Ovarian Tumors Histogenesis and Systemic Effects H. FOX, M.D., San Francisco * Sufficient histologic and embryologic information is now available to allow for a reasonably satisfactory histogenic classification of ovarian neoplasms. The majority of these tumors are derived from germ cells, sex cord-mesenchyme or the germinal epithelium. A few, such as the Brenner tumor, must stiU be classed as being of "uncertain histogenesis," for the cell (or tissue) of origin is not yet known. It is now realized that many ovarian neoplasms previously considered to be endocrinologically inert may, on occasion, be associated with either estrogenic or androgenic activity. This applies particularly to Brenner tumors, mucinous cystadenomas and serous cystadenomas. The common factor associated with such endocrine activity is luteinization of the tumor stroma. Ovarian neoplasms usually manifest only local symptoms, but they may, on occasion, be associated with such unusual systemic effects as hypoglycemia, hypercalcemia or a hemolytic anemia. THIS REVIEW PRESENTS a classification of primary accepted for no other hypothesis can explain either ovarian tumors that is based on current histogene- the dominance of the gonads as a site for such tic concepts; it is not proposed to discuss each neoplasms or the finding that whilst ovarian tera- tumor but to consider briefly only those neoplasms tomas are invariably sex chromatin positive, those about which fresh information has accrued in occurring in the testis may show either a male or recent years and to review also recent data con- a female sex chromatin pattern.46 The question cerning systemic manifestations of ovarian tumor. whether a teratoma develops by fusion of two with neoplastic transformation of the A. Classification and Histogenesis of Ovarian Tumors haploid cells resulting product or by parthogenetic division of Germ cell tumors haploid cells with later chromosomal reduplica- The germ cell origin of teratomas is now widely tion has been much debated; this debate has been stimulated by the fact that teratomas usually have From the Department of Obstetrics and Gynecology, University of California Medical Center, San Francisco. a diploid chromosome content but it has been Supported by United States Public Health Service International out2 that neither of these two hypotheses Research Fellowship (1-F05-TW-1275-01). pointed Submitted 26 April 1968. need be invoked inasmuch as the ovarian germ Reprint requests to: Department of Obstetrics and Gynecology, Uni- versity of California Medical Center, San Francisco 94122. cells, until immediately before ovulation, are in CALIFORNIA MEDICINE 295 TABLE 1.Classification of Ovarian Tumors concept is supported by the finding that, in chil- 1. Of germ cell origin dren, the average age at which teratocarcinomas i. Dysgerminoma occur is lower than that at which benign teratomas ii. Teratoma are found, whilst the average age of patients with a. Undifferentiated Embryonal carcinoma an embryonal carcinoma is lower still.I The embry- b. Partially differentiated onal carcinoma is formed of undifferentiated cells Embryonic differentiation-teratocarcinoma Extraembryonic differentiation-choriocarci- similar to those found during the earliest stages of noma, endodermal sinus tumor embryonic development, and further maturation c. Fully differentiated may be toward or Benign extraembryonic embryonic cystic teratoma structures, the former giving rise to an endodermal struma ovarii sinus tumor or a choriocarcinoma. The endo- mucinous cystadenoma With malignant change dermal sinus tumor is formed of loose, vascular squamous cell carcinoma connective tissue admixed with "glomerular-like" malignant melanoma thyroid adenocarcinoma structures; it was originally thought that this neo- carcinoid tumor plasm was a mesonephroma but the suggestion50 2. Origin from sex cord mesenchyme that the histological appearances represent a repro- i. Ovarian differentiation Granulosa cell tumor duction of stages in the phylogenetic development Thecoma of extraembryonic membranes is now more fa- Lipid cell tumor ii. Testicular differentiation vored. According to this interpretation the con- Arrhenoblastoma nective tissue is homologous with the allantoic Sertoli cell tumor Hilar cell tumor mesoderm of the labyrinthine placenta whilst the iii. Mixed testicular-ovarian differentiation glomeruloid structures are the homologs of the Gynandroblastoma yolk sac endodermal sinus of the rodent placenta. 3. Origin from coelomic (germinal) epithelium i. Via tubal differentiation Partial maturation of a teratomatous neoplasm serous cystadenoma into embryonic or adult structures gives rise to a serous cystadenofibroma serous cystadenocarcinoma teratocarcinoma or "solid teratoma." Such tumors ii. Via endocervical differentiation are usually frankly malignant both clinically and Mucinous cystadenoma Mucinous cystadenocarcinoma histologically but a few solid teratomas appear suf- iii. Via endometrial differentiation ficiently histologically mature to hardly merit the endometriosis term endometroid carcinoma "teratocarcinoma," and it has been claimed35 adenoacanthoma that neoplasms of this type may behave in a rela- clear cell adenocarcinoma tively benign fashion. It is, however, extremely mixed mesenchymal sarcoma rhabdomyosarcoma difficult to exclude, in any large solid tumor, the 4. Origin from non-specialized stroma presence of small foci of undifferentiated or poorly Fibroma differentiated cells, and this may account for the Fibrosarcoma Lipoma experience of those4 who have found that even Hemangioma histologically innocuous solid teratomas run a 5. Mesonephric origin highly malignant clinical course. It does appear, Mesonephroma though, that if the only malignant constituent of an 6. Lymphoma otherwise mature teratoma is neuroglial tissue, the Lymphosarcoma Hodgkin's Disease prognosis is relatively go&d.27 Burkitt tumor The benign cystic teratoma (dermoid) is very 7. Of uncertain origin common but the histologic appearances may be Brenner tumor Gonadoblastoma altered by the partial or complete overgrowth of Adenomatoid tumor one particular tissue. This is usually accepted as the mode of development of a struma ovarii, and the prophase of the first meoitic division and are it is probable that some mucinous cystadenomas therefore diploid. develop in a similar fashion by overgrowth, with- The embryonal carcinoma, the teratocarcinoma in a teratoma, of gastrointestinal type epithelium. and the benign cystic teratoma are now considered This is suggested by the fact that a proportion of as simply representing different stages along the such tumors contain argyrophil and argentaffin maturation pathway of a single neoplasm, and this cells in numbers that are otherwise only seen in the 296 OCTOBER 1968 * 109 * 4 gastrointestinal tract.14 It is not implied that all adrenocortical tissue. An origin of this tumor from mucinous cystadenomas are teratomatous in origin; adrenal rests, although often proposed, has never indeed, the majority contain no argentaffin or argy- been demonstrated and it has been suggested20 rophil cells and -almost certainly arise from the that it is really a luteinized thecoma developing germinal epithelium via a process of metaplasia usually against a background of stromal hyper- and endocervical differentiation. plasia. Recently, though, it has been shown48 that Malignant change- occurs in about 1.5 percent lipid cell tumors usually contain an admixture of of benign teratomas38 and usually results in- a cell types, some resembling hilar cells and others squamous cell carcinoma; occasionally an adeno- adrenocortical cells. This has prompted the sug- carcinoma may develop and rarely a malignant gestion that the tumors are derived from medullary melanoma.6 Mesenchymal malignant lesions, such ovarian mesenchyme that is capable of transform- as a chrondosarcoma,'8 can develop in benign tera- ing into either of these two cell types. tomas and a small number of granulosa cell tumors Germinal (coelomic) epithelial tumors have been shown to originate in ovarian "der- moids."52 Thyroidal adenocarcinoma may arise This group requires little comment, for the abil- in a struma ovarii16 and carcinoid tumors can de- ity of ovarian germinal (coelomic) epithelium to velop from gastrointestinal or bronchial epithelium undergo metaplasia into various types of Mullerian contained in a benign teratoma.' epithelium is well documented.36 Ovarian endo- metriosis may develop in other ways but it is prob- Sex cord-mesenchymal tumors able that metaplasia accounts for a proportion of The, origin of granulosa cell tumors and theco- cases and that, in such cases, endometriosis can be mas from sex cord-mesenchyme is now widely ac- considered as a benign neoplasm.36 -Malignant cepted, although whether the sex cords them- change in ovarian endometriosis is probably not selves are of mesenchymal or epithelial origin is uncommon, for in recent years it has become in- still debated.32 It is possible that granulosa cell creasingly apparent that the endometroid carci- tumors may also develop from atretic Graafian noma is one of the commoner malignant ovarian follicles.29 neoplasms.26 This tumor is morphologically iden- tical with the uterine endometrial adenocarcinoma The indifferent, gonad of the early embryo has and almost certainly originates in a focus of en- the potential to develop into either a testis or an dometriosis.43 ovary. This ambivalency is retained by sex cord- The clear cell carcinoma of the ovary was for-