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Home , Adenomatoid tumor, Luteoma, Mucinous cystadenoma

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 . The majority of these tumors are derived from germ cells, sex cord-mesenchyme or the germinal . 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 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 . whether a 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 is now widely tion has been much debated; this debate has been stimulated by the fact that teratomas usually have From the Department of 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. occur is lower than that at which benign teratomas ii. Teratoma are found, whilst the average age of patients with a. Undifferentiated Embryonal an 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 sinus tumor or a . The endo- mucinous With malignant change dermal sinus tumor is formed of loose, vascular admixed with "glomerular-like" malignant thyroid structures; it was originally thought that this neo- 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 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 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 serous cystadenoma into embryonic or adult structures gives rise to a serous cystadenofibroma serous teratocarcinoma or "solid teratoma." Such tumors ii. Via endocervical differentiation are usually frankly malignant both clinically and 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 that neoplasms of this type may behave in a rela- clear cell adenocarcinoma tively benign fashion. It is, however, extremely mixed mesenchymal difficult to exclude, in any large solid tumor, the 4. Origin from non-specialized stroma presence of small foci of undifferentiated or poorly differentiated cells, and this may account for the 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 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 . This ambivalency is retained by sex cord- The clear cell carcinoma of the ovary was for- mesenchymal structures in the mature ovary and is merly thought to be of mesonephric origin and was shown by the development of tumors containing often referred to as an "ovarian hypernephroma"; structures morphologically similar to testicular recently, however, it has been demonstrated that tissue. The tubular arrhenoblastoma is a parti- these tumors are simply histologic variants of en- cularly well differentiated form of this tumor and dometroid .42 This is not surpris- contains easily recognizable Sertoli cells.24 In less ing, for in many areas of the body well differentiated arrhenoblastomas the resem- may, on occasion, show a clear cell pattern, and blance to testicular tissues is less apparent, but the supposition that tumor cells of this type are hilar cells are present in many cases and it is now diagnostic of a renal or mesonephric type lesion is clear that these are the homolog of testicular Ley- incorrect. dig cells.24 Pure hilar cell tumors also occur, but The rare mixed mesodermal sarcoma of the if the presence of Reinke crystalloids is insisted ovary is identical with that more commonly arising upon as a diagnostic criterion the number of proven in the endometrium and is thought to develop in cases is small.12 The bisexual potential of ovarian pre-existing ovarian endometriosis: 10 Carcinosar- sex cord mesenchyme is perhaps seen most clearly comas of the ovary are merely variants of this in the gynandroblastoma, which contains elements tumor whilst overgrowth of one particular tissue histologically resembling both arrhenoblastoma in a mixed sarcoma may give rise to such curiosities and granulosa-cell thecoma patterns. as a rhabdomyosarcoma37 or osteogenic sarcoma47 Reported series of lipid cell tumors have often of the ovary. included examples of hilar cell tumors. If these are excluded, however, a well characterized neoplasm Tumors of non-specialized stroma remeins which, histologically, often resembles These tumors are similar to those occurinng

CALIFORNIA MEDICINE 297 elsewhere in the body, although, with the exception islands of Brenner tissue closely resemble transi- of the fibroma, they are surprisingly uncommon. tional epithelium, and this is seen even more It is doubtful if a true morphologic distinction can clearly in the rare malignant Brenner tumors be drawn between a thecoma and a fibroma; the which mimic very closely transitional cell carci- constituent cells are identical at both the light and nomas. The well known fact that Brenner tumors electron microscopic level" and the presence or often contain mucinous columnar epithelium has absence of free fat has not been found to be a been compared with the frequent occurrence of reliable differentiating feature.7 this phenomenon in the urinary tract, where it is seen in such conditions as cystitis glandularis.45 Mesonephric tumors The gonadoblastoma40°' contains a mixture of A mesonephric origin has been disproved for germ cell and sex cord mesenchymal derivatives both the "Schiller mesonephroma" and the clear and characteristically is formed of mingled areas cell carcinoma of the ovary, whilst the evidence of dysgerminoma and granulosa cell tumor or suggesting that the adenomatoid tumor is a meso- arrhenoblastoma. This tumor occurs almost en- nephric neoplasm is far from convincing.21 There tirely in patients with dysgenetic gonads and this, is, however, a rare ovarian tumor for which meso- together with the impossibility of reconciling the nephric histogenesis appears likely. This tumor is histologic features with an origin from a single cell characterized by the presence of tubular struc- type and the benign nature of the lesion, suggests tures, and eosinophilic cells set in a loose that this may be a hamartoma rather than a true edematous stroma.54 The contained tubular struc- neoplasm. tures resemble closely the normal vasa efferentia Adenomatoid tumors, although seen more com- of the male and, as these latter are derived from monly in the and Fallopian tubes, do occa- mesonephric tubules, it has been suggested that sionally occur in the ovary.22.55 They were origi- the ovarian mesonephroma is similarly derived.54 nally classed as lymphangiomas or endotheliomas, but in recent years an origin from mesonephric or Lymphoma mesothelial tissue has been more favored.22.49 Per- The ovary is not infrequently involved in dis- haps the most satisfactory suggestion has been that seminated malignant lymphomas,25'" but it has these neoplasms are derived from Mullerian duct been doubted whether primary lymphomas of the mesenchyme and that they are benign "Mullerian ovary exist. There have been, however, well docu- mesenchymomas."'21 This theory explains the fre- mented cases of lymphosarcoma9 and Hodgkin's quent presence of fibers in adeno- disease3 that were apparently confined to the matoid tumors, a finding that is not satisfactorily ovary. Burkitt's tumor very frequently involves the accounted for by any of the other histogenetic , and, although this disease is seen most theories. commonly in Africa, examples of ovarian lym- phomas having a histologic appearance identical B. Systemic Effects of Ovarian Tumors with the African cases have occurred in temperate Endocrine effects zones.44 In the past, a clear distinction has usually been drawn between "functioning" and "non-function- Tumors of debatable histogenesis ing" ovarian tumors, but in recent years this dis- The histogenesis of the Brenner tumor remains tinction has become progressively blurred by the an enigma. The theory that this neoplasm develops recognition that many neoplasms previously con- from Walthard's rests fails to reconcile the disparity sidered as functionally inert may be accompanied between the anatomic disposition of such rests and by evidence of either estrogen or androgen effect, the site of Brenner tumors. Other suggestions have more commonly the former.32'39 This has been included an origin from germ cells, from germinal particularly noted with Brenner tumors, muci- epithelium, from the rete ovarii, from follicular nous cystadenomas, serous cystadenomas and structures or from gonadal stroma, but perhaps the adenocarcinomas (and is also quite common in most acceptable hypothesis is that the tumor is metastatic ovarian deposits of gastrointestinal formed of urinary tract epithelium, this arising adenocarcinomas). The common factor linking either from mesonephric remnants or by meta- these disparate neoplasms is believed to be plasia of the germinal epithelium.45 Certainly, the luteinization of the tumor stroma, and there is

298 OCTOBER 1968 * 109 * 4 usually a good correlation between this mor- tissue and that the histologic features of Hashi- phologic change and endocrine effect.39 It has been moto's disease have been noted in a struma suggested that, in these tumors, the ovarian stroma ovarii.13 undergoes luteinization because it reacts to any Carcinoid tumors developing in a benign cystic expanding lesion as it would to a developing teratoma may secrete serotonin and be associated follicle,19 and this has prompted the hypothesis with a partial "carcinoid" syndrome,11 for in many that stromal luteinization (and hence endocrine of the reported cases the patients have had hot effect) is greater in multifocal lesions, Brenner flushes together with blotchiness or discoloration tumors, for example-because of the greater sur- of the skin; bowel disturbances have been noted face area presented by such tumors to the ovarian in occasional cases but heart lesions have not been stroma.39 The fact that such tumors may show clinically apparent (although in one case endocar- either estrogen or androgen effect denotes the en- dial fibrosis was noted at autopsy). No case of docrine flexibility of the ovarian mesenchyme, metastasis of an ovarian carcinoid has been re- and this is further reflected by the finding that corded and this contrasts with the intestinal car- tumors usually considered as feminizing may, on cinoids, in which symptoms of the "carcinoid" occasion, have a virilizing effect and vice versa.39 syndrome only appear when metastatic deposits are present. It has been suggested that this dis- Unusual systemic effects crepancy is due to the entry of serotonin directly Most ovarian neoplasms manifest only local into the systemic circulation via the ovarian vein symptoms but a few are accompanied by systemic in the gonadal cases without having to pass first clinical side effects that, whilst clearly related to through the portal circulation as is the case with the presence of the tumor, are difficult to explain. the intestinal neoplasms. Thus, recurrent attacks of hypoglycemia have been of the ovary are, of course, well noted in association with ovarian fibromas and known for their association with Meigs' syn- ,'5'30 although analysis of these drome, although in fact this syndrome may com- neoplasms has failed to detect any insulin-like plicate a wide variety of benign ovarian tumors. It substance. Similarly, hypercalcemia has been re- is of interest that ovarian fibromas may, in some corded in several cases of ovarian carcinoma,5,33 cases, be an integral part of the genetically deter- despite the absence of bone secondaries and with- mined multiple basal cell syndrome8 for, in out any parathyroid-like substance being isolated a recent report of this rare disease, three of the from the tumor. In these unusual cases the meta- five patients discussed had fibromas of the ovary. bolic disturbance has disappeared after removal of the tumor. REFERENCES A rare feature of ovarian neoplasms is the con- 1. Abel, M. 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F.: Mesonephroma of ovary. cell hyperplasia with special reference to excretion, J. Obstet. Tumor of Mullerian origin related to the endometroid carcinoma, Gynaec. Brit. Comm., 72:285-291, 1965. Cancer, 20:1405-1417, 1967. 18. Heath, L. P.: Chrondosarcoma of the ovary arising in dermoid 43. Scully, R E., Richardson, G. S., and Barlow, J. F.: The devel- cyst, Harper Hosp. Bull., 25:169-173, 1967. opment of malignancy in endometriosis, Clin. Obstet. Gynec., 9:384. 19. Hughesdon, P. E.: Thecal and allied reactions in epithelial 411, 1966. ovarian tumors, J. Obstet. Gynaec. Brit. Comm., 65:702-709, 1958. 44. Seed, P. G.: Burkitt's tumor in Britain, J. Obstet. Gynec. Brit. 20. Hughesdon, P. E.: Ovarian lipoid and theca cell tumors: their Comm., 73:808-811, 1966. origins and interrelations, Obstet. Gynec. Survey, 21:245-288, 1966. 45. Sternberg, W. H.: Non-functioning ovarian neoplasms, In The 21. Jackson, J. R.: The hisoogenesis of the "adenomatoid" tumor Ovary, ed. H. G. Grady and D. E. Smith, Williams and Wilkins, of the genital tract, Cancer, 11:337-350, 1958. Baltimore, 1963, p. 209. 22. Jones, E. G., and Donovan, A. J.: Adenomatoid tumor of the 46. Stevens, L. C.: The biology of teratomas, In Advances in Mor- ovary versus mesothelial reaction, Amer. J. Obstet. Gynec., 92:694- phogenesis, ed. M. Abercrombie and J. Brachet, Academic Press, New 698, 1965. York and London, 1967, Vol. 6, p. 1. 23. Krause, D. E., and Stembridge, V. A.: Luteomas of , 47. Stone, L. M., and Wyatt, J. Y.: Osteogenic sarcoma of the Amer. J. Obstet. Gynec., 95:192-206, 1966. ovary, Amer. J. Obstet. Gynec., 64:422, 1952. 24. Langley, F. A.: "Sertoli" and "Leydig" cells in relation to 48. Taylor, H. B., and Norris, H. J.: Lipid cell tumors of the ovarian tumors, J. Clin. Path., 7:10-17, 1954. ovary, Cancer, 20:1953-1962, 1967. 25. Lathrop, J. C.: Malignant pelvic lymphoma, Obstet. Gynec., 49. Teilum, G.: Histogenesis and dassification of mesonephric tu- 30:137, 1967. mors of the female and male genital system and relationship to benign 26. Long, M. E., and Taylor, H. C.: Endometroid carcinoma of the so-called adenomatoid tumors (). A comparative hisco- ovary, Amer. J. Obstet. Gynec., 90:936-950, 1964. logical study, Acta Path. Microbiol. Scand., 34:431-481, 1954. 27. Malkasian, G. D., Symmonds, R. E., and Docherty, M. B.: 50. Teilum, G.: Endodermal sinus tumor of the ovary and testis. Malignant ovarian teratomas, Obstet. Gynec., 25:810-814, 1965. Comparative morphogenesis of the so-called "Mesonephroma ovarii" 28. McAndrew, G. M.: Haemolytic anaemia associated with ovarian (Schiller) and extraembryonic (yolk sac allantoic) structures of the teratoma, Brit. Med. J., 2:1307-1308, 1964. rat's placenta, Cancer, 12: 1092-1105, 1959. 29. McKay, D. G., Hertig, A. R., and Hickey, W. F.: The histo- 51. Teter, J.: A new concept of dassification of gonadal tumors genesis of granulosa and theca cell tumors of the human ovary, Obstet. arising from germ cells (gonocytoma) and their histogenesis, Gynae- Gynec., 1:125-136, 1953. cologia (Basel), 150:84-102, 1960. 30. Michael, C. A.* Pelvic fibroma causing recurrent attacks of 52. Thompson, J. P., Dockerty, M. B., and Symonds, R. E.: Granu- hypoglycemia in a post-menopausal patient, Proc. Roy. Soc. Med., losa cell carcinoma arising in a cystic teratoma of the ovary. Report of 59:835, 1966. a case, Obstet. Gynec., 28:549-552, 1966. 31. Minkowitz, S., Friedman, F., and Henniger, G.: Xanthoganu- 53. Toker, C.: Theca cell tumor, Amer. J. Obstet. Gynec., 100: loma of the ovary, Arch. Path., 80:209-213, 1965. 779-784, 1968. 32. Morris, J. M., and Scully, R. E.: Endocrine Pathology of the 54. Wade-Evans, T., and Langley, F. A.: Mesonephric tumors of Ovary, C. V. Mosby Co., St. Louis, 1958. the female genital tract, Cancer, 14:711-719, 1961. 33. Noenincux, F., Six, R., and Laethem, V.: Tumeur maligne 55. Williamson, H. O., and Moore, M. P.: Ovarian and para- d'ovaire a effet hypercalcemiant et phosphaturique, Acta Clin. BeIg. ovarian adenomacoid tumors. Case reports, Amer. J. Obstet. Gynec., 17-406-415, 1962. 90:388-394, 1964. 34. Norris, H. J., and Taylor, H. B.: Nodular theca-lutein hyper- 56. Woodruff, J. D., and Marley, R. L.: Struma ovarii. Demon- plasia of pregnancy (so-called "pregnancy luteoma"), Amer. J. ain. stration of both pathologic change and physiologic activity: report of Path., 47:557-566, 1967. four cases, Obstet. Gynec., 9:707-719, 1957. 35. Novack, E. R.: Solid teratomas of the ovary; with respect to five 57. Woodruff, J. D., Castillo, N., and Novack, E. R.: Lymphoma cases, Amer. J. Obster. Gynec., 56:300-310, 1948. of the ovary. A study of 35 cases from the ovarian tumor registery of 36. Numers, C. von: Observations on metaplastic changes in the the American Gynecological Society, Amer. J. Obstet. Gynec., 85:912- germinal epithelium of the ovary and on the aetiology of ovarian endo- 918, 1963. metriosis, Acta Obstet. Gynec. Scand., 44:107-116, 1965. 58. Yan, L. T., Ruzzki, C., Busch, S., and Leitholid, S. L.: Ovarian 37. Payan, H.: Rhabdomyosarcoma of the ovary. Report of a case, neoplasm associated with autoimmune hemolytic anemia, Amer. J. Obstet. Gynec., 26:393-395, 1965. Obstet. Gynec., 95:207-211, 1966.

CARCINOMA OF THE NASOPHARYNX IN CNESE MEN "In San Francisco we have a large Chinese population. We consider that any Chinese male who comes to us with a blocked ear has a carcinoma of the naso- pharynx until proved otherwise. Actually, it's about 20 times as common in Can- tonese-Chinese (which is the type we have) as it is in the population at large; so that in every case and certainly in the male Chinese, it is absolutely imperative to have a good look, not just a passing glance with a mirror, at the nasopharynx." -ROBERT C. MCNAUGHT, M.D., San Francisco Audio-Digest Otorhinolaryngology, Vol. 1, No. 1

300 OCTOBER 1968 * 109 * 4