the tongue, the superficial layers were typical squamous-cell carcinomas,
while in the deeper layers, besides the obvious carcinoma cell groups, smaller,
347
CARCINOSARCOMA
TABLE
VI : Carcinosarcomas of Esophagus *
No.
Year of
Publication
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1904
1908
1912
1918
1921
1921
1928
1929
1930
1930
1931
1932
1932
1934
* Kobb’s report referred
Author
v. Hansemann
Herxheimer
Sokolbw
Herxheimer
Lang
Lang
Cilotti
Scarff
Kahlstorf
Kahlstorf
Carnevale-Ricci
Kesch
Bosenberg
Blackburn
Metastases
0
0
0
0
0
0
+0
0
0
0
0
0
0
to as carcinosarcoma (Inaug. Dis. Frankfurt 1921) was not available
t o us.
diffusely infiltrating spindle-shaped and pleomorphic anaplastic tumor cells
were noted. Histologic evidence of chronic productive inflammation was
present in the areas of pleomorphism. The anaplastic and spindle-shaped
cells in the deeper layers were considered sarcomatous.
In case No. 6 a pedunculated tumor had been previously removed surgically. This consisted microscopically of spindle cells and pleomorphic
tumor cells which were interpreted as sarcomatous. Subsequent autopsy revealed at the base of the excised tumor diffusely infiltrating squamous cells
with much anaplasia and also spindle-shaped tumor cells which were interpreted as of a sarcomatous nature.
In a previous study, mentioned above, a number of tumors of the oral
cavity and esophagus were reported which showed both features, squamous
cells and transitional cells. The latter, in these locations as in other regions,
were often spindle-shaped and could have been confused on superficial examination with sarcoma cells. From our observations it seems that the
spindle cells in the tumors described in the literature, which were interpreted
as sarcoma cells, were more likely transitional epithelial cells. These tumors,
reported as carcinosarcomas, with the possible exception of case 6 seem to us,
therefore, to be carcinomas and may be designated as “ predominantly transitional-cell carcinomas ” or as “ transitional-cell carcinomas with squamouscell features.”
Herzog referred to an instance of “ apparent” carcinosarcoma of the
esophagus. He pointed out the difficulties in differentiating carcinoma and
sarcoma cells in tissues which show much newly formed connective tissue,
Carnevale-Ricci’s case and also the tumor described by Cilotti seem to contain
excellent examples of transitional epithelial cells simulating sarcoma cells.
It should be mentioned, also, that Herzog implied that Herxheimer’s original
carcinosarcoma of the esophagus may perhaps be interpreted as a squamouscell carcinoma with transitional-cell features. I t is of interest to note that
the question of the possible dual origin of tumors was first suggested in con-
348
OTTO SAPHIR AND ALOYSIUS VASS
TABLE
VII: Carcinosarcomas of Stomach
Metastases
No.
Year of
Publication
Author
1
2
3
4
5
1904
1908
1923
1931
1931
Queckenstedt
I-indemann
lioesch
Gotting
Schuback
-~____~___
Site
Pylorus
Anterior wall
Fundus
Pylorus
Diffuse
Carcinoma Sarcoma
-I-
++
-
-
Mixed
-
-
-
nection with these tumors of the esophagus. Thus Herxheimer first coined
the expression, “ carcinoma sarcomatodes,” in reference to an esophageal
tumor,
Stomach: Table VII lists 5 carcinosarcomas of the stomach. Tumors 2 ,
3 , and 5 were in some regions typical adenocarcinomas. In others, however,
diffusely infiltrating anaplastic (round, spindle-shaped, oval, and irregularly
shaped) tumor cells were seen, which were considered sarcomatous. In these
areas a particularly marked degree of chronic inflammatory change was evident. In tumors l and 4 a pedunculated growth was found in the pyloric
region. These tumors consisted mainly of spindle-shaped cells and fibrous
tissue in which diffusely infiltrating anaplastic tumor cells were noted. At
and surrounding the base the tumor was a typical adenocarcinoma. The
pedunculated growths were considered by the authors sarcomatous. On reviewing these last two instances critically, it seems that these pedunculated
tumors were either fibromas or leiomyofibromas which were invaded secondarily by a primary adenocarcinoma.
The tumors of the stomach and of the large intestines which in our experience might easily be confused with carcinosarcomas are the carcinomas
of the linitis plastica type. The minute glandular structures which are seen
in these instances invading the entire wall are, on the one hand, indicative of
carcinoma, On the other hand, the infiltration of the characteristic round or
oval individual cells with barely any recognizable cytoplasm not in connection
with glandular structures may suggest sarcoma. Though the presence of cells
containing mucinous material with signet-shaped nuclei is pathognomonic of
carcinoma, these may be absent in many fields. If the diffusely infiltrating
cells with hyperchromatic nuclei and with no evidence of secretion are seen
intermingled with the adenocarcinomatous structures, and if, as is so common
in these instances, there is a large amount of newly formed connective tissue,
then it might be conceivable that on superficial examination these fields would
be confused with sarcomas and an erroneous diagnosis of carcinosarcoma be
made. Tumors 2 , 3, and 5 seem to belong in this group.
Liver: Saltykow in his review of carcinosarcomas mentioned the case of
Yamagiwa, called by the author a mixed, malignant tumor of embryonal origin,
Similar tumors collected by us (those of Philipp, Hippel, Idzumi) also fall in
this category and are obviously organoid, teratoid tumors and were so considered by the authors. They therefore fall outside the discussion.
The only carcinosarcoma available to us was that reported by Bosenberg.
This tumor occurred in a cirrhotic liver which revealed in other portions a
typical adenocarcinoma. In the more cirrhotic regions irregular spindle-
CARCINOSARCOMA
349
Fig.
I 9.
x
FIG. 17. PREDOMINANTLY
SQUAMOUS-CELL
CARCINOMA
OF ESOPK.AGCS
Note transitional type of tumor cells in addition to squamous cells. Iron hematoxylin-eosin.
120
FIG. 18. PRIMARY
SQUAMOUS-CELL
CARCINOMA
OF PYRIPORM
SINUS WITH TRANSITIONAL-CELL
FEATURES
Note chronic inflammation with fibrosis and many connective-tissue cells. Similar instances
are reported in the literature as carcinosarcoma. Iron hematoxylin-eosin. X 90
FIGS. 1 9 AND 2 0 . LINITISPLASTICA
TYPEOF CARCINOMA
OF THE STOMACH
(SAME CASE)
Note the characteristic signet-shaped cells in the right portion of Fig. 1 9 . The field in Fig. 20
may suggest sarcoma. Iron hematoxylin-eosin. X 85 and 1 2 0
FIGS. 2 1 AND 22. PRIMARY CARCINOM4 OF LUNG(SAME CASE)
The field in Fig. 2 1 suggests squamous-cell carcinoma, that in Fig. 22 transitional-cell or oatcell carcinoma. Iron hematoxylin-eosin. X 1 2 0
shaped and pleomorphic tumor cells were noted and considered by the author
sarcomatous in nature. It seems that this tumor is a simple adenocarcinoma
with individual tumor cells compressed by the connective tissue of the cirrhotic liver. Karsner has pointed out that the epithelial cells of a carcinoma
of the liver may become elongated by connective-tissue overgrowth and confused with sarcoma cells.
350
OTTO SAPHIR AND ALOYSIUS VASS
In none of the primary carcinomas of the liver which have come under
our observation were there any cell formations which could have been confused
with sarcoma.
Gallbladder: Two instances of carcinosarcoma of the gallbladder were
encountered. One was in the fundic region of the gallbladder (Kleinknecht
et al.). Foci of adenocarcinoma were found, and spindle-shaped cells which
were thought to be portions of a spindle-cell sarcoma. The authors would
not have been convinced of their sarcomatous nature within the gallbladder
had not metastases in the liver also shown carcinoma and sarcoma cells. This
may be significant because of the fact that morphologic variations of tumor
cells in metastatic growths may be marked. Another instance perhaps belonging in this group was reported by Landsteiner. This was called squamous-cell carcinoma and sarcoma, the latter probably a myosarcoma. The
metastases in the liver were sarcomatous in nature.
Pancreas: According to Claessen and Mathias, Michelsohn has described
an instance of carcinosarcoma of the pancreas. The original publication,
however, was not available to us.
L a r y n x and Lung: Of the 6 carcinosarcomas of the larynx in this series
(Table VIII) , 4 were pedunculated growths, which microscopically showed
TABLE
VIII: Curcinosarcomas of Larynx
--____
____
Year of
NO.
1
2
3
4
5
6
Publication
1894
1908
1922
1933
1936
1936
Metastases
Author
Szmurlo
Kahler
Ullmann
Iticci
Schwarz
Schwarz
Carcinoma
-
Sarcoma
-
+-
-
-
-
-
-
-
-
Mixed
-
-
-
anaplastic spindle-shaped cells lying in a dense stroma. In one of these
tumors (No. 3 ) cancroid pearls were also in evidence. At and surrounding
the base of these growths the mucosa was replaced by a typical squamous-cell
carcinoma (so interpreted by the authors). Histologic signs of chronic inflammation were evident. In the other two cases the superficial portions of
the tumor presented the typical picture of squamous-cell carcinoma (so interpreted by the authors). In other areas, where chronic inflammatory and
fibrotic changes were particularly conspicuous, anaplastic spindle-shaped and
pleomorphic tumor cells were noted. These were considered by the authors
to be sarcomatous. It seems likely that the first three tumors of the larynx
may be explained on the basis of primary carcinomas which secondarily
invaded pedunculated fibromas.
Of the 7 carcinosarcomas of the lungs (Table I X ) , tumors 1 and 4 occurred in lungs showing chronic inflammatory changes. Both presented a
typical transitional-cell carcinoma in their superficial portions, while in the
fibrotic areas anaplastic spindle-shaped tumor cells were found and interpreted
as sarcomatous. Tumor No. 6 arose from a bronchus close to the hilus, lined
by squamous epithelial cells. The superficial portions of the tumor presented
typical squamous-cell carcinoma. In the deeper regions, however, besides the
351
CARCINOSARCOMA
TABLE
IX: Carcinosarcomas of Lung
No.
Metastases
Year of
Publicat ion
Author
1908
1914
1915
1928
1929
1932
1933
Kika
Saltykow
Frank
Selye
Ogawa
Bosen berg
Nowicki
~
1
2
3
4
5
6
7
Carcinoma
Sarcoma
++
+-
++-
-
-
-
+
Mixed
+?
-
-
typical carcinomatous features, elongated, spindle-shaped and pleomorphic
cells were seen and were considered sarcomatous. Productive inflammatory
changes were particularly evident here. Tumor 7 was partly a mucinous
adenocarcinoma, while other portions showed spindle and pleomorphic cells.
These were interpreted as sarcomatous. It may be that this tumor is a true
carcinosarcoma, though the metastases were purely carcinomatous. Tumor 5
supposedly showed, in addition to carcinoma, a spindle-cell sarcoma. Though
the original publication was not available, it seems evident from a study of
an abstract of the case report that the spindle-cell sarcomatous fields were
transitional or oat-cell
carcinomatous portions. Tumor 3 showed an adenoh
carcinoma and spindle-cell sarcoma. A mere glance at the photomicrographs
accompanying the report, however, indicates that this tumor is a simple adenocarcinoma with much fibrous connective tissue. Tumor 2 was interpreted as
a large round-cell sarcoma with a few giant cells and squamous-cell carcinoma
without keratinization. The accompanying photomicrographs of the supposedly carcinoma cells do not at all depict, or even resemble, carcinoma cells.
All the lung tumors, with the possible exception of tumor 7, when reviewed critically, seem to be carcinomas. In both the larynx and the lungs, in
addition to other types of carcinoma, transitional-cell carcinomas are relatively
frequently encountered. In a previous communication it was shown that in
these laryngeal carcinomas, in addition to the transitional cells, squamous-cells
with keratinization are quite often found. I t seems clear that since transitional cells, as stated before, resemble connective-tissue cells, the finding of
transitional and squamous cells may lead to the erroneous diagnosis of carcinosarcoma. In the lungs are described tumors (Karsner and Saphir) often
called oat-cell carcinomas, which, if not identical, are very similar to transitional-cell carcinomas. Tumors of the lungs have come to our observation
in which predominantly transitional or oat-cells were found in some fields
while in others squamous cells were seen. Because of the resemblance of
these oat cells to malignant connective-tissue cells, an erroneous diagnosis of
carcinosarcoma might be made. The metastases in the lung tumors 1 and 3 ,
considered in part sarcomatous, apparently consist of transitional cells.
Urinary Tract: Of the 8 tumors of the urinary tract (Table X ) 4 arose
in the urinary bladder, 3 in the prostate, and 1 in the ureter. The tumors of
the urinary bladder were similar in histopathologic structure. Early in their
history they were diagnosed as papilloma and carcinoma. Later, often after
a history of many years, the tumors presented, besides the obvious carcino-
352
OTTO SAPHIR AND ALOYSIUS VASS
TABLE
X: Carcinosarcomas of Urinary Tract
-
No.
__--
Year of
Publication
__
1910
1912
1931
1932
1932
1933
1934
1936
~~~~~
Author
Site
'Tanton
Leuenberger
Kenner
Gabe
Rijsen berg
€'and
Ehrhardt
Schwarz
Urinary bladder
Urinary bladder
Ureter
Urinary bladder
Urinary bladder
Prostate
Prostate
Prostate
__
Metastases
~_______Sarcoma
Mixed
Carcinoma
matous features, anaplastic spindle-shaped cells of varying size, with little
intercellular substance, which cells were interpreted as sarcomatous. These
tumors are apparently purely transitional-cell carcinomas, which are known to
develop in the bladder the most bizarre anaplastic features. The long history,
the early diagnosis of papilloma and carcinoma, the obvious chronic inflammatory changes, and the lack of an intercellular fibrous network seem to indicate the probability of this interpretation. Nor do the so-called sarcomatous
metastases reported by the authors seem characteristic of sarcoma.
In the last two " carcinosarcomas " of the prostate large grcups of distinctly carcinomatous cells were evident. In addition, more diffusely infiltrating single, irregular, anaplastic, spindle-shaped tumor cells were dispersed
throughout whorls and bundles of large muscle fibers. There were also some
multinucleated giant cells with centrally located nuclei. Chronic productive
inflammatory changes were evident histologically. After a critical review of
these tumors it seems probable that they are transitional-cell carcinomas of
the urinary bladder which have invaded the prostate secondarily. The first
tumor was described as a small-cell sarcoma and early adenocarcinoma. According to the accompanying photomicrographs the " sarcomatous " portions
may be interpreted as portions of a " carcinoma solidum '' (Kaufmann) .
Kaufmann also states that transitions exist between diffusely infiltrating smallround-cell carcinomas (carcinoma solidum) and adenocarcinomas. This socalled carcinosarcoma of the prostate, therefore, seems to be similar to the type
of carcinoma mentioned by Kaufmann.
There is also on record a carcinosarcoma of the ureter. This was a pedunculated growth arising in the middle third of the ureter and hanging down
into the urinary bladder. The more distal portion of the tumor consisted of
closely packed elongated, spindle cells and a myxomatous connective tissue
with islets of cartilage. At and around the base a typical transitional-cell
carcinoma was present. Islets of carcinoma cells (so interpreted by the
author) also were noted in the proximal portion of the pedunculated mass.
This tumor was interpreted by the author as a carcincsarcoma of embryonal
origin. Although we cannot definitely deny the correctness of this diagnosis,
we may interpret this t u m x as chondromyxofibrosarcoma, invaded secondarily
by a transitional-cell carcinoma of the ureter. Thus may be explained the
presence of carcinoma cells around the base of the tumor and in its proximal
portions, and their absence in the distal portions of the pendulous mass.
Fiq. 25.
Fisj.26.
F x . 2 3 . PRIMARY
CARCINOMA
OF LUNG
Note the transitional type of tumor cells and more differentiated apparent squamous-cells.
Iron hematoxylin-eosin. X 165
FIG. 24. PRIMARY CARCINOMA O F URINARY BLADDER
Note the spindle-shaped transitional cells in the middle portion of the picture. Iron hematoxylin-eosin. X 225
FIG. 25. CARCINOMA OF URINARY BLADDER
Note the resemblance of the tumor cells of transitional type to sarcoma cells. Iron hematoxylin-eosin. X 90
FEATURES
FIG. 26. SQUAMOUS-CELL CARCINOMA O F MOUTHWITH TRANSITIONAL-CELL
Note the infiltrating transitional cells which in some instances are interpreted as sarcoma cells.
Hematoxylin-eosin. X 75
353
3 54
OTTO SAPHIR AND ALOYSIUS VASS
Transitional-cell carcinoma of the urinary bladder is one of the malignant
epithelial tumors which in many respects may resemble sarcoma. Thus, reported instances of sarcomas of the urinary bladder, such as studied by Jelm
and others, probably are not sarcomas, but transitional-cell carcinomas. In
the absence of papillary excrescences, when the fibrous cores from which the
cells arise have disappeared, the cells often become more spindle-shaped and
infiltrate the surrounding tissues in the form of clusters, or diffusely. Ewing
speaks of spindle-cell carcinoma, to indicate the peculiar form of these cells.
Carcinoma cells of this spindle shape are more commonly encountered in recurrent tumors and in tumors invading the peritoneal surface or space of
Retzius. When in some fields well preserved papillae are noted, with their
cells still clearly recognizable as transitional epithelial cells, and in other fields
transitional cells not arranged in the form of papillae, resembling sarcoma
cells, infiltrate the mucosa and muscularis diffusely, a diagnosis of carcinosarcoma may be reached. A number of tumors of this type came to our observation and only careful studies by means of serial sections revealed that
the cells first interpreted as spindle-cell sarcoma cells were transitional cells.
Gruber reported a tumor of the kidney which he called carcinosarcoma.
This is the only instance on record of this type of tumor arising in the kidney
which we have been able to find. I t seems clear, however, that the tumor in
question belongs to the Wilms tumor group. Carpi, also, according to
.Claessen and Mathias, reported a carcinosarcoma of the kidney, but in the
reference quoted, the report was not found.
Tumors in MisceZZaneous Locatiorts (Table XI) : Five carcinosarcomas of
TABLE
XI : Curcinosarcomas in Miscellaneous Locations
Year of
Publication
No.
1
2
3
4
1913
1923
1932
1932
1933
1928
1930
1921
5
6
7
8
9
10
11
.
19241930
1932
Metastases
Author
Site
Simmonds
Ferrero
Resenberg
Hecker
Bezza
%lye
Tjokonegoro
Claessen and
Mathias
Traina
Rerger
Morax and
Kerbrat
Skin
Skin
Skin
Skin (lip)
Skin (joint fistula)
Middle ear
Nasal cavity
Salivary gland
Carcinoma
Sarcoma
....
Mixed
Maxillary sinus
Labium majus
Ciliary body
the skin,Gand one each of the middle ear, salivary gland, ciliary body, nasal
cavity, maxillary sinus, and labium majus were found in the literature. Of
those of the skin, the first showed superficially squamous-cell carcinoma
features and in the deeper regions anaplastic, spindle-shaped cells, interpreted
by the author as sarcomatous. This tumor developed in an area of dermatitis produced by x-rays. The second and third tumors were basal-cell
fi
The report by Senger, referring to a sarcoma in close relation to a lupus carcinoma, as quoted
by Bczza, could not be verified.
CARCINOSARCOMA
355
carcinomas in their superficial layers, while the deeper portions consisted of
spindle-shaped cells in an abundant connective-tissue stroma with chronic
inflammation. These portions were considered sarcomatous by the author.
The fourth tumor was a metastatic growth of a previously excised unidentified
tumor of the lip. Following excision of the primary tumor, irradiation was
applied. An apparent metastatic growth in the neck consisted in part of
typical malignant squamous cells, while in other portions there was an
abundance of newly formed connective tissue with many spindle-shaped and
pleomorphic cells, which were interpreted as sarcomatous. T o judge from
the microscopic pictures, this tumor seems to be a simple squamous-cell carcinoma. This case is referred to as carcinosarcoma of the neck. The fifth
tumor apparently arose in a joint fistula. The microscopic picture may perhaps be interpreted as squamous-cell carcinoma with basal-cell features. The
“ sarcomatous ” portions, however, seem to consist of non-malignant fibroblastic cells.
The carcinosarcoma of the middle ear occurring in a woman sixty-three
years of age, who had had otitis media with discharge since childhood, was a
squamous-cell carcinoma, in some areas exhibiting anaplastic, spindle-cell
features. The tumor of the nasal cavity can also be interpreted as a squamous-cell carcinoma with transitional-cell features.
In the study to which we have referred before (Saphir) a number of
cancers of the skin were reported which undoubtedly are similar to these skin
tumors and the tumor arising in the middle ear. I t was pointed out at that
time that in these cases we were dealing not with two primary tumors but
rather a single carcinoma with both squamous-cell and basal-cell features.
The latter may occasionally be confused with malignant connective-tissue cells.
The salivary gland tumor was found in the submaxillary region. It consisted of epithelial and connective-tissue portions and resembled a malignant
mixed tumor of salivary gland origin and was so interpreted by the author.
Three months after excision and after x-ray therapy the patient died. The
tumor had recurred and presented spindle-shaped and polymorphous, anaplastic cells, which were interpreted by the author as sarcomatous. While
this interpretation probably is correct, it seems that this tumor should not be
classified as carcinosarcoma, in view of the fact that the original neoplasm was
a mixed tumor. I t is possible, however, that the morphologic alterations
might have been caused by the intervening irradiation.
In Traina’s tumor a number of giant cells were present, apparently of
the type found in the epulis. This tumor is perhaps a carcinoma with inflammatory changes resembling a giant-cell tumor. Berger’s tumor of the
labium is interpreted by us as basal-cell carcinoma with squamous-cell features, severe chronic inflammatory changes, and much fibrosis. I t seems
likely that basal cells compressed by the fibroblastic stroma were interpreted
as sarcoma. Morax and Kerbrat’s tumor of the ciliary body was an outspoken
melanotic tumor with spindle-shaped cells and epithelial-like structures which
were interpreted as constituents of a melanotic carcinosarcoma. Such a combination, however, is often found in malignant melanotic tumors. A picture
of a similar tumor is reproduced in a paper previously mentioned (Saphir).
356
OTTO SAPI-IIR AND ALOYSIUS VASS
DISCUSSION
A review of the available literature on carcinosarcomas and an analysis
of tumors which have come to our observation which seemingly belong in thi:
group reveal that most of the so-called carcinosarcomas are neither collision
nor combination tumors but most commonly are primary carcinomas. The
individual cells either show what has been called morphologic variation or
have been distorted by chronic productive inflammatory changes within or
close to the tumor. In some instances a primary sarcoma had invaded nonmalignant epithelial structures forming inclusions which led to the erroneous
diagnosis of carcinosarcoma. Occasionally a so-called carcinosarcoma could
be interpreted as a primary carcinoma which had invaded a benign connectivetissue tumor.
I n a study to which reference has been made (Saphir), it was brought
out that various types of carcinomas may show distinct variations of the individual cells or groups of cells to such an extent as to render their classification difficult. In many instances which had the appearance of squamous-cell
carcinoma, islets of basal cells were found. Nests of transitional cells were
present in squamous-cell carcinomas arising from mucous membranes, particularly in the region of the oral cavity, esophagus, and cervix uteri. Vice
versa, islets of squamous carcinoma cells were often present in carcinomas
which at first appeared to be purely transitional-cell carcinomas. As stated
previously, in some instances the transitional cells in these squamous-cell
carcinomas were elongated and spindle-shaped, and could easily be confused
with sarcoma cells. Thus, there are morphologic similarities between carcinosarcomas as described in the literature and squamous-cell carcinomas with
“ transitional-cell features.”
The morphologic similarity of certain kinds
of transitional cells of the bladder to spindle-cell sarcomas is well known and
was discussed previously. I t was mentioned that Ewing speaks of “ spindlecell ” carcinomas of the urinary bladder. In short, it seems obvious that a
number of carcinosarcomas reported in the literature can be interpreted on the
basis of such morphologic cellular variations. It is of interest to note that
Martin and Stewart emphasized that transitional-cell carcinomas, because
of the fact that some of the tumor cells are spindle-shaped, are sometimes
erroneously referred to as carcinosarcomas. They mentioned particularly
tumors of the larynx, lungs, esophagus, bladder, and urethra,
A number of other reported carcinosarcomas are seemingly primary carcinomas complicated by chronic productive inflammatory changes. Ewing
pointed out that malignant tumors, when altered by inflammation, etc., tend
to assume indifferent structures in which most of the original features are
lost and from which it is usually hazardous to attempt to reach any conclusion
regarding histogenesis. Inflammatory changes were most marked in those
organs exhibiting cyclic changes, such as the uterus, breast and thyroid, and,
conversely, those organs were more commonly the site of these tumors. I t
seems quite plausible that connective-tissue proliferation with hyalinization,
etc., resulting in compression of epithelial cells of tumors, may lead to morphologic changes in these cells and perhaps constitutes a factor in the faulty
CARCINOSARCOMA
3 57
diagnosis of these tumors. These changes are most evident in the thyroid
gland and may explain some of the “ carcinosarcomas ” in this organ.
It is clear that tumors of organs which easily become infected, such as the
oral cavity, cervix uteri, etc., also quite frequently show evidence of chronic
inflammation. Still another factor causing chronic inflammatory changes of
and around a primary tumor is x-ray irradiation, which was applied according
to the history of some of the cases. I t seems evident that chronic inflammatory changes with fibrosis, and also with the presence of many lymphocytes,
may have suggested a connective-tissue tumor or occasionally a lymphosarcomatous element in primary carcinomas.
It is, of course, true that chronic productive inflammatory changes are not
necessarily confined to “ carcinosarcomas,” but are present in many malignant tumors. The inflammation seen in the latter, however, is more commonly acute or chronic exudative in character rather than of a long-standing,
chronic productive type, such as is almost invariably seen in “ carcinosarcomas.” This is borne out particularly in the linitis plastica type of carcinoma, which was found to be the underlying malignancy in some of the
reported instances of ‘‘ carcinosarcoma ” of the stomach.
In another group of tumors it seemed unquestionable that a carcinoma had
invaded a previously existing benign connective-tissue tumor. The carcinoma
was present in those organs in which connective-tissue tumors are not rare,
particularly in the uterus and larynx, but also in the esophagus and stomach.
Histologically the benign tumors were myomas, fibromyomas, and fibromas.
Because of the occasional difficulties in differentiating malignant carcinoma
cells from the cells of young benign connective-tissue tumors, and because of
the presence of giant cells in some of these instances, the cells of the connective-tissue tumors were interpreted as portions of a sarcoma. I t is known,
however, that giant cells are not unusual in benign myofibromas. Also it is
easily understood that because of the pressure of the fibers of the benign
connective-tissue tumors, the carcinoma cells secondarily become altered, are
compressed, and resemble sarcoma cells. Close inspection of the histologic
pictures accompanying the case reports invariably lead us to believe in the
carcinomatous nature of these cells.
In two instances, both of which presented adenomatous structures within
spindle-cell sarcomas, the adenomatous structures were interpreted by the
authors as blastomatous. These adenomatous structures were not found,
however, in the recurrences, which were sarcomatous. From the accompanying illustrations it was not apparent that these adenomatous structures were
malignant, whereas the connective-tissue tumor was obviously a sarcoma.
Thus, a study of the carcinosarcomas reported in the literature and our
own pertinent experience indicate that many of these tumors are not carcinosarcomas, but single malignant tumors, predominantly carcinomatous.
SUMMARY
One hundred and fif ty-three so-called carcinosarcomas reported in the
literature are recorded. A critical review indicates that the carcinosarcomatous nature of these tumors is very questionable. Perhaps only three
358
OTTO SAPHIR AND ALOYSIUS VASS
or four of them may be designated as true carcinosarcomas. A number of
our own observations are given on tumors which were at first thought to be
carcinosarcomas but which, on more careful examination, were interpreted as
primary carcinomas.
In evaluating the seemingly sarcomatous features of the reported carcinosarcomas, the following complicating factors which play a r61e in the alteration of the fundamental histologic appearance of the tumors must be considered: variations of carcinoma cells, some of which assume spindle shapes
and may be interpreted as cells of a spindle-cell sarcoma, a factor particularly
true of (‘ squamous-cell carcinomas with transitional features ”; marked anaplasia of the carcinoma cells; chronic inflammation which either leads to
morphologic changes of tumor cells, produces much connective tissue which
may be regarded as part of a malignant connective-tissue tumor, or provokes
a lymphocytic reaction sometimes taken as the lymphosarcoma component
of some of these tumors; the invasion of a benign connective-tissue tumor by
a carcinoma. Other instances of so-called carcinosarcomas are believed to be
sarcomas which had invaded normal or metaplastic epithelial structures, the
latter being interpreted as the “ carcinomatous ” elements.
REFERENCES
ALBRECHT,
H.: Frankfurt. Ztschr. f . Path. 2: 191, 1909.
H., A N D HECHT,V.: Wien. klin. Wchnschr. 22: 1737, 1909.
ALBRECHT,
APOLANT,
H.: Verhandl. d. deutsch. path. Gesellsch. 12: 3, 1908.
ASADA,T.: Gann 16: 2 2 , 1922.
BALTZER,
H.: Virchows Arch, f . path. Anat. 259: 252, 1926.
BASSAL,L., A N D RIGAUD:Arch. de mCd. expCr. 25: 491, 1913.
BENTHIN,W.: Beitr. z. path. Anat. u. z. allg. Path. 60: 163, 1914-15.
BERCER,L.: Bull, de 1’Assoc. franc. pour 1’Ctude du cancer 19: 292, 1930.
A N D BOTELHO:
Gynbc. et obst. 1: 139, 1920.
BERCERET
BEZZA,P.: Tumori 7 : 601, 1933.
G.: St. Bartholomew’s Hosp. J. 41: 138, 1934. Abst. in Am. J. Cancer 23:
BLACKBURN,
167, 1935.
BOSENBERG,
M.: Ztschr. f . Krebsforsch. 36: 416, 1932.
BRUN,A.: Centralbl. f. allg. Path. u. path. Anat. 33: 51, 1922.
F. : Oto-rho-laring. ital. 1 : 221, 1931.
CARNEVALE-RICCI,
CARPI,U.: Gazz. med. ital. 61: 471, 1910. Quoted by Claessen and Mathias.
CILOTTI,M.: Pathologica 20: 608, 1928.
CLAESSEN,
M., A N D MATHIAS,E.: Beitr. z. klin. Chir. 123: 584, 1921.
COENEN,
H.: Beitr. z. klin. Chir. 68: 605, 1910.
COHN,M.: Virchows Arch. f . path. Anat. 259: 30, 1926.
DAL Pozzo, G.: I1 cancro 2: 217, 1931. Quoted from Abstract in Ztschr. f. Krebsforsch.
36: 9, 1932.
DALPozzo, G.: I1 cancro 3 : 156, 1932.
S.: Rev. franq. de gynCc. et d’obst. 30: 883, 1935.
DANIEL,G., A N D LAZARESCO,
DORSCH:Ueber Carcinom und Sarkom derselben Mamma, Inaug. Diss., Wiirzburg 1896.
Quoted by Coenen.
EHRHARDT,
W.: Centralbl. f . allg. Path. u. path. Anat. 59: 355, 1934.
EHRLICH,
P., AND APOLANT,
H.: Centralbl. f . allg. Path. u. path. Anat. 17: 513, 1906.
EHRLICH,
P., AND APOLANT,
H.: Berl. klin. Wchnschr. 44: 1399, 1907.
EWINC,J.: Neoplastic Diseases, W. B. Saunders Co., Philadelphia, Ed. 3, 1928.
EWINC,J.: Am. J. Path. 5: 99, 1929.
FERRERO,
V.: Arch. per le sc. med. 46: 285, 1923.
CARCINOSARCOMA
359
FORSSNER,
H.: Arch. f. Gynak. 87: 445, 1909.
FRAENKEL,
E.: Monatschr. f . Geburtsh. u. Gynak. 14: 684, 1901.
FRANK,
A,: Schmidt’s Jahrb. d. ges. Med. 322: 149 (Erg. H.), 1915.
FRANKL,
0.: Arch. f. Gynak. 124: 67, 1925.
v. F R A N Q U0~.,: Ztschr. f . Geburtsh, u. Gynak. 47: 211, 1902.
GABE,J.: Brit. J. Urol. 4: 145, 1932.
DE GAETANI,G.: Pathologica 23: 197, 1931.
GIAVOTTO,
G.: Pathologica 13: 95, 1921.
GOTTING,P.: Frankfurt. Ztschr. f. Path. 41: 107, 1931.
GOLDSTINE,
M. T.: Am. J. Obst. & Gynec. 30: 143, 1935.
R. B.: Am. J. Path. 9: 525, 1933.
GREENBLATT,
GRUBER,B.: Deutsche mil-arztl. Ztschr. 45: 404, 1916.
HAACKE,R. : Ueber Geschwulstbildungen endothelialen Ursprungs in eincm Ovarialkystom,
Inaug. Diss., Halle, 1901.
v. HANSEMANN,
D.: Berl. klin. Wchnschr. 2 7 : 353, 1890.
D.: Ztschr. f . Krebsforsch. 1: 183, 1904.
v. HANSEMANN,
HARBITZ,F.: Beitr. z. path. Anat. u. z. allg. Path. 62: 503, 1916.
T. D.: Edinburgh M. J., 42: 337, 1935.
HARVEY,
W. F., A N D HAMILTON,
HECKER,
H.: Deutsche Ztschr. f. Chir. 237: 177, 1932.
HEDREN,
G.: Centralbl. f . allg. Path. u. path. Anat. 26: 265, 1915.
HELWIG,F. C.: Arch. Path. 4 : 162, 1927.
HERRENSCHMIDT,
A.: Bull. et mkm. SOC.anat. 9 (6th series): 300, 1907.
HERXHEIMER,
G.: Beitr. z. path. Anat. u. z. allg. Path. 44: 150, 1908.
HERXHEIMER,
G.: Centralbl. f. allg. Path. u. path. Anat. 29: 1, 1918.
HERZOG,
G.: Verhandl. d. deutsch. path. Gesellsch. 17: 346, 1914.
HIPPEL,B.: Virchows Arch. f . path. Anat. 201: 326, 1910.
IDZUMI,G.: Arch. f. klin. Chir. 100: 1181, 1913.
N. S.: Monatschr. f . Geburtsh. u. Gynak. 7: 295, 1898.
IWANOFF,
JAFFE,R. H.: Surg. Gynec. & Obst. 37: 472, 1923.
JELM, C. E.: J. Urol. 33: 599, 1935.
JESSUP, D. S. D.: Proc. New York Path. SOC.23: 21, 1923.
KAHLER,0.: Deutsche med. Wchnschr. 34: 644, 1908.
KAHLSTORF,
A,: Fortschr. a. d. Geb. der Kontgenstrahlen 42: 421, 1930.
H. T.: Human Pathology, J. B. Lippincott Co., Philadelphia, 1926.
KARSNER,
KARSNER,
H. L., AND SAPHIR,0 . : Am. J. Path. 6: 553, 1930.
C.: Deutsche Ztschr. f . Chir. 11: 401, 1879. Quoted by Loeb.
KAUFMANN,
E. : Lehrbuch der speziellen pathologischen Anatomie, Walter de Gruyter & co.,
KAUFMANN,
Berlin and Leipzig, 1931 (9-10 Aufl.).
KERBIRIOU
AND DANEL:J. d. sc. mkd. de Lille 1 : 175, 1897. Quoted by Helwig.
KETTLE,E. H . : Lancet. 2 : 750, 1912.
KETTLE,E. H.: Pathology of Tumors, H. K. Lewis & Co., London, Ed. 2, 1925.
KIDNER,F. C.: Boston M. & S. J. 157: 836, 1908.
KIKA, G.: Gann 2 : 84, 1908.
KLEE,F.: Zentrlbl. f. Gynak. 46: 166, 1922.
KLEINKNECHT,
A., NESSMANN,
V., AND OBERLING,CH.: Bull. Assoc., franc. p. l’ktude du
cancer 20: 476, 1931.
KLEINSCHMIDT,
R.: Ztschr. f. Krebsforsch. 18: 126, 1922.
KREIBIG,W.: Virchows Arch. f. path. Anat. 256: 649, 1925.
E.: Beitr. z. path. Anat. u. z. allg. Path. 44: 88, 1908.
KROMPECHER,
V. KUBINYI,P.: Arch. f. Gynak. 97: 237, 1912. Quoted from Bezza.
KUCKENS,H.: Beitr. z. path. Anat. u. z. allg. Path. 80: 116, 1928.
E.: Rev. mCd. de la Suisse Rom. 18: 702, 1898. Quoted by Loeb.
KUMMER,
KUNSEMULLER,
G. : Uber ein Karcinosarkom der Mamma, h u g . Diss., Breslau, 1920.
LANDSTEINER,
K.: Ztschr. f . klin. Med. 62: 427, 1907.
LANG,F. J.: Virchows. Arch. f . path. Anat. 234: 485, 1921.
R., A N D PERROT,
M.: Bull. Assoc. franq. p. 1. Ctude du cancer 20: 283, 1931.
LEROUX,
LEUENBERGER,
S. G.: Deutsche Ztschr. f . Chir. 114: 1, 1912.
3 60
OTTO SAPHIR AND ALOYSIUS VASS
LEWIN, C.: Verhandl. d. deutsch. path. Gesellsch. 12: 50, 1908.
LINDEMANN,
A.: Ztschr. f. Krebsforsch. 6: 419, 1908.
LIPPMANN,
H.: Ztschr. f. Krebsforsch. 3: 293, 1905.
LOEB,L.: Am. J. M. Sc. 125: 243, 1903.
F. W.: Am. J. Cancer 24: 273, 1935.
MARTIN,H. E., AND STEWART,
MASON,R., AND WELLS,H. G.: J. Cancer Research 13: 207, 1929.
MEYER,H.: Centralbl. f. allg. Path. u. path. Anat. 30: 291, 1919.
MICHELSOHN
: Ein Fall von primarem Sarcocarcinom des Pancreas, Inaug. Diss., Wiirzburg,
1894. Quoted from Claessen and Mathias.
MILONE:Arch. per le sc. med. 48: 112, 1925-26. Quoted from Pan&.
MONDOR,
H., GAUTHIER-VILLARS,
P., AND GOTTESMANN,
H.: Ann. d’anat. path. 13: 783, 1936.
AND KERBRAT:
Bull. SOC.d’opht. de Paris, 1932, p. 186. Abst. in Am. J. Cancer 18:
MORAX
195, 1933.
MOTTA,G.: Ann. di ostet. 48: 611, 1926.
F.: Policlinico (sez. chir.) 16: 429, 1909.
NASSETTI,
NEBESKY,0.: Arch. f. Gynfk. 73: 653, 1904.
NIEBERGALL,
E.: Arch. f. Gynak. 50: 129, 1896.
NOWICKI,W.: Virchows Arch. f . path. Anat. 289: 564, 1933.
OESTERLIN,
E. J.: Ann. Surg. 91: 610, 1930.
OGAWA,K.: J, Orient, Med. 11: 133, 1929. Abst. in Ztschr. f . Krebsforsch. 31: 53, 1930.
ORTH,J.: Charitk Ann. 34: 357, 1910.
PAN&C.: Tumori 7: 244, 1933.
PASTERNACK, J. G., AND WIRTH,J. E.: Am. J. Path. 12: 423, 1936.
PERRIER,
H.: Rev. mCd. de la Suisse Rom. 32: 447, 1.912.
PHILIPP,P. W.: Jahrb. f. Kinderh. 18: 353, 1905.
QUECKENSTEDT,
H. : Ueber Karzinosarkome, Inaug. Diss., Leipzig, 1904. Quoted by Claessen and Mathias.
QUIN, J. S.: Irish J. M. Sc., 1929, p. 579.
RENNER,M. J.: Surg., Gynec. & Obst. 52: 793, 1931.
RESCH,B.: Centralbl. f. allg. Path. u. path. Anat. 53: 275, 1932.
RICCI, B.: Oto-rho-laring. ital. 3: 259, 1933.
ROCADE VIGALS,R.: Compt. rend. SOC.de biol. 110: 729, 1932.
ROESCH,H.: Virchows. Arch. f . path. Anat. 245 : 9, 1923.
ROLANDO,
S.: Arch. ital. di chir. 2 5 : 502, 1930.
ROTHACKER,
A.: Ztschr. f . Krebsforsch. 12: 39, 1913.
RUSSELL,B. R. G.: J. Path. & Bact. 14: 344, 1910.
SALTYKOW,
S.: Centralbl. f . allg. Path. u. path. Anat. 16: 547, 1905.
S.: Verhandl. d. deutsch. path. Gesellsch. 17: 351, 1914,
SALTYKOW,
SAILER,S.: Am. J. Cancer 31: 183, 1937.
SAPHIR,0.: Morphologic Variations of Tumor Cells, To be published.
SCARFF,G. R.: J. Laryng. & Otol. 44: 324, 1929.
J.: Monatschr. f . Geburtsh. u. Gynak. 78: 287, 1928.
SCHIFFMANN,
SCHLAGENHAUFER:
Centralbl. f. allg. Path. u. path. Anat. 17: 385, 1906.
SCHMINCKE,
A.: Monatschr. f. Geburtsh. u. Gynak. 39: 841, 1914.
SCHONE,G.: Virchows. Arch. f. path. Anat. 195: 169, 1909.
SCHUBACK,
A.: Ztschr. f . Krebsforch. 33: 126, 1931.
SCHWARZ,
H.: Frankfurt. Ztschr. f . Path, 49: 247, 1936.
SEHRT,E.: Beitr. z. Geburtsh. u. Gynak. 10: 43, 1905-06.
SELYE,H.: Med. Klin. 24: 1197, 1928.
SEMB,C.: Acta chir. Scandinav., vol. 64, Supp. X, 1928. Quoted by Dal Pozzo.
SENGER:Berl. klin. Wchnschr. 48: 662, 1911. Quoted by Bezza.
SHIMODA:Acta dermat. 9: 187, 1927. Quoted by Bezza.
SIMMONDS,
M.: Ztschr. f . Krebsforsch. 13: 307, 1913.
SLYE,M., HOLMES,H. F., A N D WELLS,H. G.: J. Cancer Res. 10: 175, 1926.
SOKOLOW,
A. N.: Centralbl. f . allg. Path. u. path. Anat. 23: 91, 1912.
STEIN,A.: Monatschr. f. Geburtsh. u. Gynak. 36: 417, 1912.
STROPENI,
L.: I1 cancro 3: 236, 1932. Ahst. in Am. J. Cancer 20: 906, 1934.
CARCINOSARCOMA
361
SUSSI,L.: Policlinico (sez. chir.) 38: 514, 1931.
SZMURLO:
Medicyna, 29. Jahrgang, Warschau 1894. Quoted by Ullmann, H.
TAKANO,
N . : Arch. f. klin. Chir. 103: 155, 1913.
TANTON:
Bull. et mCm. SOC.de chir. de Paris 36: 57, 1910. Quoted by Leuenberger, S. G.
TJOKONEGORO,
HADJIDHARMO:
Nederl. Tijdschr. v. Geneesk. 74: 4792, 1930.
TRAINA,
S.: Tumori 11 : 36, 1924.
ULLMANN,
H.: Ztschr. f . Hals-, Nasen- u. Ohrenh. 1: 130, 1922.
VIRCHOW,R. : Die krankhaften Geschwiilste, A. Hirschwald, Berlin, 1864-65, Vol. 2.
WAECHTER,
H. : Uber Carcino-Sarcome der Schildruse, Inaug. Diss. Freiburg i. Br. 1909.
WAELLE,H.: Ueber das Carcinoma sarcomatodes der Mamma, Inaug. Diss. Zurich, 1913.
WEHNER,E.: Frankfurt, Ztschr. f. Path. 16: 167, 1915.
WELLS,H. G.: J. Path. & Bact. 7 : 357, 1901.
WILLIS,R. A,: The Spread of Tumors in the Human Body, J. & A. Churchill, London, 1934.
WOGLOM,
W. H.: J. Cancer Res. 3: 47, 1918.
WOGLOM,
W. H.: Arch. Path. 2: 709, 1926.
YAMAGIWA,
IS.:Verhandl. der japon. path. Ges. I. Quoted by Saltykow in Verhandl. d.
deutsch. path. Gesellsch. 1 7 : 351, 1914.
ZOLLNER,F.: Deutsche Ztschr. f. Chir. 219: 321, 1929.