Ovarian Dysgerminomas Pathology Overview of Ovarian Dysgerminomas

An ovarian dysgerminoma consists of primitive, undifferentiated germ cells. ^{[1, 2]}  These are the most common types of malignant ovarian cell tumors (see the following image). ^[1]

Ovarian dysgerminomas pathology. Percentages of malignant germ cell tumors.

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Although germ cell tumors arise from primordial ovarian and testicular germ cells, the pathogenesis of the ovarian germ cell tumors is unknown. ^[1] The majority of ovarian germ cell tumors (95%-97%) are benign (ie, mature teratomas), with the remainder a small percentage (3%-5%) consisting of malignant proliferations ^[3] (eg, immature teratoma, dysgerminoma, yolk sac tumor, embryonal cell carcinoma, choriocarcinoma). ^[2]

Lines of differentiation distinguish germ cell tumors. ^[1] Primitive, unipotential germ cells are the precursors to ovarian dysgerminomas, whereas pleuripotential germ cells diverge along several lines of differentiation. ^[1]

Ovarian dysgerminomas primarily affect adolescents and young adults, with about 60% diagnosed in patients younger than 20 years (median age at diagnosis: 16-20 years ^[4] ). ^{[1, 5]} The clinical presentation most commonly involves abdominal/pelvic pain, followed by an abdominal mass, fever, vaginal bleeding, and, occasionally, ascites. ^[1] Unusual for germ cell tumors, dysgerminomas occur bilaterally in 10%-20% of cases. ^[1]

Extraovarian tumor spread of dysgerminomas often involves the retroperitoneal and pelvic lymph nodes. ^[3] In addition, hematogenous spread may occur; common sites of involvement are the lungs, liver, and bone. ^[5]  These tumors are highly susceptible to radiotherapy. ^[3]

See Ovarian Cancer and Borderline Ovarian Cancer for more information on these topics.

The main neoplasms in the differential diagnosis of ovarian dysgerminoma are lymphoma/leukemia, yolk sac tumor, embryonal carcinoma, and Sertoli cell tumor.

Large-cell lymphomas typically occur bilaterally. It can be distinguished immunohistochemically by positive staining for CD45 (LCA) and negative staining for OCT3/4, PLAP, or SALL4. ^[6]

Yolk sac tumors may exhibit a solid pattern, simulating dysgerminoma, but other classic architectural patterns of yolk sac tumor (ie, reticular, microcystic, glandular, or Schiller-Duvall bodies) are also invariably present. 

Pure embryonal carcinoma is rare in the ovary. However, a small percentage of mixed germ cell tumors occur. When present, embryonal cell carcinoma exhibits more nuclear hyperchromasia and nuclear pleomorphism, amphophilic cytoplasm, high mitotic index, and necrosis than ovarian dysgerminomas. Often, a glandular or papillary architecture is present. The cells of embryonal carcinoma express CD30 and cytokeratin (strong, diffuse), whereas those of dysgerminoma do not.

Sertoli cell tumors may be mistaken for dysgerminoma when tubules are indistinct and/or solid, especially if they are poorly fixed. However, Sertoli cell tumors do not usually have a background lymphocytic infiltrate; and they express sex cord stromal markers such as calretinin, inhibin, and steroidogenic factor-1, and they lack germ cell markers.

A study that investigated nuclear protein in the testis (NUT) expression in ovarian germ cell tumors found that most malignant ovarian germ celll tumors express NUT protein, albeit focally. ^[7] The investigators indicated this should be considered when evaluating immunostaining in the differential diagnosis of poorly differentiated malignancies, particularly NUT midline carcinoma. They further advised that because NUT protein appears to play a role in normal germ cell maturation, it may influence intestinal or hepatoid differentiation within malignant germ cell tumors. ^[7]

Ovarian dysgerminomas are associated with elevated serum levels of lactate dehydrogenase (LDH).

Although these tumors are thought to be hormonally inert, at least one case of precocious puberty occurring in association with ovarian dysgerminoma has been reported. ^[8] The patient was a 6-year-old girl whose precocious puberty was caused by elevations in the levels of beta–human chorionic gonadotropin (beta-hCG), alpha-fetoprotein (AFP), and estradiol.

Elevated serum levels of neuron-specific enolase, ^[9] calcium, ^[10] inhibin, ^[11] placental alkaline phosphatase (PLAP), and prolactin ^[12] have also been reported. These serologic elevations readily resolve following surgical excision; after the elevations resolve, the serum levels may be used as tumor markers to monitor for recurrence.

Because these markers are more commonly associated with other germ cell tumors (ie, yolk sac, embryonal carcinoma, choriocarcinoma), many scientists contend that secreting ovarian dysgerminomas are misdiagnosed as pure lesions and that they actually represent mixed tumors containing other malignant germ cell components. ^[5]

See Gynecologic Tumor Markers for more information on this topic.

A characteristic feature of ovarian dysgerminomas is their solid nature and rapid growth. Grossly, these tumors often measure more than 10 cm in maximum dimension at the time of diagnosis. The classic histology of dysgerminomas features a proliferation of epithelioid cells  arranged in sheets, nests, or small clusters separated by thin, fibrous septae that contain a sprinkling of lymphocytes. The neoplastic cells are large with distinct cell borders, and have moderate to high nuclear-cytoplasmic ratios, squared-off to round nucle; vesicular chromatin, prominent nucleoli, clear to eosinophilic cytoplasm rich in glycogen and lipid. 

Multinucleated forms may be present. Mitotic activity may be significant and may vary greatly, even within the same tumor; atypical mitoses may be seen. Noncaseating granulomas, syncytiotrophoblast-like giant cells, and germinal center formation are frequently noted. The syncytiotrophoblast-like giant cells are responsible for the mild to modest elevation in beta-human chorionic gonadotropin (beta-hCG) seen in these patients. Additionally, foci of hemorrhage, necrosis, and small microcalcifications may also be identified.

Examples of ovarian dysgerminoma histology are shown below.

Ovarian dysgerminomas pathology. Histology sections of ovarian dysgerminoma (hematoxylin-eosin, ×100).

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Ovarian dysgerminomas pathology. Histology sections of ovarian dysgerminoma. The arrows indicate syncytiotrophoblastlike giant cells. A and B: Hematoxylin-eosin, ×200. C: hematoxylin-eosin, ×400. D: hematoxylin-eosin, ×600.

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Although numerous architectural variants of ovarian dysgerminomas exist, the cytologic features remain constant. These varying architectural patterns include but are not limited to sparse lymphocytes, trabeculae, microcysts, and tubules, as well as extensive hyalinization. As yet, no prognostic significance has been attributed to these architectural patterns.

Ovarian dysgerminomas demonstrate a characteristic tigroid background and loosely cohesive, polygonal cells with round to oval nuclei, vesicular chromatin, and multiple (1-4) distinct nucleoli on cytology preparations.

Immunohistochemistry (IHC) plays an important role in characterizing germ cell tumors. Although the wide range of architectural patterns may make establishing the pathologic diagnosis difficult, the immunohistochemical profile is often informative. ^{[3, 5]}

The neoplastic cells of ovarian dysgerminomas express placental alkaline phosphatase (PLAP), CD117 (c-kit), OCT 3/4, SALL4, and, variably, cytokeratin (see the images below). They do not express epithelial membrane antigen (EMA), S100 protein, CD45 (LCA), or alpha-fetoprotein (AFP).

Ovarian dysgerminomas pathology. Dysgerminoma immunohistochemistry (×200). CD117 = a proto-oncogen (c-kit); CKAE1/CAM5.2 = cytokeratins; D2-40 = a monoclonal antibody; H&E = hematoxylin-eosin; OCT 3/4 = a transcription factor; PLAP = placental alkaline phosphatase.

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Syncytiotrophoblast-like giant cells are the source of beta-human chorionic gonadotropin (beta-hCG) production; this protein expression is confirmed by immunohistochemistry. D2-40 membrane expression has been established in testicular seminoma ^[13] but has not been extensively explored in ovarian dysgerminoma.

Isochromosome 12 (i(12p)) is seen in ovarian dysgerminomas, as well as in seminomas of the testes. A wide array of genetic syndromes has been associated with ovarian dysgerminomas; however, many associations are loose, and establishing molecular/genetic relationships is problematic. These syndromes include but are not limited to Frasier syndrome, ^[14]  pseudo-Meigs syndrome, ^[15]  ataxia-telangiectasia, ^[16]  and Apert syndrome. ^[17]

More recently, whole-exome sequencing data has shown that "KIT mutations are frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas." ^[18]

Swyer syndrome is an important intersex disorder that has been shown to have a close relationship with dysgerminoma, as well as its in-situ counterpart, gonadoblastoma. ^{[19, 20]} Swyer syndrome (pure gonadal dysgenesis) is a disorder of sexual differentiation that is characterized by mutations of the SRY gene responsible for male sex characteristics. This gene is located on the Y chromosome (p11.31); mutations at this site result in phenotypic females with müllerian external genitalia, underdeveloped (streak) internal gonads, amenorrhea, and rudimentary development of breasts, pubic hair, and axillary hair. These patients are at increased risk (approximately 20-50% by adulthood) for dysgerminoma/gonadoblastoma in one or both ovaries. ^[20]

Gonadoblastomas are neoplastic proliferations found almost exclusively in patients with gonadal dysgenesis (pure or mixed), male pseudohermaphroditism, and Turner syndrome (45,XO and mosaics). More than 90% of patients with gonadoblastomas have a Y chromosome. ^[21]

Gonadoblastomas are histologically characterized by expanded nests containing Sertoli cells, germ cells, and granulosa cells admixed with variable amounts of hyaline. These nests morphologically resemble the Call-Exner bodies associated with granulosa cell tumors. Leydig cells may also be found within the interstitium. Characteristically, these neoplastic nests and/or fibrotic stroma between nests often contain large, irregular calcifications. Mitotic activity, cytologic atypia, and necrosis are minimal or absent.

The following images depict examples of gonadoblastoma histology.

Ovarian dysgerminomas pathology. Dysgerminoma and gonadoblastoma histology. A: Dysgerminoma with an adjacent zone of necrosis and large calcifications (×40). B: Gonadoblastoma with an adjacent dysgerminoma (×40). C: Gonadoblastoma with an adjacent dysgerminoma (×40). D: Gonadoblastoma (×200).

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Ovarian dysgerminomas pathology. Gonadoblastoma immunohistochemistry (×200). CD117 = a proto-oncogen (c-kit), ; CKAE1/CAM5.2 = cytokeratins; D2-40 = a monoclonal antibody; H&E = hematoxylin-eosin; OCT 3/4 = a transcription factor; PLAP = placental alkaline phosphatase.

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It is not uncommon to see regions of neoplastic overgrowth by ovarian dysgerminoma; however, other malignant germ cell elements may also be seen, such as yolk sac and choriocarcinoma. ^{[3, 5]}

The prognosis and treatment of ovarian dysgerminomas primarily depend on their clinical stage. The overwhelming majority (approximately 75%) of these tumors are limited to one or both ovaries (International Federation of Gynecologists and Obstetricians [FIGO] stage 1) at the time of diagnosis. Regardless of stage, fertility-sparing surgery is recommended for patients desiring fertility preservation, with ultrasound monitoring; after completion of child-bearing, completion surgery should be considered. ^[4]

For patients with stage IA disease (ie, disease that is limited to one ovary), unilateral oophorectomy alone with close clinical, radiologic, and serologic follow-up is the treatment of choice, especially when fertility is to be maintained. The relapse rate ranges from 10% to 20%; overall survival is 90%-100%. ^[22] Patients who suffer relapses usually receive chemotherapy; survival for such patients is over 90%.

For those patients with disease presenting in stages IB, II, and III who wish to maintain fertility, unilateral oophorectomy followed by combination chemotherapy (3-4 cycles of adjuvant chemotherapy with cisplatinum, etoposide/vinblastine, and bleomycin) may be curative and spare ovarian function. ^[23]  Although these tumors are radiosensitive and radiotherapy was previously used for the treatment of dysgerminomas, there is a risk of radiation toxicity to the bowel; hence, chemotherapy is the current preferred modality of treatment for disease above stage IA as well as relapses. ^[4]