Germ Cell Tumors and Mixed Germ Cell−Sex Cord Tumors of the Ovary

Dysgerminomas account for nearly 50% of primitive germ cell tumors, for 1% of all ovarian cancers, and for 5–10% of those in the first three decades.

The tumors usually occur between 5 and 30 (mean, 19) years of age and are rare in those <5 and >50 years old.

Patients usually present with abdominal swelling and have a palpable mass. The serum lactic dehydrogenase (isoenzymes 1 and 2) is typically elevated.

Dysgerminomas occur with greatly increased frequency in phenotypic females with gonadal dysgenesis. The involved gonad is usually a streak gonad or less commonly an intra-abdominal testis that often harbors a gonadoblastoma (see that heading) from which the dysgerminoma arose.

Unusual or rare manifestations include:

• An elevated serum level of hCG (usually due to the presence of syncytiotrophoblastic giant cells) in <5% of cases. This may cause hormonal manifestations, usually estrogenic (isosexual precocity, menstrual irregularities) but occasionally androgenic.

• Paraneoplastic hypercalcemia due to tumor production of the active form of vitamin D (1,25-dihydroxyvitamin D ₃ ).

• Association with the rare autosomal dominant Cowden syndrome.

• Anti-Ma2 paraneoplastic encephalitis, in a case of microscopic dysgerminoma associated with gonadal dysgenesis (Abdulkader et al.).

Extraovarian spread (pelvic soft tissue, fallopian tube, peritoneum, retroperitoneal lymph nodes) is found at presentation in a third of cases.

The tumors have a median diameter of 15 cm, and are exclusively or predominantly solid with a soft, fleshy, lobulated, cream-colored sectioned surface, sometimes with focal or extensive cystic degeneration, necrosis, and hemorrhage. Calcified foci suggest an underlying gonadoblastoma, but may be seen in its absence.

Of the 20% of tumors that are bilateral, the tumor in the contralateral ovary is microscopic in half the cases. Molecular analysis in some cases has favored independent primaries.

The characteristic low-power appearance is that of cells with clear cytoplasm intersected by fibrous septa that contain variably prominent lymphocytes and epithelioid histiocytes in some cases, resulting in characteristic large nests or smaller aggregates (‘alveolar’ pattern). The lymphocytes and histiocytes are also variably dispersed beyond the septa contributing to a varied low-power appearance.

Other patterns are sheets, cords, or singly disposed cells. Uncommonly, the cells form solid or hollow tubules or surround spaces that may be small or large and follicle-like. Variable degrees of necrosis and/or hemorrhage may be seen.

The neoplastic cells, which resemble primordial germ cells, are large and rounded with a discrete cell membrane (in well-fixed specimens), clear cytoplasm, and a central, large, rounded nucleus with typically angulated edges, coarse chromatin, and a prominent nucleolus. Mitotic figures are usually numerous.

The tumor cells are particularly prone to morphologic variations likely due to suboptimal fixation. These include loss of cell cohesion, lack of well-preserved cell membranes, cells with eosinophilic cytoplasm, and rarely, shrunken hyperchromatic cells with scant cytoplasm and signet-ring-like cells.

The stroma ranges from barely perceptible collagen to thin to thick fibrous bands, to occasionally edematous or rarely myxoid, and almost invariably contains mature lymphocytes (including lymphoid follicles) and sometimes plasma cells and/or eosinophils.

A granulomatous reaction, which is usually ill-defined but rarely sarcoid-like, occurs in 20% of tumors; Langerhans’-type giant cells may also be present.

• Granulomatous inflammation within the primary and metastatic tumor may obscure the underling neoplastic cells.

• Conversely, histiocytes within lymphatics and regional nodes in the absence of tumor cells should not be misinterpreted as tumor, an error we have seen made.

Unusual features include:

• hCG+ syncytiotrophoblastic giant cells (SGCs) occur in <5% of tumors (unlike choriocarcinoma, the SGCs are unassociated with cytotrophoblast). Dysgerminoma cells themselves may rarely be hCG+.

• Luteinized stromal cells, either mixed with the neoplastic cells or at the periphery of the tumor, may occur, especially in hCG-producing tumors, and are the source of the hormone excess noted above.

• One unique tumor was associated with a fibrosarcomatous component.

Most dysgerminomas stain for OCT4 (nuclear staining), D2-40 (podoplanin), SALL4, CD117 (c-kit) (membranous staining), and LIN28, but unlike embryonal carcinomas, are CD30−. Occasional tumors are CK+.

found c-kit mutations in a third of tumors, a finding associated with high stage and offering a potential therapeutic target.

Solid pattern of yolk sac tumor (YST).

• Helpful features indicating YST include minor foci of more typical patterns, basement membrane deposits, hyaline globules, nuclei lacking angulated edges, and a usual absence of lymphocytes.

• Solid YSTs may be AFP−, but unlike dysgerminomas, are AE1/AE3+/glypican 3+/OCT4−/D2-40−.

Solid pattern of embryonal carcinoma. Differential features favoring or diagnostic of embryonal carcinoma (which is rare in the ovary) include glandular and papillary patterns, larger, more variable and hyperchromatic nuclei than those of dysgerminoma, a usual absence of a lymphocytic or granulomatous stromal infiltrate, and a CD30+/CD117− phenotype.

Clear cell carcinoma (CCC) with a solid pattern (sometimes with fibrovascular septa) and rare OCT4+ CCCs. Features indicating CCC include postmenopausal age, associated endometriosis, tubulocystic and papillary patterns, luminal and intracellular mucin, hobnail cells, a basement membrane-rich stroma, a plasma cell-rich inflammatory infiltrate, and a PAX8+/HNF+/SALL−/LIN28− phenotype.

Undifferentiated carcinoma. This diagnosis may be suggested in poorly preserved areas of dysgerminoma, but foci with characteristic cytologic features and typical septa with lymphocytes will almost always be found elsewhere. Immunostaining for OCT4 will help if needed.

Small cell carcinoma, hypercalcemic type (HSCC). The similar age range and gross appearance of the tumors, the occasional association of dysgerminoma with hypercalcemia, and the presence of small shrunken cells in some dysgerminomas can result in treacherous overlap.

• The diagnosis of dysgerminoma rests on the presence of foci with characteristic patterns and cytologic and immunohistochemical features.

• Follicle-like spaces are much more common in HSCCs and their frequent content of cells with eosinophilic cytoplasm (often with a rhabdoid appearance) is rarely mimicked by the eosinophilic cells of a dysgerminoma. Columnar mucinous cells are seen in occasional HSCCs but not in dysgerminoma if one excludes the rare possibility of entrapped teratomatous glands that would place the tumor in the category of a mixed germ cell tumor.

Lymphomas. The differing nuclear features of the two tumors and a variety of differing immunohistochemical reactions facilitate the differential diagnosis.

Sex cord–stromal tumors. Rarely large nests, alveolar aggregates, and cords in dysgerminoma may initially suggest a sex cord tumor, particularly Sertoli–Leydig cell tumor (SLCT), but any well-sampled tumor will exhibit numerous differences.

The 5-year survival rate is now almost 100% due to effective therapy, even for patients with high-stage or recurrent tumor. Most recurrences appear within 2 years, but rare tumors have recurred years, even decades, after removal.

YSTs (‘endodermal sinus tumor’ in the seminal studies of Teilum) account for 20% of malignant primitive germ cell tumors. They are most common in the second and third decades (median age, 16–19 years), and rare in those >40 years of age. Some of the latter arise from surface epithelial tumors, as detailed below. A few YSTs have occurred in patients with gonadal dysgenesis, usually arising from a gonadoblastoma.

The usual presentation is abdominal pain with a large abdominal or pelvic mass, and in half the cases, extraovarian spread (peritoneum, retroperitoneal lymph nodes). An elevated serum AFP is almost always present; very high levels are suggestive of the diagnosis. SLCT, another tumor of the young, is rarely associated with elevated serum AFP but usually at lower levels than encountered with YSTs.

YSTs have a median diameter of 15 cm and typically solid and cystic sectioned surfaces. The solid tissue is soft, friable, yellow to gray, and often hemorrhagic and necrotic. Bilaterality is rare in stage I tumors.

A honeycomb appearance (many small cysts) is usually associated with a polyvesicular-vitelline component (see below).

Other germ cell elements are grossly recognizable in 15% of cases, most commonly a dysgerminoma or dermoid cyst, warranting a diagnosis of mixed germ cell tumor (see below). If streak gonads are present, a unilateral or bilateral gonadoblastoma may be recognizable.

Most of the typical histologic patterns of YST reflect extraembryonal (predominantly yolk sac) differentiation, and include the following: reticular–microcystic, endodermal sinus (with Schiller–Duval bodies), parietal, polyvesicular vitelline, and tubular. Large dilated cysts may also be present.

The reticular or microcystic pattern, which occurs at least focally in most YSTs and often predominates, is characterized by a loose meshwork of variably sized, anastomosing spaces and cysts lined by primitive-appearing cells.

The tumor cells usually have a moderate amount of pale to clear cytoplasm, a hyperchromatic irregular nucleus often with a prominent nucleolus, and variable mitotic activity. The cells lining microcystic spaces may be flattened with a less obviously malignant appearance.

Schiller–Duval bodies (SDBs), which are found in only 20% of tumors, appear as rounded to elongated papillae with a fibrovascular core ensheathed by primitive columnar cells. The papilla may occupy a space lined by cuboidal, flat, or hobnail cells. When numerous, SDBs create a distinctive ‘endodermal sinus’ pattern.

Other patterns are micropapillary (without the distinctive features of SDBs), solid, labyrinthine, festoon, and adenofibromatous. These rarely predominate, usually being accompanied by dominant reticular-microcystic foci.

Eosinophilic, PASD+, intracellular and extracellular hyaline bodies occur in most YSTs, but are nonspecific, being encountered in many ovarian tumors.

Rare features that reflect somatic differentiation are a glandular pattern (in most cases likely reflecting intestinal differentiation) and hepatic differentiation.

Unfamiliarity with these rare patterns can lead to diagnostic problems, especially when they are pure. In almost all cases, however, the diagnosis is facilitated by the presence of at least minor foci of typical YST (thorough sampling is obviously crucial) and an immunoprofile similar to that of typical YST.

The traditional marker for YST and YST variants has been alpha-fetoprotein (AFP) (cytoplasmic reactivity). However, the staining is often focal and weak (especially in glandular patterns), is often negative in the solid pattern ( ), and is typically negative in the parietal and mesenchyme-like patterns.

More recent markers superior to AFP include ZBTB16 (a sensitive and specific marker for all YST patterns including metastatic YSTs) ( ) and the oncofetal protein glypican-3, which typically has more diffuse and intense staining than AFP even in solid YSTs (Zynger et al.). YSTs also immunoreact for LIN28 (an RNA-binding protein), SALL4, and villin.

The immunoprofile of hepatoid YSTs is similar to that of hepatocellular carcinoma, including reactivity for CEA (in a canalicular pattern), AFP, and glypican 3.

Shojaei et al. found high-level expression (>25%) of one or more endodermal markers (TTF-1, CDX2, Hep Par 1, napsin A) in ~40% of YSTs. TTF-1 and CDX2 expression was predominantly seen in reticular/cystic and glandular areas; Hep Par 1 was most frequent in myxoid/solid and glandular areas.

YSTs are usually negative for CD117, OCT4 (unlike dysgerminoma), and CD30 (unlike embryonal carcinoma). An exception is the solid pattern of YST that was CD117+ in ~60% of cases studied by Kao et al.

In contrast to CCC, sometimes in the differential with YST, the latter are CK7− and EMA− or contain only rare positive cells. Focal staining for Leu-M1 can be seen in YSTs and CCCs, but diffuse positivity favors the latter.

CCC. Features favoring or indicating this diagnosis include an age >40; normal serum AFP; papillae with hyalinized or hollow cores; negativity for AFP, glypican-3, SALL4, and LIN28; and positivity for Leu-M1, cytokeratin 7, EMA, and HNF.

Other primitive germ cell tumors (see Dysgerminoma and Embryonal Carcinoma ).

Sex cord–stromal tumors, particularly juvenile GCT and SLCT. Cysts (both small and large) and follicles in these tumors may mimic cysts in YSTs including those of polyvesicular type. Many other patterns of each tumor are, however, diagnostic.

Extraovarian pelvic YST. These rare tumors may spread to the ovary but ovarian involvement in these cases is clearly secondary or metastatic.

Endometrioid adenocarcinoma (vs endometrioid-like YST).

• Features favoring or diagnostic of endometrioid-like YST include a young age, elevated serum AFP, primitive appearing nuclei, and other patterns of YST or other types of germ cell tumor. An AFP+/SALL4+/villin+/PAX8−/CK7− immunoprofile indicates endometrioid-like YST, and the opposite, endometrioid carcinoma.

• Complicating this differential are rare mixed tumors comprised of endometrioid carcinoma (or rarely another type of surface epithelial carcinoma) and typical YST (see Associations with Other Tumors ).

Other tumors composed of cells with abundant eosinophilic cytoplasm (vs hepatoid YST) ( Appendix 14 ).

Adverse prognostic factors in earlier studies included stage II or greater, gross residual tumor after cytoreductive surgery, and liver involvement.

A recent large series found an overall 5-year survival of 86% (Wang et al.). In that study, serum AFP decline was a significant prognostic factor for overall survival; AFP levels are also useful in detecting recurrence.

Experience is limited by their rarity, but polyvesicular vitelline tumors may have a better prognosis than conventional YSTs.

About two-thirds of YSTs in older women (arising from surface epithelial tumors or with no detectable epithelial component) have died of disease, but aggressive treatment with platinum-based chemotherapy to treat both epithelial and germ cell components may improve survival.

These tumors are much rarer than their testicular counterparts, accounting for <1% of primitive ovarian germ cell tumors. When present, it is typically a minor component of a mixed primitive germ cell tumor (see corresponding heading).

The patients with pure or almost pure tumors have ranged from 4 to 28 (median, 12) years of age and usually present with an adnexal mass. In 50% of the cases, there are endocrine manifestations such as isosexual pseudoprecocity, irregular bleeding, amenorrhea, and hirsutism. Serum hCG and AFP levels are typically elevated.

Peritoneal spread, sometimes with involvement of pelvic or intra-abdominal viscera, is present in about half the cases.

Gross examination usually reveals a predominantly solid unilateral large mass with soft, white, tan–grey, to yellow tissue; cysts containing mucoid material and foci of hemorrhage and necrosis may be present.

Solid sheets and nests (often with central necrosis), glands, and papillae are composed of or lined by large pleomorphic tumor cells with abundant dusky, almost purple cytoplasm. Hyaline bodies similar to those in YSTs may be present. The nuclei are round and vesicular with coarse, irregular membranes, one or more prominent nucleoli, and numerous mitotic figures.

Syncytiotrophoblastic giant cells (SGCs) are almost always present, usually singly disposed within or at the periphery of the tumor nests or within the stroma, in the absence of cytotrophoblast.

The tumor cells are usually positive for CD30, OCT4, LIN28, and SALL4, only occasionally positive for AFP, and negative for glypican and CD117. SGCs are reactive for hCG. CD30 staining may be lost or diminished after chemotherapy.

Dysgerminoma (see corresponding heading).

YST. Features favoring or diagnostic of YST include a reticular pattern; SDBs; polyvesicular vitelline, endometrioid-like, or hepatoid patterns; less pleomorphic nuclei, and an OCT4−/CD30−/glypican 3+ immunoprofile.

Poorly differentiated adenocarcinoma or undifferentiated carcinoma. These tumors usually occur in the late reproductive and postmenopausal age, have at least a minor glandular component of surface epithelial type, and with rare exceptions, lack evidence of AFP and hCG production.

Juvenile GCT. The presence of follicle-like spaces, luteinized tumor cells, no SGCs, and an inhibin+/calretinin+/AFP− immunoprofile favor or indicate this diagnosis.

Poorly differentiated SLCTs ( Chapter 16 ). This is rarely a diagnostic issue as SLCTs almost always contain foci of at least moderately differentiated SLCT and are positive for inhibin and/or calretinin.

There was only a 50% 5-year survival for patients with stage I disease in the one reported series, but most did not receive chemotherapy.

Postoperative chemotherapy was curative in some cases in that series and in other reported cases, including some with extraovarian spread.

Gestational choriocarcinoma. This is excluded by prepubertal age, an absence of other germ cell elements, or by DNA polymorphism analysis.

Malignant germ cell tumors with isolated syncytiotrophoblastic cells, particularly embryonal carcinoma and dysgerminoma. These tumors lack the admixed cytotrophoblast and syncytiotrophoblast of choriocarcinoma.

Rare poorly differentiated adenocarcinomas of surface epithelial origin, usually occurring in older women, which contain syncytiotrophoblast-like tumor giant cells or exhibit definite trophoblastic differentiation confirmed by hCG-reactivity ( Chapter 14 ).

In a study of 21 patients who received chemotherapy, Jiao et al. found that 16 achieved complete remission and 4 partial remission, with one death. With a median follow-up of 71 months, the 5-year OS rate was 79.4%.

These are one of the commonest ovarian tumors, accounting for almost half of them and for almost 60% of benign ones.

They occur during the reproductive years in >80% of cases (most commonly in the third decade), and account for up to half of the ovarian neoplasms in the first two decades due to the rarity of other tumors in that age group. They are the only germ cell tumor seen with any frequency after menopause, some tumors not being detected until years after its onset.

The patients may have the typical symptoms and signs of a benign ovarian tumor, but up to 60% are asymptomatic. The radiologic presence of teeth and calcification may suggest or indicate the diagnosis.

Complications include:

• Torsion with one or more of: infarction, perforation, hemoperitoneum, and autoamputation.

• Perforation into the peritoneal cavity or a hollow viscus. A sudden rupture may cause an acute abdomen, whereas a slow leak may lead to a granulomatous peritonitis that intraoperatively can mimic metastatic carcinoma.

• Bacterial infection.

• Peritoneal ‘melanosis’ characterized by tan to black, peritoneal staining or tumor-like nodules that may intraoperatively mimic metastatic melanoma ( Chapter 20 ).

• Paraneoplastic disorders, including hemolytic anemia and anti-NMDR-receptor encephalitis (Dalmau et al.).

Fifteen percent are bilateral; rarely multiple tumors involve one ovary. The tumors (unlike immature teratomas) are predominantly cystic with usually only one locule but occasionally two or more. They vary in size but are uncommonly >8 cm and on average are about half the size of immature teratomas.

The cysts typically contain yellow to brown sebaceous material and hair, a lining that resembles squamous mucosa, and one or more round, polypoid solid masses (mamillae or Rokitansky's protuberances) usually composed predominantly of fat. Occasionally a large mass of brain-like tissue may be seen.

Teeth occur in one-third of the cases, either in the cyst wall or cavity, occasionally within a rudimentary mandible or maxilla. Bone, cartilage, mucinous cysts, adipose tissue, thyroid, and soft brain tissue are occasionally visible grossly.

An unusual but striking finding on imaging studies and gross examination is the presence of innumerable, floating, intracystic ‘fat balls’ consisting of spherical aggregates of mostly sebaceous material.

Adult-type tissues, usually representing all three germ layers, sometimes arranged in an organoid fashion, are seen. Foci of fetal-type tissues are encountered in many otherwise typical cases and have no prognostic significance and should not lead to the diagnosis of immature teratoma.

Ectodermal derivatives predominate in almost all the tumors, and include keratinized epidermis, sebaceous and sweat glands, hair follicles, and neuroectodermal elements (glial and peripheral nervous tissue, ependymal tubules, cerebrum, cerebellum, and choroid plexus). Rare foci of immature neuroectodermal tissues are allowable in an otherwise typical dermoid cyst (Yanai-Inbar and Scully).

Mesodermal derivatives include smooth muscle, bone, teeth, cartilage, and fat. Endodermal derivatives include respiratory and gastrointestinal epithelium and thyroid and salivary gland tissue. Occasional to rare tissues include retina, pancreas, thymus, adrenal, pituitary, kidney, lung, breast, prostate, and seminal vesicle.

Escaped cyst contents elicit a characteristic lipogranulomatous response in the wall of the cyst or the surrounding ovarian tissue resulting in an almost diagnostic sieve-like pattern with variably prominent foreign-body giant cells. Rarely, this finding may be the sole microscopic evidence of a dermoid cyst.

The neuroectodermal elements can incite a florid vascular proliferation identical to that described in immature teratomas and their implants. In one such case, the vascular proliferation was associated with the presence of Wagner–Meissner-like corpuscles.

Chen et al. found that 40% of dermoid cysts contained foci resembling ectopic meningothelial hamartomas. The latter abutted cranially derived tissues, especially scalp-like skin and glial tissue. Anastomosing slit-like channels lined by flat to cuboidal EMA+ cells were arranged within dense collagen bundles; pigmented dendritic cells and psammoma bodies were also typically present.

In a study of teratoma-associated anti-N-methyl D-aspartate receptor encephalitis (NMDAR encephalitis), Dabner et al. found lymphoid infiltrates around mature glial elements, sometimes with reactive germinal centers, lymphoplasmacytic infiltrates within the neuroglial matrix, and degenerative neuronal changes. Clark et al. found NMDA receptors in squamous tissue in all teratomas tested, including in women without NMDAR encephalitis.

Immature teratoma.

• Normal cerebellar, ependymal, pituitary, or retinal tissue, or fetal-appearing mesenchymal tissue may suggest immature teratoma; however, the latter diagnosis requires the presence of unequivocal embryonal elements.

• The differential with immature teratoma is also aided by the different gross features of the two tumors. The former diagnosis should be made cautiously when the gross features are those of a dermoid.

The sieve-like pattern may not be recognized as diagnostic and considered nonspecific fat necrosis.