Germ Cell Neoplasms of the Ovary

Clinical Features

Most cases of dysgerminoma (∼80%) are diagnosed during early adulthood (second to third decades, median age 22 years); they rarely affect premenarchal and postmenopausal women. Approximately 10%–20% manifest during pregnancy, either symptomatically or discovered incidentally at the time of cesarean section. When symptomatic, patients usually present with a rapidly enlarging pelvic mass causing pain or pressure. Intraperitoneal tumor rupture and/or torsion can occur, leading to hemoperitoneum and symptoms of acute abdomen. In patients with gonadal dysgenesis, the mass is often found incidentally during work-up for amenorrhea or after prophylactic resection of the gonads. Estrogenic hormonal manifestations and, rarely, androgenic manifestations may occur. Elevated serum lactate dehydrogenase (LDH) is detected in most patients. A minority (∼3%) is also associated with elevated serum β-human chorionic gonadotropin (β-hCG), suggesting trophoblastic disease. Less specific markers detected include placental alkaline phosphatase (PLAP), CA125, and inhibin. Alpha-fetoprotein (AFP) levels are normal in pure dysgerminomas. Paraneoplastic hypercalcemia has been documented.

Pathologic Features

Gross Findings

Dysgerminoma usually presents as a large (median 15 cm) bulky solid mass with a lobulated, tan to pink soft uniform cut surface ( Fig. 16.1 ). Areas of hemorrhage and necrosis can be seen. Bilateral ovarian involvement occurs in up to 25% of cases, either as obvious masses (10%–15%) or visible tumor in one ovary with microscopic tumor in the contralateral ovary (5%–10%). Microscopic and bilateral tumors usually occur in the setting of gonadal dysgenesis.

Microscopic Findings

At scanning magnification, the tumor cells grow in nodules, sheets, trabeculae, and cords separated by fibrous septa ( Figs. 16.2 and 16.3 ). On occasion, poorly formed tubular and glandular structures may be apparent. The septal connective tissue is usually indistinct but may contain prominent lymphocytic aggregates, sometimes forming lymphoid follicles as well as plasma cells, eosinophils, and histiocytes forming epithelioid granulomas ( Fig. 16.4 ). Inflammatory cells (mostly lymphocytes) can also be seen within tumor nests, trabeculae, and cords and may be numerous enough to obscure the neoplastic cell population. The tumor cells are polygonal to round with visible cell borders and contain abundant eosinophilic cytoplasm. The nuclei are typically central or slightly eccentric with a round to “boxy” outline (“squared-off” appearance), coarse chromatin, and visible nucleoli, often more than one per nucleus ( Fig. 16.5 ). Mitotic activity is brisk and easily identifiable in most. A minor syncytiotrophoblast cell component is observed in 2%–3% of tumors, often around vessels or areas of hemorrhage ( Fig. 16.6 ). Other rare findings include luteinized stromal cells and microcalcifications (which, when present, may suggest an underlying gonadoblastoma).

Ancillary Studies

Histochemistry and Immunohistochemistry

Periodic acid–Schiff (PAS) stain highlights the abundant glycogen in the tumor cells; the staining will disappear after diastase treatment. By immunohistochemistry, dysgerminoma cells are positive for PLAP (strong, cytoplasmic staining), SALL4, CD117, and OCT4 ( Fig. 16.7 ). Other (less specific) positive markers include vimentin, LDH, neuron-specific enolase (NSE), and D2-40. Keratin expression, usually patchy, is seen in ∼30% of tumors. Dysgerminoma cells are negative for CD30, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), S-100 protein, CD45, glypican-3, and AFP. Staining for β-hCG is confined to syncytiotrophoblast, if present.

Differential Diagnosis

Dysgerminoma must be distinguished from other malignant germ cell tumors that may present with solid or nested growth. Yolk sac tumor will show a variation of architectural patterns, more primitive-appearing nuclei, presence of hyaline bodies, and absence of septa or prominent lymphocytic infiltrates. These tumors also typically show diffuse and strong immunoreactivity for cytokeratin and AFP and, in contrast to dysgerminoma, are positive for glypican-3 and negative for OCT4. CD117 is not helpful in this differential, as ∼50% of yolk sac tumors with solid pattern express CD117 to a variable degree. Embryonal carcinoma is extremely rare in the ovary and features a more primitive population with higher degrees of pleomorphism and hyperchromasia than dysgerminoma. In addition, embryonal carcinoma has glandular and papillary architecture, at least focally. Embryonal carcinoma is strongly and diffusely positive for cytokeratin and CD30 and in most cases is negative for CD117. OCT4 is not helpful in this differential diagnosis as both tumors are strongly and diffusely positive. Large cell lymphoma may mimic dysgerminoma grossly and microscopically; however, lymphoma is more often bilateral and involves other organs. Lymphoma typically grows in sheets, lacks septa, exhibits less uniform cytomorphology, and shows immunoreactivity for lymphoid markers. Clear cell carcinoma with a predominantly diffuse pattern may overlap with dysgerminoma; however, this tumor is typical of peri- or postmenopausal women and very rarely affects adolescents and young adults. A background of endometriosis and the more classic tubulocystic and papillary architecture are helpful clues for this diagnosis. Cytokeratin and EMA are weakly positive and negative, respectively, in dysgerminoma, whereas they are both strongly and diffusely positive in clear cell carcinoma. Clear cell carcinomas are, unlike dysgerminomas, positive for PAX8 and typically negative for SALL4 (although focal staining has been reported). Dysgerminomas with poorly formed pseudoglandular spaces or tubules may raise concern for Sertoli cell tumor . However, in the latter, the characteristic nuclear features of dysgerminoma are lacking, and inhibin, calretinin, and SF1 are positive, whereas OCT4 and PLAP are negative. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) may be confused with dysgerminoma; however, in most cases of SCCOHT, there are focal follicle-like spaces containing eosinophilic fluid. These tumors show loss of nuclear expression for SMARCA4 (BRG1) and are also negative for OCT4, PLAP, and SALL4 and may be positive for EMA. Metastatic melanoma features large round nuclei with prominent nucleoli and thus shows morphologic overlap with dysgerminoma. A previous history of melanoma and the presence of intratumoral pigment are helpful clues. Immunohistochemistry for melanocytic markers, such as SOX10, HMB45, or Melan-A, should be considered and usually suffices to confirm this diagnosis. Undifferentiated carcinoma can be negative or only focally positive for epithelial markers; however, it is also negative for OCT4, SALL4, and PLAP and occurs in older (postmenopausal) patients.

Prognosis and Therapy

The overall 5-year survival of dysgerminoma is 75%–90% and is highly dependent on stage, being 90% for patients with stage IA (∼67% of all cases) compared to 63% in patients with extraovarian disease. Most tumor recurrences occur during the first year. Metastases usually occur in the peritoneum, bone, liver, and lung, as well as pelvic, para-aortic, and retroperitoneal lymph nodes. Primary treatment includes unilateral salpingo-oophorectomy and biopsy of contralateral ovary as a fertility-sparing option or standard bilateral salpingo-oophorectomy and hysterectomy, followed by multiagent chemotherapy, most commonly BEP (bleomycin, etoposide, and cisplatin). Monitoring for tumor recurrence includes imaging and serum markers (LDH, PLAP, and β-hCG).

Gross Findings

The tumor is unilateral and large (median size 17 cm). It shows a smooth outer surface and a solid, soft to friable cut surface with frequent hemorrhage and necrosis.

Microscopic Findings

In its classic appearance, embryonal carcinoma features a highly pleomorphic cell population growing in solid sheets and poorly formed aggregates ( Fig. 16.8 ). Gland-like spaces and papillae are often admixed with solid areas ( Fig. 16.9 ). The tumor cells are highly atypical, which is noticeable at low power magnification. Their nuclei are irregularly contoured, have vesicular to coarse chromatin and display prominent nucleoli. The cytoplasm is variable in amount, vaguely granular and eosinophilic with indistinct cell borders ( Fig. 16.10 ). Mitotic activity is readily identified and includes frequent aberrant mitoses. Necrosis is common, either as focal confluent foci or as single cell necrosis. The presence of syncytiotrophoblast cells correlates with elevated β-hCG and hormonal manifestations; they are usually located at the periphery of the tumor or within hemorrhagic areas ( Fig. 16.11 ).

Immunohistochemistry

Embryonal carcinoma is strongly and diffusely positive for cytokeratin, PLAP, CD30 ( Fig. 16.12 ), SALL4, and OCT4. NSE may be positive, whereas C-KIT, EMA, CEA, glypican-3, and vimentin are usually negative. SOX2 is positive in ∼50% of the ovarian embryonal carcinomas and appears to be a less reliable marker compared to testicular embryonal carcinomas, most of which are positive for this marker. Positive immunoreactivity for AFP can be found in up to one-third of cases. β-hCG staining is usually confined to syncytiotrophoblast cells.

Molecular Analysis

Most embryonal carcinomas contain an isochromosome or overrepresentation of 12p.

Gross Findings

Choriocarcinoma is, like other germ cell tumors of the ovary, typically unilateral, large, and solid, often with extensive hemorrhage and necrosis.

Microscopic Findings

Nongestational choriocarcinomas are indistinguishable from gestational choriocarcinomas on histology. They are defined by the presence of syncytiotrophoblast cells intimately admixed with cytotrophoblast cells and, less often, intermediate trophoblast cells ( Fig. 16.13 ). By definition, chorionic villi are absent. Syncytiotrophoblast is composed of large multinucleated cells with abundant eosinophilic, sometimes vacuolated cytoplasm and hyperchromatic smudgy nuclei. As these cells are terminally differentiated, mitotic figures are absent. Cytotrophoblast is comprised of smaller, medium-sized polygonal mononuclear cells with abundant clear to eosinophilic cytoplasm and monomorphic, centrally located nuclei containing conspicuous nucleoli and vesicular chromatin. Mitoses are frequent and often include atypical forms. Intermediate trophoblast cells are also mononuclear, round to polygonal, and relatively uniform but tend to be surrounded by fibrinoid material and cluster around dilated vessels, often showing vascular invasion. The syncytiotrophoblast component is usually the most prominent; however, in rare cases, sheets of cytotrophoblast or intermediate trophoblast comprise most of the tumor. Extensive hemorrhage and necrosis may obscure the tumor cell morphology.