Recent progress in ovarian cancer

R E C E N T PROGRESS IN OVARIAN CANCER Robert E. Scully, M.D.*

Abstract This article reviews recent progress in the classification of ovarian cancer and summarizes c u r r e n t knowledge o f the gross and microscopic pathology, prognosis, and surgical treatment of specific forms o f this disease. Emphasis is placed on t.be comparative value of conservative and more radical operations in the m a n a g e m e n t of unilateral cancers in y o u n g women.

With the apparent decline in incidence of invasi~:e carcinoma o f tim cervix, investigators in the field of gynecologic malignant disease have been t n r n i n g their attention more and more to the problem of ovarian cancer. This recent surge in interest as it affects the practicing pathologist has been predominantly on two fronts - t h e formulation of a universally acceptable classification so that more information can be obtained about tim behavior and treatment o f specific forms of the disease, and the reporting of n u m e r o u s large series of cases containing valuable data on prognosis and therapy. T h e new knowledge that lms emerged from these endeavors deserves the careful consideration of the pathologist, for he is expected not only to make a correct microscopic diagnosis using m o d e r n terminology but also to supply accurate information about the natural lfistory of a given tumor, thereby guaranteeing the possibility of optimal treatment. Tiffs review will emphasize current trends in the classification of ovarian cancer and their significance in relation to prognosis and therapy, par-

ticularly the surgical m a n a g e m e n t o f the unilateral encapsulated forms encountered in y o u n g women. CLASSIFICATION Ill 1961 a committee of tile International Federation o f Gynecology and Ob.stetrics (FIGO) formulated a classification o f the c o m m o n epithelial tumors o f the ovary, 1 and more recently a g r o u p o f pathologists appointed by the World Health Organization has been deliberating on the classification of all types of ovarian neoplasms. My modification of the incomplete FIGO and tentative W H O classifications, presented in Table 1, is based primarily on morphology and histogenesis. A h l m u g h it is admittedly imperfect because o f the imprecision o f current embryological knowledge a n d the difficulties encountered in identifying specific cell types, it has the advantages of grouping together closely related ovarian tumors, which nmy be mixed or difficult to distinguish fi'om one anotlmr,

*Pathologist,James tlomer Wright PathologyLaboratories, MassachusettsGeneral tlospital. Associate Professor, Department of Patholog}.;,Harvard MedicalSchool, Boston Massachusetts.

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HUMAN PATHOLOGY--VOLUME 1, NUMBER 1 March, 1970 and separating neoplastic types that have a dissimilar prognosis and reqnire diff e r e n t therapy. Table 2 places the various forms o f ovarian cancer in statistical perspective. T h e ranges o f incidence given for each tumor reflect to a considerable extent a lack o f uniform diagnostic criteria, which can be corrected only by continuing progress in classification. TABLE

1.. CLASSIFICATION OF OVARIAN" NEOPLASMS

1. T u m o r s of Surface-Epithelial and Ovarian-Strolnal Origin (Common Epithelial Tumors) A. Serous B. Mucinous* C. Endomctrioid l',enigu Borderline D. Clear cell Cmesonephric") Malignant E. Brenner* F. Mixed forms of A-E* G. Adenocarcinomas and undifferentiated carcinomas, othenvise unclassifiable" ti. Carcinosarcomas and malignant mixed mfillerian tumors 2. Germ Cell T u m o r s A. Dysgerminoma B. T u m o r s in teratoma group 1. Extraembryonal forms a. Endodermal sinus tumor b. Choriocarcinoma* 2. Embryonal teratomas, solid and cystic 3. Adult teratomas a. Solid b. Cystic (dermoid cyst) I. Benign 2. With malignant change 4. Struma ovarii 5. Carcinoid C. Mixed forms of A and B 1-5 3. G o n a d o b l a s t o m a - W i t h o u t and With Germinoma 4. Sex Cord-Mesenchyme Tumors (Mesenchynmmas; Gonadal Stromal Tumors) A. Of female cell types 1. Granulosa cell tumor 2. T u m o r s in fibroma-thecoma group 3. Strolual luteomat 4. Pregnancy luteomat:l: B. Of male cell types 1. Sertoli-Leydig cell tumor (arrl~enoblastoma; androblastoma) 2. Sertoli cell tumor (androblastoma tubulare) 3. llilus (Leydig) cell tumor'l" C. Of nfixed cell types (gynandroblastoma) D. Of indeterminate cell types 5. 7Fumors of Lutein, Eeydig, and Adrenocortical Types of Cells A. Strontal luteomat B. l'regnancy l u t e m n a t + , C. tlilus (t.e)dig) cell t u u m r t D. Adrenal rest tumor E. Lipoid cell tumor (of indeterntinate cell type) 6. T u m o r s Not Specific for Ovary 7. Metastatic T u m o r s A. Krukenbcrg (signet cell carcinoma) 1',. Adenocarcinoma of large intestinal origin C. Carcinoid D. Miscellaneous

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* O t h e r o r i g i q s possible. ~Classified in two c a t e g o r i e s . :~Not a t r u e n e o p l a s m .

TABLE 2. CO*IPARATIVEINCmENCEOF OVARIAN CANCERS AT O P E R A T I O N * Serous borderline tumor Serous carcinoma Mucinous borderline tumor Muciuous carcinoma Endometrioid borderline tumor Endometrioid carcinoma Clear cell carcinoma Undifferentiated carcinomas and adenocarcinomas, otherwise unclassifiable Dysgerminoma Embryonal teratoma Malignant tumors in dermoid cysts Granulosa cell tumor Metastatic carcinomas Others '

10-15% 25-35% 5-10% 5-10% 1-2% 15-20% 4-6% 5-10% 1-2% 1-2% I-2% 5-10% 4-8% 1-2%

* T h e i ) e r c e n t a g e s a r e estintates b a s e d o n t h e a u t h o r ' s e x p e r i e n c e a n d variotts s o u r c e s in t h e l i t e r a t u r e . T h e y d o n o t a p p l y to o v a r i a n c a n c e r s in the Orient, where the incidence of the common c a r c i n o m a s is l o w e r , b u t t h a t o f n m l i g n a n t g e r m cell t u m o r s is at least r e l a t i v e l y h i g l t e r .

T U M O R S OF S U R F A C E E P I T H E L I A L A N D OVARIAN STROMAL ORIGIN ( C O M M O N EPITHELIAL

TUMORS)

Tile classification o f tumors in this category depends on t h r e e - o f their att r i b u t e s - t b e epithelial . cell type, the a m o n n t of stromal c o m p o n e n t derived from the ovarian stroma, and the degree of malignancy, particularly of tbe epithelial element. The serons, mucinons, and endometrioid tnmors and the nnclassifiable forms o f carcinoma are the only ones originally inchlded by FIGO in the category o f " C o m m o n Epithelial T u m o r s o f the Ovary," but more recently, in their instructions for reporting ovarian cancers, they have added the clear cell form, to which they refer as "mesonephric." I shall present my reasons for including not only the cleat" cell but also the Brelmer tunlor.

Any of the neoplasms in this category may have either an epithelial or a stromal I)redomilmnce. T h e Brenner tumor is the only one that typically contains a larger amount of stroma than epithelium. The terms "adenofibroma" or "cystadenofibroma," preceded by "serous," "mucinous," "endometrioid," or "clear ceil," are used whenever the strolnal element forms the major portion of a neoplasm characterized by those cell types. The degree of malignancy of tumors-

RECENT PROGRESS IN OVARIAN CANCER--ScuL~.Y in tiffs group has generally been appraised according to two microscopic f e a t u r e s (1) the a m o u n t of nucleai" atypicality and mitotic activity and (9) the presence or absence o f invasion ot~tite stromai component by tlte epithelialelement. T h e latter criterion was adopted by FIGO as the primary basis for classification and has been attaining widespread acceptanceJ Accordingly, these tumors are divided into three groups: benign, possibly malignant (also called tuntors of "borderline malignanc)"'), and carcinomas. T h e borderline tumors are characterized b)',proliferative activity and nuclear abnormalities of the epithelial ceils, but not by infihrative destructive growtlt. It is important to em9 phasize, however, tlt~t tltese intermediate tumors ntay i m p l a n t / o n the peritoneum. T h e implants may iJeconte invasive, and rarely tuntors of this type metastasize by lympltatic or hematogenous routes. Nevertireless, tire diagnosis of a borderline t u m o r is made by examining the primary neoplasm witltout consideration o f whether it has spread beyond the ovary. Serous Tumors

T h e epithelial cells o f the serous tumors resemble to varying degrees those of the fallopian tube. Papillae, ciliated ceils, and p s a m m o m a bodies are commonly encountered. T h e term "serous" is

Figure 1. Serous cystadenoma of borderline malignancy.The cyst has been opened, revealing an exuberant growth of strolnal polyps and finer, more celhdar papillae.

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misleading, because althougla the fltfid secreted characteristically resembles serum, tumors in this category may also produce considerable mucus, the presence ofwltich m a y be a p r o m i n e n t feature on gross examination. T h e mucus, however, tmlike that in the mucinous cystic tumors, appears to be secreted from the free surfaces of the epithelial cells, and wlten present within the cytoplasm occupies only a small portion adjacent to the lumen. Unlike other neoplasms in the common epithelial category the serous tumors often have a surface or exophytic component, which may predominate and justify addition of the words "surface papillary" to tlte diagnosis. T h e borderline serous tumors contain not only the broad and predominantly stromai polyps that characterize papillary serous cystadenomas, but fine papillae as well (Fig. 1). W h e n the latter are closely packed or the ttnnor has an a b t m d a n t stroma, it may assume a solid form. Microscopic examination reveals epithelial cell proliferation with solid buds of neoplastic cells appearing to float.'in tlte lumens of the cysts (Fig. 2), as well as varying degrees o f nuclear atypicality and mitotic activity. Glandulai" extensions o f the epithelium may be present in the underlying stroma, but there is no true invasion, as in serous carcinomas (Fig. 3). Wlten a borderline tumor implants on the

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F i g u r e 2. Serot,s c y s t a d e n o m a o f b o r d e r l i n e malignancy. Solid b u d s o f epithelial cells have s e p a r a t e d f r o m the polyps a n d papillae, which a r e lined by stratified e p i t h e l i u m . T h e r e is no invasion o f t h e s t r o m a .

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s peritoneun~, it may invade tmderlyiug tissue, such as the m y o m e t r i u m or the wall o f tim intestine? Serous carcinomas are characterized by a solid pattern o f growth but may have cystic domponenfs as well (Fig. 4). Microscopic examination discloses stromal invasion by cellular papillae, small acini, solid epithelial masses o f varying sizes, or aggregates o f neoplastic cells With ir-

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F i g u r e 3, Serous cystadenocarcinoma. T h e r e ~s not only proliferation o f papillae into cystic spaces, but also invasion o f t h e u n d e r l y i n g s t r o m a . Occasional foci o f p s a m m o m a calcification are present.

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+.::y+:'_< regular slit-shaped lumens (Fig. 3). T h e formation o f p s a m m o m a bodies is a common feature. T m n o r giant cells are o f t e n e n c o u n t e r e d , and occasionally a portion o f the neoplasm is m a d e up o f malignant a p p e a r i n g clear cells. T h e distinction between the b o r d e r line t u m o r and the true carcinoma is m o r e meaningful f r o m a prognostic viewpoint when applied to serous tumors than to any o t h e r category o f ovarian cancer. T h e ten year survival rate in cases o f serous carcinoma has been r e p o r t e d to be only 13 per cent, whereas the c o r r e s p o n d i n g figure for b o r d e r l i n e serous cystadenomas has been 76 per cent? It is even m o r e surprising that tim ten )'ear survival rate o f w o m e n with borderline tumors that could not be completely r e m o v e d has been as high as 74 per cent.' (Most o f these w o m e n received postoperative radiation therapy.) O t h e r notable characteristics o f borderline serous t u m o r s are a generally leisurely course when clinically malignant, a t e n d e n c y to late recurrence, and rare spontaneous regression. 2 T h e accumulated observations, therefore, justify separating b o r d e r l i n e and invasive serous tumors f r o m the vimvpoint o f their natural course and prognosis. One feature o f both neoplastic types that is i m p o r t a n t in r e g a r d to t h e r a p y is bilaterality in almost twotlfirds o f the cases. 3 Since tiffs figure includes t u m o r s that Imve spread exten-

RECENT PROGRESS IN OVARIAN CANCER--ScuLLV

Figure 4. Serous cystadenocarcinoma. T h e sectioned surfaces reveal the solid n a t u r e o f the tumor.

sively, a m o r e meaningful one is tile a p p r o x i m a t e l y one-third incidence o f bilateral involvement in those cases in which t h e r e has been no extension beyond the uterus, tubes, and ovaries. 3 Mucinous Tumors

T h e s e tumors contain cells whose cytoplasm is filled with mucns, so that the linings o f the glands and cysts may resemble endocervical mucosa. In some cases, however, the presence o f goblet cells is m o r e suggestive o f intestinal epithelium, and, indeed, argentaffin cells are demonstrable in about 20 per cent o f the cases; 4 even Paneth cells have been identified on rare occasions. 5 T i l e presence o f these three e n d o d e r m a l types o f cells, as well :as the association with a d e r m o i d cyst in 5 per cent o f the cases, 6 raises the question o f a germ cell origin for some mucinous tumors. On the o t h e r band, the finding o f e n d o m e t r i o i d o r serous elements in others supports their inclusion within the category o f t u m o r s o f surfaceepithelial and ovarian-stromal origin. Placing all o f them there at the expense o f a possible histogenetic discrepancy in certain c a s e s is o f practical importance because these neoplasms have more in c o m m o n with serous and e n d o m e t r i o i d tumors than with those o f germ cell origin. A n o t h e r problem in classification

arises in cases o f p s e u d 0 m y x o m a peritonei, in which a mucocele o f tile a p p e n d i x is c o m m o n l y associated with tile ovarian " t u m o r . " In such instances it is t~ossible that tile ovarian lesion is an implant f r o m the mncocele, but again Classification in the category o f p r i m a r y mucinous t u m o r s o f tile ovary is a p p r o p r i a t e for clinical reasons. B o r d e r l i n e mucinous tumors are characterized by proliferative activity o f the epithelial cells with varying degrees o f papillosity and nuclear atypicality. Alt h o u g h a distinction can often be made between b o r d e r l i n e and truly malignant mucinous tumors on tile basis o f the absence or presence o f stromal invasion, such a differentiation is more difficult than in tile serous category. Since mucinous tumors are c o m m o n l y both multilocular and parvilocular, it may be impossible to decide in a given case whether glandtflar structures lying in tile stroma are the result o f b u d d i n g from a larger gland or cyst or reflect t r u e invasion. Because o f tiffs problem authorities on ovarian tumors have had difficulty agreeing where to draw the line between borderline and invasive mucinous tumors. I n d e e d it may b e c o m e evident in the f u t u r e that such a division is too subjective to be practical, a n d that grading on the basis o f nuclear abnormalities is a m o r e objective m e t h o d o f assessing the d e g r e e o f malignancy.

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Santesson,s nevertheless, applying the FIGO criteria, reported a 68 per cent ten year survival in cases o f borderline mucinous tumors in contrast to a 34 per cent figure for the true carcinomas) Froln the viewpoint of therapy it is important to point out that both pathologic types are much less often bilateral than their serous counterparts, invoh'ing both ovaries in only about a fifth of the cases? Also, mucinous carcinomas that have not extended beyond tlle uterus, tubes, and ovaries have been reported to be bilateral in only 10 per cent of the cases? Endometrioid Tumors

These tumors, first described by Sampson 9 moi'e than 40 years ago, but only recently named.by FIGO, are characterized by the presence of tubular glands that resemble benign or malignant glands of the uterine endometrium (Fig. 5). Endometrioid carcinomas may take the form of adenocarcinoma or adenoacanthoma, They have been confused in the past with

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Figure 5. Endometrioid carcinoma. The tumor is partly solid and partly made up of tubular glands. (• 80,) (Reprimcd by permission from Scvlly, R. E.: Classification, pathology and biologic behavior of ovarian tumors. Meadowbrook StaffJ., 1:148, 1968.)

either serous or mucinous carcinomas, or have been classified simply as "adenocarcinomas." When they have a striking papillary architectnre with inconspicuous gland formation, their resemblance to adenocarcinoma of tile endometrium diminishes and they simulate serous carcinomas; in such cases the endometrioid appearance of the epithelial cells and occasional foci of squamous differentiation may be the only clues to the correct diagnosis. Like their counterparts in the body of the uterus, endometrioid tumors o f the ovary can produce mucus, which may be considerable in amount. As in serous tumors, it is generally secreted from tile surfaces of tile cells and does not fill their cytoplasm, but occasionally small foci of a mature endocervical type of epithelium are present as well. Benign and borderline forms o f e n d o metrioid neoplasia are unusual, but true carcinomas have been reported to account for between 15 and 20 per cent of alI ovarian cancers.a, a0.1~ Some observers who have been finding a m u c h lower incidence are probably using very strict criteria and diagnosing only the well differentiated forms, whereas' those who present the higher figures are also including the poorly differentiated carcinomas in which only occasional glands of tile endometrial type are encountered. On gross examination an endometriold carcinoma may be partly or entirely solid, form a cyst with a velvety neoplastic lining, or occasionally present as an endophytic mass within an endometriotic cyst containing chocolate-colored fluid (Fig. 6). It must be emphasized, however, that other forms of cancer, especially the clear cell type, may develop in endometriotic cysts, and that such tumors should be named according to their cytologic features and not placed in tile endometrioid category on the basis of the origin alone. A problem arises in the classification of endometrioid carcinomas of the ovary, because about a third of them are accompanied by a carcinoma of the endometriu m (Fig. 7), which is generally similar in microscopic appearance?,~2 Many of the associated uterine tumors are very small) z The evidence suggests that when both organs are involved, the carcinomas are usually separate primaries: (1) the

RECENT

PROGRESS IN OVARIAN

CANCER--SC:oLLY

Figure 6. Endometrioid carcinoma arising from the epithelium o f an endometriotic c)'st. T h e opened cyst contains a cauliflower-like mass attached to the wall. T h e r e are patches of brown discoloration on the inner lining of the cyst, which was filled with chocolate colored fluid.

survival rate in cases Of e n d o m e t r i o i d carcinoma o f the ovary in the presence o f uterine cancer (44 per cent at five years) is not appreciably lower than in its absence (55 per cent at five years); 3 (2) o n e may be able to d e m o n s t r a t e dysplastic lesions elsewhere in an e n d o m e t r i n m containing

a small carcinoma, suggesting that the latter arose in situ and was not a metastasis f r o m the a c c o m p a n y i n g ovarian cancer. Some gynecologists have solved the problem o f classifying combined ovarian and uterine carcinomas by categorizing the case as ovarian if the patient p r e s e n t e d

Figure 7. Adenoacanthoma of endometrium and ovary. Tile uterine cancer did not invade the m)'ometrium. Tile patient was alive and free of disease 41/2 )'ears after hysterectomy and bilateral salpingo-o~phorectomy. (Reprinted by permission from Scully, R. E., Ricfiardsoi~, G. S., and Barlow, J. F.: T h e development of malignancy in endometriosis. Clin. Obstet. Gynoc., 9:384, 1966.)

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a b u n d a n t clear cytoplasm (Fig. 8), rich in glycogen, or hobnail cells, the nuclei o f which bulge into the lumens o f cysts o r tubules (Fig. 9). ~s Although these two cell types, which have no exact c o u n t e r p a r t s in the n o r m a l female genital tract, differ in appearance, their very c o m m o n association suggests that they are morphologic variants o f a single cell; possibly the hobnail cell is a clear cell that has discharged its contents into a lumen. Mucus may be secreted by the neoplastic cells but does not accumulate in their cytoplasm. T h e clear cell tumor, which may also exist in benign, borderline, and invasive forms, is one o f the two neoplastic types Schiller ~* n a m e d " m e s o n e p h r o m a . " Many authors lmve retained that designation o r a related term because some t u m o r s in this category resenable the renal cell carcinoma or have a p r o m i n e n t tubular architecture, and morphologically identical neoplasms are f o u n d rarely in the broad ligament, cervix, a n d vagina, sites o f m e s o n e p h r i c r e m n a n t s in the female. We consider such evidence unconvincing for a m e s o n e p h r i c origin because tumors arising in" organs r e m o t e f r o m m e s o n e p h r i c rests may contain clear cells resembling "those o f the renal cell carcinoma, or have a tubular architecture, and clear cell t u m o r s have n e v e r been p r o v e d to originate in meson e p h r i c remnants. I n d e e d the few neoplasms that have been d e m o n s t r a t e d to arise therein were not characterized by the presence o f clear or hobnail cells? s

with clinical manifestations o f that disease; if, on the o t h e r hand, the first symptoms were those o f e n d o m e t r i a l cancer, the case is so designated? This approach is probably the most practical for purposes o f r e p o r t i n g cancer statistics and comparing t r e a t m e n t at various centers, but it is m o r e logical otherwise to base one's decision on the size and extent o f the associated cancers. If, for example, the endometrial carcinoma is less than 2 cm. in diameter, is well differentiated, and no m o r e than minimally invades the myometrium, it is practically certain that the a c c o m p a n y i n g ovarian t u m o r is primary. When, on the o t h e r hand, the uterine carcinoma is larger, poorly differentiated, or m o r e invasive, a significant possibility exists that the ovarian cancer is a metastasis: G r a d i n g o f e n d o m e t r i o i d carcinomas has been helpful in d e t e r m i n i n g the prognosis in o u r e x p e r i e n c e ~z a n d that o f Santesson, s who r e p o r t e d a 62 per cent five year survival when the t u m o r was well differentiated, but only a 23 per cent survival for the h i g h e r g r a d e carcinomas. Ahnost one third o f all cases o f endometrioid carcinoma involve both ovaries, but a m o n g those that have not e x t e n d e d b e y o n d the u t e r u s , tubes, and ovaries only 13 per cent are bilateral? Clear

March,

Tumors

T h e s e tumors are characterized by the presence o f large epithelial cells with

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Figure 8. Clear cell carcinoma resembling renal cell carcinoma. (X 140.) (Reprinted by permission from Scully, R. E., Richardson. G. S.. and Barlow, J. F.: Tile development of malignancy in endometriosis. Clin. Obstet. Gynec., 9:384, 19.66.)

RECENT PROGRESS IN OVARIAN CANCER--SCULLV

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Figure 9. Clear cell carcinoma. The tubular structures are lined b)" hobnail cells and contain mucus. (x 200.) (Reprinted by permission from Scull)', R. E., and Barlow, j. F.: "Mesonephroma" of the ovary. Tumor of miillerian nature related to the endometrioid carcinoma. Cancer, 20:1405, 1967.)

Figure I0. Focus of clear cell carcinoma iu an endometrioid carcinoma. (x 290.) (Reprinted by permission from Scull)', R. E., and Barlow, J. F.: "Mesonephroma" of the ovary. Tumor of miillerian nature related to the endometrioid carcinoma. Cancer, 20:1405, 1967.)

We have recently a c c u m u l a t e d evidence that not only ovarian clear cell carcinomas but also those in the c o r p u s a n d cervix o f tile uterus a n d vagina are o f miiilerian n a t u r e a n d are related to an e n d o m e t r i a l type o f epithelium, t3"t6 (1) In a small series o f cases o f clear cell c a r c i n o m a o f tile ovary the incidence o f pelvic endometriosis was six times as high as that r e c o r d e d for ovarian c a r c i n o m a in general, lz (2) T h e patterns o f e n d o m e t r i oid a n d clear cell carcinomas m a y coexist within tile s a m e ovarian t u m o r (Fig. I0). (3) We have seen o v e r a d o z e n cases in which clear cell carcinomas have arisen f r o m the e p i t h e l i u m o f an e n d o m e t r i o t i c cyst o f tile ovary. (4) Tile clear cell carcin o m a s o f the uterine corpus usually originate in the e n d o m e t r i u m , w h e r e meson e p h r i c r e m n a n t s are not located, a n d may be" m i x e d with otherwise typical e n d o m e t r i a l carcinomas. (5) In o n e e x a m ple o f a clear cell c a r c i n o m a o f tile cervix we have f o u n d a m i x t u r e with m a l i g n a n t epithelium o f the e n d o m e t r i a l type. (6) Clear cell c a r c i n o m a o f tile vagina m a y

arise on tile b a c k g r o u n d o f a miillerian f o r m o f adenosis, t6 O n gross e x a m i n a t i o n clear cell tum o r s can be p r e d o m i n a n t l y solid or cystic. Tile solid f o r m s "may have a p r o m i n e n t f i b r o m a t o n s c o m p o n e n t in which tubules, cysts, o r solid nests containing neoplastic epithelial cells are scattered. Such t u m o r s m a y be benign, borderline, or malignant. Perhaps tile single most characteristic gross expression o f a clear cell c a r c i n o m a is a cyst filled with chocolate-colored fluid into which single o r multiple, yellow o r pale b r o w n p o l y p o i d masses p r o t r u d e (Fig. 11). Clear cell carcinomas are bilateral in less t h a n 10 p e r cent o f tile cases. T i l e five ),ear survival rate has been rep o r t e d to be 37 p e r cent? Brenner Tumor

T h i s t u m o r is characterized by cells o f a trausitional type resembling those o f tile u r i n a r y bladder; mucinous cells are also p r e s e n t in a b o u t a third of tile cases. 6 A h l t o u g h a n origin f r o m tile fete ovarii

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Figure 11. Polypoid clear cell carcinoma arising in an endometriotic cyst. There is patchy discoloration of the lining of the chocolate cyst.

has been d e m o n s t r a t e d in an occasional case, G it is preferable to place tile B r e n n e r t u m o r in the category o f t u m o r s o f surface-epithelial and ovarian-stromal origin for the following reasons: (1) continuity between the neoplastic epithelial cells and tile ovarian-surface epithelium has been

d e m o n s t r a t e d in several cases, is (2) tile f r e q u e n t presence o f mucinous cells and the occasional presence o f ciliated serous elements indicate a relationship to the mucinous and serous cystadenomas, and (3) tile cell nests o f the t u m o r are indistinguishable morphologically f r o m Walthard nests, which are e n c o u n t e r e d most often in tile serosa o f the fallopian tube and mesosalpinx, a n d are generally believed to be o f pelvic mesothelial origin. Alt h o u g h tile B r e n n e r t u m o r is almost always benign and solid with a p r e d o m i nance o f its stromal c o m p o n e n t , occasional cases containing cysts lined by actively proliferating transitional epithelium are o f borderline malignancy. Very rarely the epithelial element is cytologically malignant and invades the stromal c o m p o n e n t , but unless benign as well as malignant B r e n n e r nests can be identified, it may be difficult to be certain o f the diagnosis (Fig. 12). T o o few authentic cases o f b o r d e r l i n e and invasive B r e n n e r tumors have been r e p o r t e d to draw conclusions about their prognosis.

Mixed Forms of Common Epithelial Tumors

82

Figure 12. Malignant Brenner tumor. Two small, benign, cystic Brenner nests and one large. irregular, solid malignant nest lie in the fibromatot,s component of the tumor. (• 100.)

Ovarian neoplasms often contain mixtnres o f two or m o r e o f the five epithelial cell types just described, but it is impractical to place a turhor in the mixed category except on the rare occasion whell

R E C E N T PROGRESS IN O V A R I A N CANCER--ScuLLY

significant c o m p o n e n t s o f m o r e than one cell type are present. I f only a small portion o f the t u m o r contains a n o t h e r variety o f cell, its presence should be i g n o r e d as far as classification is concerned.

Adenocarcinomas and Undifferentiated Carcinomas, Otherwise Unclassifiable Most ovarian adenocarcinomas and undifferentiated carcinomas that cannot be specifically classified probably arise f r o m the surface epithelium, but some may be o f sex cord, germ cell, or o t h e r origin. For purposes o f classification, distinguishing a m o n g poorly differentiated tumors o f specific cell types a n d undifferentiated carcinomas may be difficult, and u n i f o r m criteria for so d o i n g have not been established. However, the prognosis o f all these tumors is very poor, and the precise classification may be o f little m o m e n t in an individual case. T u m o r s in the unclassifiable category have been reported to be bilateral in 54 per cent o f the cases 3 and in o u r e x p e r i e n c e have been associat.ed with a survival rate even lower than that o f the serous carcinoma.

Carcinosarcoma and Malignant Mixed Miillerian Tumor It has become increasingly evident that m a n y tumors previously classified as embryonal teratomas o f the ovary are actually carcinosarcomas o r malignant nfixed mfillerian tumors similar to those seen in the u t e r u s ) 9"2o Although heterologous elements such as cartilage, bone, and striated muscle may be e n c o u n t e r e d in these neoplasms, their presence can be explained on the basis o f mesoderrnal differentiation, and no e n d o d e r m a l derivatives or elements o f ectodermal origin, such as skin and n e u r o e p i t h e l i u m , can be found. Unlike the e m b r y o n a l teratoma, which occurs in children and y o u n g adtflts, the malignant mixed mfillerian t u m o r has almost ahvays been e n c o u n t e r e d in menopausal o r postmenopausal women. No patient with this type o f t u m o r has been r e p o r t e d to survive for five years. SURGICAL APPROACH TO COMMON OVARIAN CANCERS

Because borderline and invasive tumors in the c o m m o n epithelial categol-y

may be bilateral, it is advisable to r e m o v e both a d n e x a in o l d e r women even t h o u g h it appears tlmt only one ovary is involved at the time o f operation. Most snrgeons also r e m o v e the u t e r u s in such cases, but it can be conserved instead for the subsequent insertion o f radium. Seven to 8 per cent o f c o m m o n malignent epithelial t u m o r s are e n c o u n t e r e d in females u n d e r the age o f 35 years. W h e n such tumors are unilateral and encapsulated, and the preservation o f fertility is an i m p o r t a n t consideration, the path01ogist is often asked to help the s u r g e o n decide between conservative unilateral s a l p i n g o - o o p h o r e c t o m y and a m o r e radical a p p r o a c h including the removal o f both ovaries. This choice is not exclusively d e p e n d e n t on the predicted behavior o f the t u m o r i n q u e s t i o n , but also reflects the philosophy o f the surgeon and sometimes even the patient, who must balance the preservation o f fertility against a possible risk o f inadequate treatment. What is the risk o f conservative surgery u n d e r these circumstances? T h e results o f unilateral and m o r e radical surgical operations for c o m m o n carcinomas confined to a single ovary have been c o m p a r e d in two large series o f cases. Moench, 2t who analyzed cases o f " a d e n o carcinoma" o f the ovary, including "papillary cystadenomas, c a r c i n o m a t o u s cystadenomas, and solid adenocarcinomas," r e p o r t e d a 78 per cent survival a m o n g 72 patients treated conservatively and a 79 per cent survival a m o n g 67 treated m o r e radically. Munnel122 reviewed 127 cases o f ovarian cancer treated by some type o f operation that included bilateral o o p h o rectomy and 38 cases in which conservative t h e r a p y was used, but his series included examples o f ovarian cancer outside the category o f the c o m m o n carcinonms. I f one eliminates such cases, the five year survival figure for the 28 patients treated conservatively and the 105 treated m o r e radically is 75 per cent in each instance. T h e s e findings indicate at most a minimal risk in conserving an ovary that appears uninvolved at the time o f operation. Kottmeier, 3 using a different approach, concluded that the more radical operatio n in y o u n g women should be restricted to those types o f c o m m o n carcinoma characterized by a high incidence o f bilaterality. On the basis o f his figures

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HUMAN PATHOLOGY--VOLUME 1, NUMBER 1 March, 1970

84

for bilateral involvement, which have already been cited, he considers it justifiable to treat Conservatively the unilateral mucinous and e n d o m e t r i o i d tumors, w h e t h e r borderline or invasive, whereas the serous and undiffereniiated carcinomas, which are m u c h m o r e often bilateral, are preferably treated by a m o r e radical operation, including the removal o f both adnexa. He has stated that when normal a p p e a r i n g opposite ovaries are rentoved in cases o f serous carcinoma, nficroscopic foci o f t u m o r can be identified therein in a small p r o p o r t i o n , 2s but he has not e n c o u n t e r e d similar foci o f microscopic involvement in cases o f naucinous or e n d o m e t r i o i d carcinoma. A h h o u g h the b o r d e r l i n e serous tumors are often bilateral, Kottmeier believes that their good prognosis justifies i:onservative therapy in the y o u n g woman whose opposite ovary appears normal at operation. One could apply his reasoning equally well to the malignant clear cell tumors, which are u n c o m m o n l y bilateral. In opposition to conservative t h e r a p y one could cite o u r e x p e r i e n c e and that o f o t h e r observers that unsuspected microscopic foci o f ovarian carcinoma can also be f o u n d rarely in cases o f c o m m o n carcinomas o f types o t h e r than the serous and undifferentiatedY z T h e r e f o r e , one can never g u a r a n t e e that a n o r m a l a p p e a r i n g ovary is free o f involvement. B u t in the studies already mentioned, appraisal o f the opposite ovary was a p p a r e n t l y m a d e on the basis o f gross examination alone at the time o f operation. A h h o u g h the answer is not yet available, it is possible that the incidence o f u n d e t e c t e d carcin o m a in a conserved ovary would be reduced to infinitesimal if an adequate biopsy were p e r f o r m e d b e f o r e the decision to retain it was made. D e p e n d i n g on the n a t u r e o f the case and his e x p e r i e n c e , a pathologist c o n f r o n t e d with such a specimen might choose to evaluate it on tile basis o f either fi'ozen o r p e r m a n e n t section. Quick-section interpretation o f either the t n m o r or the f r a g m e n t o f opposite ovary can be ditficuh, and if there is any d o u b t about the decision to do a conservative o r m o r e radical operation, the f o r m e r should be chosen; a m o r e extensive p r o c e d u r e can ahvays be carried out later if indicated by the findings on the p e r m a n e n t sections.

Although the choice o f a conservative operation in a y d u n g woman with a unilateral encapsulated cancer may be justified on a statistical basis, there are no figures to confidently guide the s u r g e o n in that direction when a unilateral t u m o r is locally a d h e r e n t o r has rupttlred. Such cases ha~,'e to be individualized, a n d the pathologist, radiotherapist, and c h e m o t h e r a p i s t may all contribute to the final decision. Needless to say, it is essential for the surgeon, with the help o f the pathologist, to determine the e x t e n t o f the neoplasm and, as far as possible, the completeness o f its removal.

G E R M CELL T U M O R S

With tile exceptions o f the various types o f cancer that arise in d e r m o i d cysts, malignant germ cell t u m o r s are almost ahvays e n c o u n t e r e d in children and y o u n g adults, and the selection o f optimal t h e r a p y d e p e n d s on a knowledge o f the behavior o f each variety.

Dysgerminoma T h e d y s g e r m i n o m a is c o m p o s e d o f germ cells that have not differentiated to f o r m e m b r y o n i c or extraembryonic structures. Its stroma is almost always infiltrated with lymphocytes and often contains g r a n u l o m a s similar to those o f sarcoid. Grossly, the t u m o r may be firm or fleshy, and cream colored o r pale tan; both its external and sectioned surfaces may be lobulated (Fig. 13). A small proportion o f dysgerminomas arise in sexually abnormal individuals, particularly those with p u r e o r mixed gonadal dysgenesis or testicular feminization. In 5 to 12 per cent o f cases both ovaries are invoh.ed s'24"2~ and the five year survival rate is between 70 and 90 per cent. 3' 2a-26

Endodermal Sinus Tumor This is tile second type o f neoplasm that Schiller called " m e s o n e p h r o m a , ''~4 bfit most pathologists now consider it a variety o f g e r m cell t u m o r u n r e l a t e d to the mesonephros. Tile term " e m b r y o n a l carcinoma" has been commonly used, 27 ~ l t is less specific than " e n d o d e r m a l sinus

RECENT PROGRESS IN OVARIAN CANCER--ScuLLY

Figure 13. D)'sgerminoma. The sectioned surface is pale and [obulated. Small discrete foci of necrosis are visible.

t u m o r '~s a n d is misleading because the t u m o r Ires a distinctive p a t t e r n differing f r o m those o f the c o m m o n varieties o f testicular e m b r y o n a l carcinoma. Microscopically, the e n d o d e r m a l sinus t u m o r is c o m p o s e d o f e m b r y o n a l cells fining a network o f spaces. T h e most specific feature, which is not seen invariably, is the presence within s o m e o f the spaces o f isolated papillary projections containing single blood vessels a n d having a p e r i p h e r a l fining o f neoplastic cells (Fig. 14). T h e s e formations, which had been c o n s i d e r e d m e s o n e p h r i c glomeruli by Schiller, ~4 were later s h o w n to be e l o n g a t e d on longitudinal section. ~9 T h e y were finally i n t e r p r e t e d by T e i l u m zs as recapitulating a yolk sac s t r u c t u r e tlmt is well d e v e l o p e d in the labyrinthine placenta o f the r o d e n t a n d Ires b e e n known for years as an e n d o d e r m a l sinus. An even m o r e c o m m o n f e a t u r e o f this t u m o r is the presence o f both intracelhdar a n d extracellular hyaline bodies r e s e m b l i n g Russell bodies. O t h e r findings are solid zones o f t u m o r cells, .g!ands tlmt m a y be lined by m u c u s - c o n t a i n i n g cells a n d cysts, interp r e t e d by T e i l u m as yolk-sac vesicles. W h e n , on r a r e occasions, these vesicles f o r m the m a j o r portion o f the n e o p l a s m (polyvesicular vitelline t u m o r ) , its g e r m cell origin has often g o n e unrecognized. 2s O n gross e x a m i n a t i o n the e n d o d e r m a l sinus t u m o r differs f r o m the d};sgermin o m a in b e i n g m o r e yellow a n d friable

and having areas o f h e m o r r l l a g e a n d gelatinous necrosis (Fig. 15); cystic deg e n e r a t i o n is o f t e n present. E n d o d e r m a l sinus t u m o r s are bilateral in less t h a n 10 p e r cent o f the cases. 3~ No five year cures

Figure 14. Endodermal sinus tumor. A papillar)" projection lined by embr)'onal cells and containing a central capillary protrudes into one of a network of cystic spaces lined by neoplastic cells. (• 300.) (Reprinted by permission from Scull)', R. E.: Germ cell tumors of the ovary and fallopian tube. In Meigs, J. v., and Sturg'is, S. H.: Progress in Gynecology~ New York, Grnne & Stratton, Inc., 1963, Vol. 4.)

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H U M A N P A T H O L O G Y - V O L U M E 1, NUMBER 1 March, 1970

Figure 15. Endodermal sinus tumor. Extensive degenerative changes are visible on the sectioned surface.

lmve b e e n r e c o r d e d in t h e literature, a l t h o u g h I a m a w a r e o f an u n r e p o r t e d case.

Choriocarcinoma T h i s very rare, lfighly m a l i g n a n t tum o r , wlfich m a y be ,'issociated with sexual precocity, can arise as a f o r m o f t e r a t o m a , f r o m an o v a r i a n p r e g u a n c y , o r as a metastasis f r o m a c h o r i o c a r c i n o m a o r i g i n a t i n g elsewhere.

Embryonal Teratoma B e c a u s e solid t e r a t o m a s a r e usually m a l i g n a n t a n d cystic t e r a t o m a s a r e a l m o s t always b e n i g n , it has b e e n c u s t o m a r y to use the gross characteristics o f these n e o plasms to d e s i g n a t e t h e m . H0w,~ver, their d e g r e e o f m a t u r i t y , as j u d g e d by m i c r o scopic e x a m i n a t i o n , is a m o r e logical basis f o r n o m e n c l a t u r e , f o r ii is o n this a n d n o t their gross a p p e a r a n c e that the p r o g n o s i s d e p e n d s . T h e e m b r y o n a l t e r a t o m a is

Figure 16. Embryonal teratoma. An 8 cm. solid nodule, which has been bisected, lies in the wall of a large cyst, which was lined by glial tissue. This cyst and several smaller cysts contained 24 liters of fluid.

86

RECENT PROGRESS IN O V A R I A N CANCER--SCULLY

generally p r e d o m i n a n t l y solid but may contain m a n y small cysts o r may be primarily cystic with solid areas in its wall (Fig. 16). Microscopically it is characterized by the presence o f e m b r y o n a l and adult tissues derived f r o m all t h r e e germ layers. A very unusual and poorly differentiated f o r m o f embryonal teratoma is the polyembryonic e m b r y o m a , 3t in which myriads o f early embryos make u p a large portion o f the tumor. T h e prognosis o f e m b r y o n a l teratomas d e p e n d s on their makeup. T!le ones that contain areas o f e n d o d e r n m l sinus tumor, e m b r y o n a l carcinoma, o r choriocarcinoma carry the worst p r o g n o s i s - a two year survival rate o f 13 p e r c e n t whereas those tlmt are free o f such elements and generally contain a b u n d a n t neural tissue (Fig. 17)'are associated with a two year survival rate o f 50 per cent? z T h e e m b r y o n a l teratoma is bilateral in 10 to 15 per cent o f the cases. 3z

Solid Adult Teratoma This rare t u m o r has often been confllsed with the embryonal t e r a t o m a and

misinterpreted as being malignant. It is composed entirely o f adult tissues derived f r o m all three g e r m layers? 3 Some o f the confusion in the literature r e g a r d i n g its prognosis is d u e to the inclusion o f cases m wlfich e m b r y o n a l elements such as n e u r o e p i t h e l i u m are present in addition to m a t u r e tissue. W h e n the adult solid teratoma is diagnosed according to rigid criteria, its prognosis is excellent? 2,33 Althongh a clinically malignant solid adult teratoma is a possibility, there is no convincing case o f that type in the literature. Rarely a solid t e r a t o m a o f either adult or embryonal type is associated with peritoneal implants o f m a t u r e glial tissue, but these do not a p p e a r to have a deleterious effect on the patient's longevity? 4

Cystic Adult Teratoma (Dermoid CysO T w o per cent o f cystic adult teratomas are complicated by the d e v e l o p m e n t o f a malignant t u m o r o f an adult r a t h e r than an e m b r y o n a l type. Four-fifths o f these cancers are squamous cell carcinomas. Most o f the r e m a i n d e r are sarcomas, adenocarcinomas, a n d carcinoids, but rare melanomas lmve also been rep o r t e d ? ~ A squamous Cell carcinoma originating in a cystic adult teratoma may have the a p p e a r a n c e o f a cauliflower mass within the l u m e n o f the cyst or a h a r d nodule in its wall. Malignant c h a n g e is often overlooked by tile surgeon, but should be suspected in cases in which the cyst is firmly a d h e r e n t or has areas o f nodularity, h e m o r r h a g e , or necrosis. Although 12 per cent o f dermoid cysts are bilateral, the r e p o r t e d cases o f secondary malignancy have all been unilateral. 35 T h e five year survival rate for all cancers originating in d e r m o i d cysts Ires been less tlmn 15 per cent, but for a squamous cell carcinoma confined to the ovary and removed without spillage tile r e p o r t e d figure is 63 per c e n t ? 5 No five year survivors have been r e c o r d e d a m o n g patients with a d e n o c a r c i n o m a o r sarconla. 35

Carcinoid Figure 17. Embr)'onal teratoma. Neuroepithelial rosettes lie in cellular glia. The center is necrotic. (• 100.)

Primary ovarian carcinoids arise most often f r o m respiratory o r gastrointestinal epitheliunl in a d e r m o i d cyst, but may develop within a solid teratoma o r a

87

HUMAN PATHOLOGY--VOLUME 1, NUMBER 1 March, 1970 mucinous cystic t u m o r or occur in an apparently p u r e form. an If the t u m o r is pure, it may be impossible to d e t e r m i n e its origin before p o s t m o r t e m examination, because very small primary carcinoids o f the intestine may give rise to large ovarian metastases. O f the more than 30 cases o f primary ovarian carcinoid in the literature all have been unilateral and only one has metastasizedY Several patients have died, but in no instance was the cause o f death stated to be spread o f tim t u m o r b e y o n d the ovary. About one-tlfird o f the r e p o r t e d cases o f primary ovarian carcinoid have been associated with a unique f o r m o f the carcinoid s y n d r o m e that develops in the absence o f metastases and may be c u r e d by the removal o f the ovarian mass. O n e explanation for this p h e n o m e n o n is that ovarian carcinoids, unlike those o f intestinal origin, often attain a large size, and u n d o u b t e d l y the presence o r absence o f e n d o c r i n e symptoms d e p e n d s partly on the n u m b e r o f secreting t u m o r cells. Secondly, tim h o r m o n e - b e a r i n g blood from tim ovary, tmlike that from the intestine, is not routed t h r o u g h tim liver, where the l!ormones may be inactivated. Struma Ovarii

88

Although 5 to 20 per cent o f dernmid cysts have been d e m o n s t r a t e d tO contain thyroid acini microscopically, the term "struma ovarii" should be restricted to those cases in which that type o f tissue comprises most or all o f tim t u m o r , or at least is sufficiently a b u n d a n t to be recognizable grossly. Strumas may o c c u r in p u r e f o r m o r in the walls o f d e r n m i d cysts or cystadeuomas. Malignant c h a n g e has been r e p o r t e d in approximately 5 per cent o f the cases, but most often the diagnosis Ires been based on microscopic examination alone. O f 45 cases o f so-called malignant s t r u m a in the literature, only 17 were associated with metastases. 3s-a~ C o m m o n sites o f s p r e a d were bone and the p e r i t o n e u m , where implants were sometimes cytologically benign and compatible with longevity ('!benign strumosis"). Many tumors categorized as microscopically malignant without metastasis have had carcinoid patterns, including the ribbon a r r a n g e m e n t characteristic o f hindgut carcinoid tumors (Figs. 18, 19).

Figure 18. Strumal carcinoid. Ribbons of epithelial cells growing in a carcinoid pattern merge with thyroid follicles. (• 80.) (Reprinted by permission from Morris, J. M., and Scully,R. E.: Endocrine Pathology of the Ovary. St. Lotfis,The C. V. Mosby Co., 1958.) Such patterns are rarely observed in tumors o f the thyroid gland itself. We have now seen a n u m b e r o f cases o f typical strmna m e r g i n g imperceptibly with a t u m o r resembling a carcinoid, and in two o f these have been able to identify argentaffin granules with special stains, n T h e r e f o r e , we believe that tim carcinoidlike areas e n c o u n t e r e d in some "malignant strumas" are, in fact, true carcinoids. T h e strmnal carcinoid is one o f the many fascinating examples o f teratogenesis, particularly because a primary carcinoid o f tim thyroid gland has not as yet t~een r e p o r t e d . However, tim thyroid parafollicular cells in the sheep have been shown to contain 5 - h y d r o x y t r y p t a m i n e , 41 and medullary carcinoma o f the thyroid gland Ires been r e p o r t e d to be associated with the carcinoid syndrome. 42,a3 T h a t type o f carcinoma, now thougllt to arise f r o m parafollicular cells,~3 has m o r p h o logic features in c o m m o n with carcinoid tumors, including tim presence o f intracytoplasmic granules o f similar n a t u r e on electron microscopic examination.a4, a~ T h u s , tim intimate mixture o f struma and

RECENT PROGRESS IN OVARIAN CANCER--SCuLLV

Figure 19. Strumal carcinoid. The tumor cells are arranged in winding ribbons. (• 130.) Elsewhere the epithelium of thyroid follicles merged imperceptibl)"with cells containing argentattin granules. (Reprinted b)" permission fi'om Scull)', R. E.: Germ cell tumors of the ovary. In Stt,rgis, S. H., and Taymor, M. L.: Progress in GynecologT. New York, Grune & Stratton, Inc., 1970, Vol. 5.)

carcinoid in ovarian teratomas may shed new light on the relation o f thyroid to argentaffin epithelium. I am aware o f only one case o f strumal carcinoid that has been associated with metastasis, and that patient was apparently c u r e d after operation and radiation t h e r a p y ? ~

Mixed Forms of Germ Cell Tumors T h e existence o f mixtures o f the various types o f g e r m cell t u m o r in a wide variety o f combinations deserves special emphasis. Because many o f these neoplastic types have markedly different prognoses, it is essential that the pathologist examine each gross specimen with meticulous care and sample judiciously all the areas that vary in appearance.

T H E R A P Y OF M A L I G N A N T GERM

CELL TUMORS Each type o f malignant g e r m cell t u m o r must be considered separately f r o m the viewpoint o f its therapy. T h e dysgel~minoma is highly radiosensitive and mt/y be radiocurable despite

tile presence o f extensive metastases. 3 T h e r e f o r e , an operation including tile removal o f both ovaries and subsequent radiation t h e r a p y are generally indicated when tile preservation o f fertility is unimportant or impossible. T h e t r e a t m e n t o f the unilateral encapsulated d y s g e r m i n o m a in a y o u n g w o m a n desirous o f having children, however, continues to be controversial. T h r e e fornls o f therapy have been advocated in such cases: (1) a conservative operation (unilateral o o p h o r e c tomy or salpingo-oophorectomy) alone, (2) a conservative operation followed by radiation t h e r a p y directed toward the retroperitoneal lymph nodes and away f r o m the opposite ovary, and (3) a m o r e radical operation, including the removal o f both ovaries, with or without postoperative radiation treatment. Recently analyses o f several large series have shed light on the comparative efficacy o f these t h r e e forms o f t h e r a p y (Table 3). T h e five year survival rate in one series o f patients treated conservatively without radiation was 94 per cent z4 and in another, 91 per cent. 25 T h e s e excellent resuhs do not imply, however, that ovarian function was p r e s e r v e d in every survivor, because in each series there was a recur-

89

HUMAN PATHOLOGY--VOLUME 1, NUMBER 1 March, 1970 TABLE 3. T R E A T M E N T OF U N I L A T E R A L ENCAPSULATED DYSGERMINOMA

O.T.R34 R a d i u m h e m m e t 4n A.F.I.P. 23 A.F.I.P35

Cases

Rx

Recurrence

5-Year Su~,iral

50 22 46 21

C.O.* C.O. + R. C.O. R.O.

22% 18% 22% 10%

94% 95% 91% 90%

* C . O . = c o n s e r v a t i v e o p e l ~ t i o n . R. = r a d i a t i o n therapy. R.O. = radical operation.

90

rence rate of 22 per cent, and undoubtedly reoperation or radiation therapy abolished ovarian activity, in most of those cases. The results at the Radiumhemmet,46 where conservative surgery followed by conservative radiation therapy has been utilized for the unilateral dysgerminoma (a 95 per cent five year survival and an 18 per cent recurrence rate), have not been significantly superior to those attained by conservative surgery alone. In the only large series of cases in which a more radical operation including bilateral oophorectomy was also evaluated, tile survival figure was 90 per cent, but the recurrence rate (10 per cent) was lower than in the comparable series of conservatively treated patients35 Thus, a conservative operation without subsequent radiation therapy is justifiable in a young woman with a unilateral encapsulated tumor. However, since occult neoplasm may be present in the opposite ovary, an adequate biopsy sample should be taken during the initial operation. Also, because the dysgerminoma appears to have a predilection to metastasize by tile lymphatic route, the para-aortic lymph nodes should be carefully palpated and likewise biopsy performed if enlarged. The performanc e of these two procedures, which generally have not been done in the past, should refine the selection of patients for conservative therapy. Needless to say, those women who are so treated Inust be followed with great care, especially during the first two postoperative )'ears, when the great majorit)' of recurrences take place. 24' 2~ As far as the more highly malignant forms of germ cell tumor (endodermal sinns tumor, choriocarcinoma, and embryonal teratoma) are concerned, the

literatnre discloses no obvious advantage of radical surgery when the tumor is unilateral and the opposite ovary is shown to be free of involvement on microscopic examination. Surgical cures of the endodermal sinus tumor and choriocarcinoma have been exceedingly rare and these neoplasms are not particularly radioresponsive. Recently, however, encouraging results have been attained with chemotherapy, especially when the tumors have had a prominent component of choriocai-cinoma.47 The adult forms of germ cell malig-. nant disease that are seen primarily in association with adult cystic teratomas almost ahvays occur in older woInen in the cancer age group, so that the problem of sparing the opposite ovary does not arise. However, conservative surgical therapy may be indicated in selected rare cases in young women because these types of cancer are almost always unilateral. GONADOBLASTOMA

Tile gonadoblastoma,as which can arise in an abnormal testis "as well as a dysgenetic ovary, is encountered most often in phenotypic females, who are usually virilized to some extent. It may also develop in phenotypic males. From tile viewpoint of classification, this neoplasm lies between the germinoma (dysgerminoma; seminoma) and tile sex cordmesenchyine tumors, containing not only germ cells but also elenlents derived from the gonadal sex cords and mesenchylne (Fig. 20). The sex cord components resemble imlnature Sertoli or granulosa cells, but are not specifically identifiable as either. They may grow in one or more of three patterns: surrounding the germ cells in a coronal fashion, enclosing rounded hyaline bodies, and lining the periphery of discrete nests, the centers of which are occupied by germ cells. Cells of tile Leydig or lutein type are present in tlle stromal component of the tumor in two-thirds of tile cases. Tile appearance of the neoplasm is often altered by calcification, which may be extensive and visible on x-ray films of the pelvis, by hyalinization, or in half the cases by a germ cell invasion of the stroma to form a germi-

RECENT PROGRESS IN OVARIAN CANCER--SCULL~ cases. Since tile gonadoblastoma is at least a premalignant neoplasm and the commonly associated g e r m i n o m a is a true cancer, and since the patients' gonads are useless organs, removal o f both is indicated except in possible rare cases in which one may be histologically normal. c.v " l~,

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Figure 20. Gonadoblastolna. Two discrete oval nests contain large germ cells, numerous small cells of sex cord origin, and ninny ronnded hyaline bodies. Cells resembling Leydig and lutein cells are seen outsid~ the nests. (x 250.) (Reprinted by permission from Scull)', R. E.: Androgenic lesions of the ovary. In Grad)', H. G., and Smitb, D. E.: The Ovary. International Academy of l'athology Monograph 3. Bahimore, The Williams & Wilkins Co., 1962.) noma. T h e pattern o f ' g o n a d o b l a s t o m a has n e v e r been e n c o u n t e r e d in a metastatic site, and no case o f metastatic g e r m i n o m a arising in a gonadoblastoma has been r e p o r t e d , but there are inadequate data for the conclusion that a germin0ma associated with a gonadoblastoma has an)' less malignant a potential titan a p u r e g e r m i n o m a . T h e absence o f metastases in the r e c o r d e d cases may be ascribed to the lack o f follow-up in most instances and the fact that many o f these tumors were discovered when they were snmll and asymptomatic, in the course o f operations on sexually abnormal patients. O t h e r malignant g e r m cell tumors, such as the e n d o d e r m a l sinus t u m o r and the embryonal teratoma, can also be seen in association w i t h gonadoblastomas. On gross examination the gonadoblastoma may be bard, firm, o r soft, dep e n d i n g on w h e t h e r calcification., fibrosis and hyalinization, or malignant g e r m cell overgrowth predominates. In m a n y cases the t u m o r is not recognized on gross examination o f a dysgenetic g o n a d at the time o f operation. Bilateral invoh'ement is e n c o u n t e r e d in. about one third o f the

Tiffs designation is applied to all ovarian tumors originating ultimately f r o m the sex cords, mesenchyme, o r both o f the e m b r y o n i c gonad, a9 Included in this category are t u m o r s containing, alone or in combination, granulosa cells, theca ceils, lutein ceils, collagen-producing cells o f ovarian stromal origin, Sertoli cells, Leydig cells, and all their embryonic precursors. Tile terms " m e s e n c h y m o m a " and "gonadal stromal t u m o r " have been used synonymously, but are based on the controversial assumption that the sex cords and their derivatives originate f r o m the mesenchyme, not the coelomic epithelium. Sex Cord-Mesenchyme Female Cell Types

Tumors

of

Tile only i m p o r t a n t malignant member o f this g r o u p is the granuiosa cell tumor, wlfich may contain not only g r a n u losa cells but also varying n u m b e r s o f spindle-shaped c o l l a g e n - p r o d u c i n g cells, elements resembling theca cells, and lutein ceils. A variety o f microscopic patterns may be e n c o u n t e r e d : microfollicular, macrofollicular, trabecular, cylindromatous, insular, gyriform, solid-tnbular, and sarcomatoid or diffuse. On gross examination, the t u m o r may be solid, firm, or fleshy and gray o r yellow d e p e n d i n g on its content o f lipid. Rarely it grows in the f o r m o f one or m o r e large thin-walled cysts . Perhaps its most c o m m o n gross expression, however, is a mtflticystic, partly solid mass in which the cysts are filled with fluid o r clotted blood (Fig. 21). Often one o f tile cysts has r u p t u r e d , causing h e m o p e r i t o n e u m . T h e s e findings should alert the s u r g e o n and the pathologist to the possibility o f a granulosa cell t u m o r even b e f o r e a microscopic examination has been done. Granuiosa cell tumors are bilateral in 91

HUMAN PATHOLOGY--VOLUME 1, NUMBER 1 March, 1970

Figure 21. Granulosa cell tumor. The sectioned surface of tiffs large tumor contained numerous cysts, some of which were filled with clear fltfid and others with clotted blood. (Repriuted by permission from Case Records of the Massachusetts General Hospital, Case 891961. New Engl. J. Med., 265:1213, 1961.)

92

only about 5 per cent o f tim cases. Tim five year survival rates in three large series have been 82, 84, and 97 per cent, and the ten )'ear survival rates, 73, 75, and 93 per cent? ~ Kottmeier and Santesson ~~ were able to correlate the d e g r e e o f differentiation o f the t u m o r with the prognosis; the five and ten year survival rates for the well differentiated forms (follicular and cylindromatous) were 87 and 82 p e r cent, and for the poorly differentiated (sarcomatoid) tumors, 64 and 29 per cent, respectively. O t h e r authors have f o u n d it difficult to relate th6 microscopic a p p e a r a n c e to the clinical o u t c o m e ? ~'52 T h e reason for the discrepancy between the survival figures o f Norris and T a y l o r 52 and those o f the Swedish investigators ~~ is not entirely apparent, but it may be that the American authors used actuarial survival rates, excluding patients who died postoperatively or o f i n t e r c u r r e n t disease, as well as those who were lost to follow-up. At any rate, all the figures attest to the relatively good prognosis o f patients with this tumor. Moreover, clinically evident malignancy is expressed typically in the f o r m o f local spread or recurrences that often become evident later than a five )'ear postoperative in/erval and may be curable by f u r t h e r radiation o r surgery, z~ Distant metastases are rare~ This tulnor's relmtation for being relatively benign has occasionally been m a r r e d

by an e r r o n e o u s interpretation o f an undifferentiated carcinoma or a poorly differentiated a d e n o c a r c i n o m a that superficially simulates a granulosa cell t u m o r on microscopic examination. Although it is possible that r a r e examples o f such neoplasms may be o f granulosa cell origin, the majority are probably poorly differentiated forms o f the c o m m o n epithelial tumors. T h e r e f o r e , o n e shonld be wary o f diagnosing as a granulosa cell t u m o r a carcin o m a that is anaplastic or has a highly malignant clinical course, unless unquestionable granulosa cells can be identified. Because o f its low grade o f malignancy and i n f r e q u e n t bilaterality, the unilateral encapsulated " granulosa cell t u m o r can justifiably be treated by conservative s u r g e r y in a young woman when the preservation o f fertility is i m p o r t a n t and the opposite ovary has been shown by biopsy to be free o f involvement. Most investigators advocate such an a p p r o a c h , and Sj~istedt and Wahlen s~ f o u n d that a m o n g 12 w o m e n trader the age o f 40 years wlio received this type o f t h e r a p y alone, only one died o f tim t u m o r , and in that case, 19 years after the initial operation. Occasional cases o f "malignant thecoma" have been reported, but m a n y o f these are b e t t e r interpreted as either sarcomatoid granulos,7---_"ell tuntors o r fibrosarcomas. I am'i~;~7-!aware o f an)~

RECENT PROGRESS-IN OVARIAN CANCER--SCULLY d o c u m e n t e d example of a "malignant thecoma" in which tlm neoplastic cells were typically r o u n d e d and lipid-laden and there was evidence of steroid hormone production by tlm tumor.

Sex Cord-Mesenchyme Tumors of Male Cell Types T h e term "Sertoli-Leydig cell tumor" has been chosen in preference to "arrhenoblastoma" because the latter connotes masculinization, and a n u m b e r of tumors in this category either do not function or have estrogenic effects.4a Also, the designation of the neoplasm according to its cell types is in keeping with the terminology in the female cell category. T h e Sertoli-Leydig cell t u m o r is grossly indistinguishable from tile granulosa cell tumor, but it has a greater variety of microscopic patterns, ranging from tim well differentiated tubular a d e n o m a with mature Leydig cells t h r o u g h the more c o m m o n intermediate form to the rare sarcomatoid type that resembles a fibrosarcoma. T h e Sertoli-Leydig cell t u m o r appears to be clinically malignant more often than the granulosa cell tumor, but its rarity has made difficult tile acquisition o f accurate prognostic figures. Mortality rates in the literature have ranged from u n d e r 10 to over 30 per cent of the cases? 3-5~ Inasmuch as m a n y varieties of ovarian tumor, both benign and malignant, primary and metastatic, may be associated with luteinization o f their stroma and virilization of the patient, 5G it has been suggested that the higher reported figures for malignancy may have been due to tim erroneous inclusion of carcinomas with an androgen-secreting stroma? 3 In view of tim wide range of differentiation of SertoliLeydig cell tumors it would appear theoretically possible to correlate their microscopic appearance with their prognosis, but Novak and Longz5 were unable to achieve this in a series of 1 1 1 cases from the Ovarian T m n o r Registry. W h e n these tumors exhibit malignant behavior, it is ustmlly manifested by intra-abdominal spread without tim development of distant metastases. Both ovaries are involved in less than 5 per cent of tile cases, 55 and the indications for conservative surgery are similar to those pertaining to the granulosa cell tumor.

Malignant forms of tile pure or almost pure Sertoli cell t u m o r are rare and may be difficult to distinguish from other types of carcinoma with tubular patterns unless the patient has estrogenic manifestations. No convincing example of a malignant hilus cell t u m o r has been reported.

Sex Cord-Mesenchyme Tumors of Mixed and Indeterminate Cell Types Sex c o r d - m e s e n c h y m e tumors of mixed cell types, or gynandroblastomas, have been overdiagnosed in tile literature, and the diagnostic criteria have varied from one a u t h o r to another. Since male and female cells may a p p r o a c h ' o n e another to tile point of being indistinguishable in their i n d M d u a l structure as well as their patterns of growth, tile positive identification of both in a single t u m o r depends on each having highly specific characteristics. T h e r e f o r e , in o r d e r to restore objectivity to the diagnosis of gynandroblastoma, it is suggested that any t u m o r so designated should contain (I) typical aggregates of granulosa' cells forming unquestionable Cali-Exner bodies and (2) either hollow tubules characteristic of the tubular a d e n o m a Or Leydig cells containing crystalloids of Reinke. T h e n u m b e r of reported cases fulfilling these criteria is very small. If there is any doubt about whether a tumor should be placed in the female, male, or mixed category, it should be classified as a sex cord-mesenchyme t u m o r of indeterminate cell types. Such neoplasms constitute about 10 per cent of all cases in the general category of sex cordmesenchyme tumors. T h e y have not been studied as a group, but there is no reason to believe that they differ significantly in their behavior from granulosa cell or Sertoli-Leydig cell tumors.

TUMORS OF LUTEIN, LEYDIG, A N D ADRENOCORTICAL TYPES OF CELLS

These tumors may arise from luteinized theca cells, luteinized stromal cells, or their mesenchymal precursors, from llilus cells, or possibly from adrenocortical rest ceils, but often their origin cannot be established.

93

HUMAN PATHOLOGY-VOLUME.l, NUMBER 1 March, 1970 T h e pregnancy luteoma is not a true neoplasm even though it may attain a diameter of over 15 cm. and have numerous mitoses.~7 It is best interpreted as a focus of reversible, nodular, lutein cell hyperplasia, since it appears to depend on chorionic gonadotropin stimulation for both its structural and functional integrity.57.5s The true tumors in this category are often grouped under the designation "lipoid cell tumor" or "lipid cell tumor, ''ao but I prefer to separate them as far as possible into the types listed in Table 1 on the basis of their morphologic, biochemical, and clinical features. I reserve the term "lipoid cell tumor" for those cases of undetermined origin. T h e incidence of malignancy of these tumors is estimate~l to lie between 20 and 30 per cent, but is difficult to establish because of the few series of cases in wlfich the pathologic material has been reviewed by a single group of authors. All the reported examples with acceptable crystalloids of Reinke have been benign. Clinically evident malignancy is occasionally indicated nficroscopically by the presence of nuclear atypicality and mitotic activity, but some of the benign appearing tnmors in this category have also behaved in a malignant fashion? 9 Taylor and Norris ~9 found that all six tulnors in their series that had recurred or metastasized were 8.0 cm. or more in greatest diameter; on the other baud, only eight of 16 that were cliifically benign had attained that size. These neoplasms are almost never bilateral, and therapeutic Conservatism is justifiable wlien there is no evidence of spread in a young woman.

TUMORS

94

NOT SPECIFIC FOR THE OVARY

This category includes a variety of r a r e neoplasms, the most interesting of which is the lymphoma.6~ An ovarian tumor may be the first manifestation of lymphoma, but almost always involvement of other regions of the body becomes evident either at operation or within a short time thereafter. T h e ovarian !ymphoma is sometimes mistaken microscopically for a granulosa cell tumor or a dysgerminoma, because growth in the

dense ovarian stroma may result in a pseudocarcinomatous pattern9 Ovarian involvement has become of particular interest recently because of its high incidence in cases of Burkitt's lymphoma, which is characterized by proliferation of a primitive lymphoreticular cell. Recognition of this form of lymphoma may be important because of the therapeutic effectiveness of cyclopbosphamide.61 Needless to say, if a lymphoma presents as a resectable mass or masses confined to the ovaries, surgical extirpation is indicated 9 Either radiation therapy or chemotherapy is probably also advisable even if there is no evidence of spread beyond the ovary at the time of the initial operation. METASTATIC TUMORS

Six per cent of ovarian cancers encountered by a surgeon exploring a pelvic or abdominal mass are metastases, 1 most often either Krukenberg tumors or metastatic adenocarcinomas of large-intestinal origin. Although metastases from carcinomas of the breast are colnmon among surgical specimens of the ovary, they are almost always incidental findings m a therapeutic o/5pborectomy and rarely form symptomatic masses that require surgical removal. 6z Tile term"Krukenberg tumor" should be reserved for those metastases that contain significant numbers of signet-ring cells and a cellular stroma derived from the ovarian stroma. Tiffs restriction is important because tumors with those microscopic characteristics also have distinctive gross pathologic aud clinical features. Almost all have metastasized from the stomach, but some have arisen in the breast, intestine, or another lnUCOUs-glandcontaining organ. I have seen one that spread from a signet cell carcinoma of the urinary bladder. On gross examination the Krukenberg tumor forms a solid, often reniform mass, the sectioned surface of which typically exhibits gelatinous necrosis and hemorrhage (Fig. 22). Occasionally some of the acini that may be present enlarge to form cysts lined by a low epithelium, and rarely a large, thin walled multicystic mass results. A small number of ovarian neoplasms microscopically indistinguishable from Krukenberg tumors have been in9

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RECENT PROGRESS IN OVARIAN CANCER--ScOt.LV

Figure 22. Krukenberg tumor. The sectioned surface is characterized b)" extensive necrosis and hemorrhage. t e r p r e t e d as p r i m a r y ovarian carcinomas. 6n T h e evidence for the existence o f such cases has been either a long survival after the removal o f the ovarian t u m o r or the failure to find an extraovarian p r i m a r y carcinoma at autopsy. Needless to say, a very detailed examination o f organs in which a mucinous carcinoma can originate, particularly tbe stomach and the breast, is necessary b e f o r e accepting p o s t m o r t e m evidence for the diagnosis o f a primary K r u k e n b e r g tumor.

Metastatic adenocarcinomas o f largeintestinal origin have been more c o m m o n than K r u k e n b e r g t u m o r s in o u r experience with surgical specimens o f ovarian masses, s6 T h e y are characterized microscopically by the presence o f large acini similar to those o f primary intestinal carcinomas. Grossly they may form solid masses, but m o r e often a p p e a r as large, partly cystic t u m o r s with areas o f h e m o r rhage and necrosis (Fig. 23). In such instances they are easily confused with tile cystic forms o f p r i m a r y ovarian cancers. T h e presence o f extensive degenerative changes and the occasional complication o f r u p t u r e should suggest the possibility o f a metastasis at operation and lead the surgeon to e x p l o r e the bowel with great care. Metastatic adenocarcinomas o f largeintestinal origin may be difficult or even impossible to distinguish from p r i m a r y ovarian carcinomas o f mucinous or e n d o metrioid types by microscopic examination alone, and the history, o t h e r findings at operation, o r a follow-up examination may be necessary to reveal the true n a t u r e o f the tumor. Ovarian metastases shotdd generally be r e m o v e d , when feasible, to avoid the possibility o f filture symptoms and ano t h e r operation. For the same reason normal a p p e a r i n g ovaries should be taken out rontinely in o l d e r women with gastrointestinal carcinoma. Rarely a patient survives for man)' years after the removal o f a primary gastrointestinal carcinoma and its ovarian metastases. 6'-'

Figure 23. Metastatic adenocarcinoma of large-intestinal origin. The huge cyst was filled widl necrotic material and altered blood.

95

HUMAN PATHOLOGY--VOLUME 1, NUMBER 1 March, 1970 T h e d e v e l o p m e n t o f ovarian metastases is occasionally the first manifestation o f an intestinal carcinoid. Since the latter can be small a n d easily o v e r l o o k e d by the s u r g e o n , the pathologist m a y be u n a w a r e at the time he examines the ovarian t u m o r that it is, indeed, metastatic, a n d m a y confltse it with o t h e r types o f ovarian neoplasm. T h e growth o f the argentaffin cells in nests a n d the f o r m a t i o n o f g l a n d u l a r structures suggest the diagnosis o f g r a n u losa cell t u m o r (Fig. 24), b u t the acini on close e x a m i n a t i o n differ greatly f r o m CallE x n e r bodies. Also the nuclei o f the carcinoid are typically r o u n d a n d have coarse c h r o m a t i n granules, unlike those o f the g r a n u l o s a cell tumor. Finally the s t r o m a o f the carcinoid is characteristically a b u n d a n t a n d densely fibrous o r hyaline, witho u t the theca-like or lutein cells tlmt are c o m m o n l y seen in the g r a n u l o s a cell tum o r . T h e presence o f isolated nests of epithelial cells in a copious fibrous s t r o m a suggests a B r e n n e r t u m o r on low p o w e r e x a m i n a t i o n , but the high p o w e r a p p e a r ance o f the cells is i n c o m p a t i b l e with that diagnosis. T h e most distinctive f e a t u r e o f the carcinoid t u m o r is the p r e s e n c e o f argentatIin granules, which can often be identified in h e m a t o x y l i n a n d eosin sections. Additionally, assays o f 5 - h y d r o x y -

96

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Figure 24. Metastatic carcinoid. True glands are present and the nuclei are round with a coarse chromatin pattern. (x 300.) (Reprinted by permission from Scull)', R. E., and Morris, J. M.: Functioning ovarian tumors. In Meigs, J. V., and Sturgis, S. H.: Progress in Gynecology. New York, Grune & Stratton, Inc., 1957, Vol. 3. indole acetic acid in the u r i n e a n d o t h e r l a b o r a t o r y tests m a y confirm the pathological diagnosis. O n gross e x a m i n a t i o n metastatic carcinoids are typically solid fibrous t u m o r s

Figure 25. Metastatic carciuoid, bilateral. The sectioned surfaces have a dense fibrous appearance. Cyst formation has taken place in the larger tumor. This patient had a primary carcinoid of the ileocecal valve with extensive metastases and the carcinoid,syndrome.

R E C E N T PROGRESS IN O V A R I A N CANCER--ScuLLY that resemble fibromas, thecomas, and Brenner tumors. Occasionally the epit h e l i a l n e s t s u n d e r g o cystic d e g e n e r a t i o n , a n d w h e n t h e cysts a r e l a r g e (Fig. 25) t h e t u m o r m a y b e c o n f i l s e d with a c y s t a d e n o f i b r o m a . I t is a d v i s a b l e to r e m o v e m e t a static c a r c i n o i d s , if p o s s i b l e , p a r t i c u l a r l y i f the patient has the carcinoid syndrome, because the ovarian masses may release large amounts of hormone into a venous s y s t e m t h a t b y p a s s e s t h e liver.

4.

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SUMMARY AND CONCLUSIONS

7.

A study of the belmvior of various t y p e s o f o v a r i a n c a n c e r i n d i c a t e s t h a t it is not one but many diseases: The prediction of the outcome and the selection of optimal t h e r a p y in e a c h case d e p e n d o n a p r e c i s e and complete diagnosis by the pathologist and a knowledge of the biologic behavior of the tumor by the pathologist and the s u r g e o n . S u c h k n o w l e d g e is n o w i n c o m p l e t e , a n d its e x p a n s i o n in t h e f u t u r e will h a v e to b e b a s e d o n d a t a f r o m m a n y institutions using a similar classification and n o m e n c l a t u r e . A l t h o u g h t h e classification p r e s e n t e d in this r e v i e w is i m p e r f e c t a n d will u n d o u b t e d l y d i f f e r in c e r t a i n r e s p e c t s f r o m t h o s e t h a t will b e finally a d o p t e d b y v a r i o u s i n t e r n a t i o n a l o r g a n i z a t i o n s , it r e flects m o d e r n t r e n d s . Broad guidelines have been presented f o r t h e s u r g i c a l t h e r a p y o f specific t y p e s of ovarian cancer, particularly the nnilateral encapsulated forms encountered in y o u n g w o m e n , b u t it is i m p o r t a n t to emphasize that these guidelines are based on incomplete contemporary knowledge a n d m u s t b e r e f i n e d b y c o n t i n u i n g clinicopathologic investigation. In conclusion, e a c h p a t i e n t with o v a r i a n c a n c e r is a n individual and willreceive the best therapy o n l y t h r 0 u g l l t h e c o o p e r a t i v e efforts o f t h e s u r g e o n a n d p a t h o l o g i s t a n d , in m a n y cases, t h e r a d i o t h e r a p i s t a n d c h e m o t h e r a pist as well.

8.

REFERENCES 1. Santesson, L., and Kottmeier, H. L.: (;eneral classification of ovarian tumors, In Gentil, F., andJnnqueira, A. C.: Ovarian Cancer. U.I.C.C. Monograph Series, Vol. 11. New York, Springer-Verlag, 1968. 2. Taylor, tl. C., Jr.: Studies in the clinical and biological evolution of adenocarcinoma of the ovary. J. Obstet. Gynaec. Brit. Comm., 66:827, 1959. 3. Kottmeier, H. L.: Surgical management-conservative surgery. In Gentil, F., and J unqueira, A. C.: Ovarian Cancer. U.I.C.C. Monograph

9. 10. 1I. 12. 13.

14. 15.

16.

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21.

22. 23. 24. 25.

Series, Vol. 11. New York. Springer-Verlag, 1968. Fox, H., Kazzaz, B., and Langley, F. A.: Argyrophil and argentatIin cells in the female genital tract and in ovarian mvcinous cysts. J. Path. Bact., 88:479, 1964. Scully, R. E.: Germ cell tumors of the ovary. In Sturgis, S. H., and Taymor, ~I. L.: Progress in Gynecology. New York, Grune & Stratton, Inc., 1970, Vol. V. ttertig, A. T., and Gore, tt.: Tumors of the Female Sex Organs. IIl. Ttimors of the Ovary and Fallopian Tube. Washington, D.C., Armed Forces Institute of Pathology, 1961. Shanks, H. G. I.: l'seudomyxoma peritonei. J. Obstet. Gynaec. Brit. Comm., 68:212, 1961. Santesson, L.: Cited by Kraus, F. T.: Gynecologic Pathology. St. Louis, The C. V. Mosby Co., 1967. Sampson,J. A.: Endometrial carcinoma of ovary, arising in endometrial tissue in that organ. Arch. Surg., I0:1, 1925. Long, M..E., and Taylor, H. C.,Jr.: Endometrioid carcinoma of the ovary. Amer. J. Obstet. Gynec., 90:936, 1964. Gray, L. A., and Barnes, M. L.: Endometrioid carcinoma of the ovary. Obstet. Gynec., 29: 694, 1967. Scully, R. E., Richardson, G. S., and Barlow,J. F.: The development of nmlignancy in endometriosis. Clin. Obstet. Gynec., 9:384, 1966. Scully, R. E., and Barlow, J. F.: "Mesonephroma" of ovary. Tumor of miillerian nature 'related to the endometrioid carcinoma. Cancer, 20: 1405, 1967. Sctfiller, W.: Mesonephroma ovarii. Amer. J. Cancer, 35:1, 1939. McGee, C. T., Cromer, D. W.,and Greene, R. R.: Mesonephric carcinoma of the cervix--differentiation from endocervical adenocarcinoma. Amer. J. Obstet. Gynec., 84:358, 1962. Herbst, A. L., and Scully, R. E.: Adenocarcinoma of the vagina in young women. A report of 7 cases including 6 clear cell carcinomas (socalled mesonephromas). Cancer. In press. Corner, G. W., Jr., ttu, C. Y., and Hertig, A. T.: Ovarian carcinoma arising in endometriosis. Amer. J. Obstet. Gynec., 59:760, 1950. Are)', L. B.: The origin and form of the Brenner tumor. Amer. J. Obstet. Gynec., 81:743, 1961. Edghill, :'~. R., Gardiner, J., and ttayes, J. A.: Mixed mesodermal tumor of the ovary. Amer. J. Obstet. Gynec., 97:578, 1967. Czernobilsky, B., and LaBarre, G. C.: Carcinosarcoma and mixed mesodermal tunaor of the ovary. A clinicopathologic analysis of 9 cases. Obstet. Gynec., 31:21, 1968. Moench, L. M.: A clinical study of 403 cases of adenocarcinoma of the ovary: papillary cystaclel~oma, carcinomatous cystadenonm, and solid adenocarcinoma of the ovary. Amer. j. Obstet. Gyncc., 26:22, 1933. Munnell, E. W.: Is conservative therapy ever justified in stage 1 (IA) cancer of the ovary? Amer. J. Obstet. Gynec., 103:641, 1969. Kottmeier, It. L.: l'ersonal communication. DeLima, O. A., Jr.: Disgerminoma do Ovario. Sao Panlo, 1966. Asadonrian, L, A., and Taylor, H. B.: Dysgerminoma. An analysis of 105 cases. Obstet. Gynec., 33:370, 1969.

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26. Breen, J. L., and Neubecker, R. D.: Ovarian malignancy in children, with special reference to the germ-cell ttunors. In Weyer, E. M.: Pediatric and Adolescent Gynecology. Monograph 142. New York, New York Academy of Sciences, 1967. 27. Neubecker, R. D., and Breen, J. L.: Embryonal carcinoma of the ovary. Cancer, 15:546, 1962. 28. Teilum, G.: Classification of endodermal sinus tnmour (mesoblastoma vitellinum) and socalled "embryonal carcinoma" of the ovary. Acta l'ath. Microbiol. Scand., 64:407, 1965. 29. Kazancigil, T. R., Laqueur, W., and Ladewig, P.: l'apillo-endothelioma ovarii: Report of 3 cases and discussion of Schiller's "mesonephroma ovarii." Amer. J. Cancer, 40:199, 1940. 30. Santesson, L., and Marrubini, G.: Clinical and pathological survey of ovarian embryonal carcinomas, including so-called "mesonephromas" (Schiller), or "'mesoblastomas" (Teilum), treated at tile Radiumhenmlet. Acta Obstet. Gynec. Scand., 36:399, 1957. 31. Simard, L-C.: Polyembryonic embryoma of the ovary of parthenogenetic origin. Cancer, 10: 215, 1957. 32. Woodruff, J. D., Protos, P., and l'eterso'n, W. F.: Ovarian teratomas. Relationship of histologic and ontogenic factors to prognosis. Amer. J. Obstet. Gynec., 102:702, 1968. 33. Thurlbeck, W. M., and Scully, R. E.: Solid teratoma of the ovary. A clinicopathological analysis of 9 cases. Cancer, 13:804, 1960. 34. Fortt, R. W., and Mathie, I. K.: Gliomatosis peritonei caused by oyarian teratoma. J. Clin. Path., 22:348, 1969. 35. Peterson, W. F.: Malignant degeneration of benign cystic teratomas of ovary; collective review of literature. Obstet. Gynec. Survey, 12:793, 1957. 36. Kelley, R. R., and ScuIly, R. E.: Cancer developing in dermoid cysts of the ovary. A report of 8 cases, including a carcinoid and a leiomyosarcoma. Cancer, 14:989, 1961. 37. Saunders, A. M., and Hertzman, V. O.: Malignant carcinoid teratoma of the ovary. Canad. Med. Assn. J., 83:602, 1960. 38. Gonzalez-Angulo, A., Kaufinan, R. H., Braungardt, C. D., Chapman, F. C., and llinshaw, A. J.: Adenocarcinonm of thyroid arising in struma ovarii (malignant struma ovarii). Report of two cases and review of the literature. Obstet. Gynec., 21:567, 1963. 39. Nieminen, 1., Von Numers, C., and Widhohn, O.: Struma ovarii. Acta Obstet. Gynec. Scand., 42:399, 1964. 40. Woodruff, J. D., Rauh,J. T., and Markley, R. L.: Ovarian strunm. Obstet. Gynec., 27:194, 1966. 41. Falck, B., Larson, B., yon Mecklenberg, C., Rosengren, E., and Sveneus, K.: On the presence of a second specific cell s)'stem in mammalian thyroid gland. Acta l'hysiol. Scand., 62:491, 1964. 42. Moertel, C. G., Beahrs, O. H., Woolner, L. B., and Tyce, G. M.: "Malignant carcinoid syndrome" associated with noncarcinoid tumors. New Eng. J. Med., 274:244, 1965. 43. Williams, E. D.: Histogenesis of medullary carcinoma of the thyroid. J. Clin. l'ath., 19:114, 1966.

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44. Braunstein, 11., Stephens, C. "L., and Gibson, R. L.: Secretory granules in medullary carcinoma of the thyroid. Electron microscopic demonstration. Arch. Path., 85:306, 1968. 45. Gonzalez-Licea, A., [tartmann, W. H., and Yardley, J. H.: Medullary carcinoma of the thyroid. Ultrastructural evidence of its origin from the parafollicular cell and its possible relation to carcinoid tumors. Amer. J. Clin. Path., 49:512, 1968. 46. Brody, S.: Clinical aspects of dysgerminoma of tile ovary. Acta Radiol. (Stockhohn), 56:209, 1961. 47. Wider, J. A., Marshall, J. R., Bardin, C. W., Lipsett, M. B., and Rose, G. T.: Sustained remissious after chemotherapy for primary ovarian cancers containing choriocarcinoma. New Eng. J. Med., 280:1439, 1969. 48. Scull)', R. E.: Gonadoblastoma. A review of 74 cases. In preparation. 49. Morris, J. M., and Scully, R. E.: Endocrine Pathology of the Ovary. St. Louis, The C. V. Mosby Co., 1958. 50. Kottmeier, H. L.: Carcinoma of the Female Genitalia. Baltimore, Tile Williams & Wilkins Co., 1953. 51. Sj6stedt, D., and Wahl6n, T.: Prognosis of granulosa cell tumours. Acta Obstet. Gynec. Scand. (Suppl. 6), 40, 1961. 52. Norris, H. J., and Taylor, H. B.: Prognosis of granulosa-theca tumors of tile ovar)-. Cancer, 21:255, 1968. 53. O'Hern, T. M., and Neubecker, R. D.: Arrhenoblastoma. Obstet. Gynec., 19:758, 1962. 54. Mathet, I'.: Les Tnmeurs Masculinisantes de rOvaire. (Thesis.)/l'aris, Libraire Arnette, i 956. 55. Novak, E. R., and Long, J. 1t.: Arrhenoblastoma of the ovary. Amer. J. Obstet. Gynec., 92:1082, 1965. 56. Scull)', R. E., and Richardson, G. S.: Luteinization of the stroma of metastatic cancer involving tile ovary and its endocrine significance. Cancer, 14:827, 1961. 57. Sternberg, W. H., and Barclay, D. L.: Luteoma of pregnancy. Amer. J. Obstet. Gynec., 95:165, 1966. 58. Mafinak, L. R., and Miller, G. V.: Bilateral ntulticentric ovarian luteonms of pregnancy associated with masculinization of a female infant. Amer. J. Obstet. Gynec., 91:251, 1965. 59. Taylor, H. B., and Norris, H. J.: Lipid cell tumors of the ovary. Cancer, 20:1953, 1967. 60. Woodruff, J. D., Noli Castillo, R. D., and Novak, E. R.: Lymphoma of tile ovary. A study of 35 cases from the Ovarian Tumor Registry of the American Gynecological Society. Amer. J. Obstet. Gynec., 85:912, 1963. 61. Cohen, M. 11., Bennett, j. M., Berard, C. W., Ziegler, J. L., Vogel, C. L., Sheagren, J. N., and Carbone, P. P.: Burkitt's tnmor in the United States. Cancer, 23:1259, 1969. 62. Johansson, H.: Clinical aspects of metastatic ovarian cancer of extragenital origin. Acta Obstet. Gynec. Scand., 39:681, 1960. 63. Joshi, V. V.: Primary Krukenberg tumor of ovary. Review of literature and case report. Cancer, 22:1199, 1968.

James Ilomer Wright l'athology l.aburatories Massachusetts General ltospital Boston, Massachusetts 02114