A 29-year-old woman presents with a complaint of abdominal fullness. An adnexal mass is noted on pelvic examination. Imaging reveals a 12.0-cm solid mass in the left ovary, as well as a few abnormal-appearing regional lymph nodes. The patient undergoes left salpingo-oophorectomy with para-aortic lymph node dissection. Grossly, the ovary is solid, with focal nodules on the external surface and a fleshy, tan, lobulated cut surface.

Master List of Diagnoses

  • Clear cell carcinoma
  • Dysgerminoma
  • Embryonal carcinoma
  • Metastatic carcinoma
  • Undifferentiated carcinoma
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 03, and is dysgerminoma of the ovary.

Criteria for Diagnosis and Comments

The slides show a proliferation of tumor cells with various growth patterns including sheets, nests, trabeculae, and single file cords. The tumor cells are polygonal with variable cytoplasm that is mostly clear, but regions with eosinophilic or amphophilic cytoplasm are present. The nuclei appear high-grade with vesicular chromatin and prominent macronucleoli. Some nuclei have angulated membranes giving a characteristic “squared off” appearance. Some slides show scattered multinucleated syncytiotrophoblastic giant cells. Mitoses are abundant and some slides show necrosis. A variably prominent lymphocytic infiltrate is present within the fibrous septae that separate tumor cells. In some slides, the stroma is eosinophilic and densely collagenized. The overall features are characteristic of dysgerminoma. This patient was classified as pathologic stage T1c (due to ovarian surface involvement) N1 (due to positive regional lymph nodes).

Dysgerminoma is the most common primitive malignant germ cell tumor of the ovary, occurring most commonly in children and young women. As in the presented case, these patients typically experience abdominal distension, mass, or pain. Serum lactic dehydrogenase is often elevated and there may be a mild elevation of human chorionic gonadotropin (hCG) in less than 5% of cases. The average size of dysgerminomas is 15.0 cm and in about 10% of cases bilateral ovarian involvement is identified. Immunohistochemistry performed on dysgerminoma shows positive staining with stem/germ cell related factors KIT, OCT4, NANOG, and SALL4. Placental alkaline phosphatase (PLAP) and D2-40 are also positive in dysgerminoma. There may be limited cytoplasmic dot or rim-like staining with cytokeratin; however epithelial membrane antigen (EMA) is negative. Most dysgerminomas are associated with isochromosome 12p. Although KIT protein expression is typically seen by immunohistochemistry, this does not correlate with KIT mutations, which are present in reportedly only 25% - 50% of cases. One study has shown an association with KIT mutation in dysgerminoma and advanced tumor stage at presentation, suggesting potential use as a prognostic factor.

Embryonal carcinoma is a rare neoplasm that may have similar clinical presentation and histologic features to dysgerminoma. Serum hCG is more commonly elevated in patients with embryonal carcinoma than in patients with dysgerminoma. Similar to dysgerminoma, embryonal carcinoma also grows in sheets of primitive/high-grade appearing cells with abundant mitoses; however, in embryonal carcinoma, the nuclei are larger and more hyperchromatic and the cytoplasm is typically more basophilic and amphophilic, and there is no significant lymphocytic infiltrate. Additionally, there are usually admixed cells lining slit-like spaces and often papillary structures. Embryonal carcinoma also expresses OCT4, NANOG, and SALL4 and is negative for EMA; PLAP may also be positive. However, unlike dysgerminoma, embryonal carcinoma is positive for CD30 with strong expression of broad-spectrum cytokeratin. Given the marked overlap and variability of immunoexpression in dysgerminoma and embryonal carcinoma, a panel of markers may be required to distinguish these two lesions in morphologically challenging cases.

While testicular primitive germ cell tumors are very commonly mixed (about one third of cases), this is noted in only an estimated 8% of ovarian malignant germ cell tumors (most commonly dysgerminoma admixed with yolk sac tumor). Although scattered syncytiotrophoblast cells can be identified in the presented case, there is no cytotrophoblast cell element, which would be required to diagnose a choriocarcinoma component. In cases of mixed germ cell tumors report the proportions of each component, as this has influenced prognosis. However, due to the effectiveness of modern chemotherapy regimens, tumor stage has become the most important prognostic indicator.

Much of the tumor in this case has clear cytoplasm, raising the differential diagnosis of clear cell carcinoma. This entity is particularly important to recognize, as it is associated with a poorer prognosis. While clear cell carcinoma may display solid architecture, there is typically a tubulocystic or papillary component with hyalinized fibrovascular cores. The nuclei are more hyperchromatic and eccentric or apical, protruding into lumens (hobnail cells). Immunohistochemistry for EMA is positive in clear cell carcinoma while negative in dysgerminoma. Of note, OCT4 and SALL4 (positive in dysgerminoma) have both been reported to show focal immunoreactivity in some clear cell carcinomas. Finally, the clinical history may be the most helpful information when considering this differential, as clear cell carcinoma typically occurs in older patients, with a mean age of 55 years.

Dysgerminomas are often grossly lobulated and microscopically may have nodules of tumor cells displaying cords and small gland-like cystic spaces, therefore a diagnosis of metastatic carcinoma may be considered. The young age group of patients with dysgerminoma makes the possibility of a previous malignancy unlikely. In patients with a known history, evaluation of the pattern of cytokeratin staining would be helpful in arriving at the correct diagnosis. The lesion would be diffusely strongly positive in metastatic carcinoma, while there would be limited expression in dysgerminoma.

Undifferentiated carcinoma is a rarely made diagnosis in the ovary, defined as a malignant epithelial tumor showing no specific Müllerian cell type differentiation. The tumor displays sheets of monotonous, ovoid, non-cohesive cells with frequent mitoses and geographic necrosis. Undifferentiated carcinoma is essentially a diagnosis of exclusion, rendered after thorough investigation yields no distinguishing histologic features or immunoreactivity. These patients present at a later age than those with dysgerminoma.

  1. Which of the following histologic features is most helpful in distinguishing dysgerminoma from embryonal carcinoma?
    1. Abundant mitoses
    2. Amphophilic cytoplasm
    3. Diffuse growth pattern
    4. Prominent lymphocytic infiltrate
    5. Prominent nucleoli
  2. Which of the following immunoprofiles is most characteristic of dysgerminoma?
    1. KIT-negative, SALL4-positive, EMA-negative, CD30-positive, cytokeratin-positive
    2. OCT4-negative, NANOG-negative, EMA-positive, CD30-negative, cytokeratin-positive
    3. OCT4-negative, NANOG-negative, EMA-positive, cytokeratin-positive, D2-40-positive
    4. OCT4-negative, SALL4-negative, EMA-negative, CD30-positive, cytokeratin-negative
    5. OCT4-positive, NANOG-positive, EMA-negative, CD30-negative, cytokeratin-negative
  3. Which of the following is considered the most significant prognostic indicator for dysgerminoma?
    1. Elevated serum human chorionic gonadotropin
    2. KIT positivity by immunohistochemistry
    3. Lymph node involvement
    4. Older age at presentation
    5. Presence of yolk sac tumor component

References

  1. Baker PM, Oliva E. Immunohistochemistry as a tool in the differential diagnosis of ovarian tumors: an update. Int J Gyn Pathol. 2004;24:39-55.
  2. Cao D, Guo S, Allan RW, Molberg KH, Peng Y. SALL4 is a novel sensitive and specific marker of ovarian primitive germ cell tumors and is particularly useful in distinguishing yolk sac tumor from clear cell carcinoma. Am J Surg Pathol. 2009;33:894-904.
  3. Cheng L, Roth LM, Zhang S, et al. KIT gene mutation and amplification in dysgerminoma of the ovary. Cancer. 2011;117:2096-2103.
  4. Cheng L, Thomas A, Roth LM, Zheng W, Michael H, Karim FWA. OCT4: a novel biomarker for dysgerminoma of the ovary. Am J Surg Pathol. 2004;28:1341-1346.
  5. Han G, Soslow RA. Nonserous ovarian epithelial tumors. Surg Pathol Clin. 2011;4:397-459.
  6. Hoei-Hansen CE, Kraggerud SM, Abeler VM, Kaern J, Rajpert-De Meyts E, Lothe RA. Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol Cancer. 2007;6:12.
  7. Kurman RJ, Carcangiu ML, Herrington CS, Young RH (eds) WHO Classification of Tumours of Female Reproductive Organs. Lyon, FR: IARC Press; 2014;11-86.
  8. McCluggage WG, Young RH. Immunohistochemistry as a diagnostic aid in the evaluation of ovarian tumors. Semin Diagn Pathol. 2005;22:3-32.
  9. Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005;18:S61-S79.
  10. Young RH. Ovarian tumors and tumor-like lesions in the first three decades. Semin Diagn Pathol. 2014;31:382-426.

Author

Rochelle A. Simon, MD
Surgical Pathology Committee
The George Washington University
Washington, DC

Answer Key

  1. d). Prominent lymphocytic infiltrate
  2. e). OCT4-positive, NANOG-positive, EMA-negative, CD30-negative, cytokeratin-negative
  3. c). Lymph node involvement