THE MERICAN JOURNAL of CANCER a Continuation of the Journal of Cancer Research

THE MERICAN JOURNAL OF CANCER A Continuation of The Journal of Cancer Research VOLUMEXXXIII JULY, 1938 NUMBER3 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 car- cinomatous or sarcomatous elements, the stromal or epithelial portions respec- tively 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 at- tempts 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. PRIMARYDUCT CARCINOMA OF BREAST. HEMATOXYLIN-EOSIN.X 85 FIGS.12 AND 13. METASTASTSIN OVARY OF PRIMARYDUCT CARCIXOMA OF BREAST(FIG. 11) Note the round tumor cells. Hematoxylin-eosin. X 75 and X 160 FIGS.14 AND 15. Two AREAS IN PRIMARYCARC~NOMA OF THYROID Note the spindle shape of the carcinoma cells in Fig. 15. Hematoxylin-eosin. X 75 FIG. 16. PRIMARYCARCINOMA 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 stimu- lating 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 trans- formation 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 care- fully studied tumors, principally epithelial, more than one type of apparently epithelial element was often present. In some tumors, particularly those re- ferred 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 TABLEI: Location of 153 Carcinosarcomas Reported in the Literature - Uterus. ............. ..... 36 Lung ......... ................. 7 Tube ................................. 2 Kidney ................... ................... 7 Urinary bla Breast ....................... 32 Ureter.. ........... .............1 Thyroid gland, ........................ 17 Prostate. ....................... ............ 1 Skin.. .... ....................... 5 Esophagus ....................... 14 Middle ear.. ........... 5 Salivary gland. ................... ........ 1 Labium majus.. ................ 1 Gallbladder. ........................... 2 Maxillary sinus. ............ ......................... 1 Nasal cavity ...................... 1 Larynx. .......... 6 Ciliary body. ..... .............. 1 Hypopharynx .......................... 1 not they were single tumors. It 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 THE LITERATUREAND PERSONALOBSERVATIONS This review is by no means complete, but it covers most of the publica- tions in the American, English, French, German, and Italian literature. In the study of the reported tumors, we were concerned only with those which, although presenting apparently mixed characteristics, were obviously not 4 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. In our interpretation of the fundamental char- acter 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 pro- jected 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. CARCINOSAkCOMA 335 TABLE11; Chrcinosarcomas of the Uterus Date

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