Final Diagnosis -- Small Cell Carcinoma of the Ovary, Hypercalcemic Type

FINAL DIAGNOSIS

Small cell carcinoma of the ovary, hypercalcemic type

DISCUSSION

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive and highly malignant tumor affecting the women under 40. It was first described as a distinct entity by Dickersin et al in 1982 (1). Fewer than 500 cases have been described in the literature and it accounts for less than 1% of all ovarian cancer diagnoses. Due to the initial consideration of epithelial origin, the term of SCCOHT has been used to distinguish this entity from its mimicker, the neuroendocrine or pulmonary type (2). In fact epithelial origin of SCCOHT was recently challenged as new immunostains and molecular studies become available. Sex cord, germ cell or neuroendocrine origin has been suggested and SCCOHT is currently listed within the category of miscellaneous ovarian neoplasms in 2014 World Health Organization (WHO) classification (3).

Clinically, SCCOHT are generally diagnosed in second or third decades of life (peak at 18-30 years). Rare familial cases have also been reported (4). The symptom is non-specific and is those related to an abdominal or pelvic mass. Approximately two-thirds patients have hypercalcemia and one-third of patients presents with signs of hypercalcemia.

SCCOHT is predominately unilateral, although familial cases can be bilateral. Macroscopically, the tumor is usually large predominately solid, tan, or cream-colored with foci of cystic degeneration. Areas of hemorrhage or necrosis are commonly seen. Microscopically, the tumor is often composed of diffuse growth of closely packed neoplastic cells with round to oval hyperchromatic nuclei and minimal cytoplasm resembling in a "small round blue cell" appearance. Other growth patterns such as nests, cords, clusters or single cells can be present. Follicle-like structures containing eosinophilic, or rarely basophilic, fluid are seen in ~ 80% of cases. In up to 50% of cases, a component of large cells with abundant eosinophilic cytoplasm, eccentric pale nuclei with prominent nucleoli can be present focally, predominately or exclusively, resulting in a rhabdoid appearance. In those cases with large cell component, SCCOHT shows striking morphologic similarity to malignant atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) and malignant renal rhabdoid tumor (MRT).

Immunohistochemical studies have described a rather non-specific profile of variably positive staining for EMA, pan-keratin, WT1, calretinin, P53 and CD10 and negativity for desmin, S100, ?-inhibin and TTF-1. Variable immunohistochemical staining for neuroendocrine markers has been reported. In 2014, 3 separate groups discovered that SCCOHT is characterized by deleterious mutation of SMARCA4, which encodes the BRG1 protein (5-7). Loss of expression of SMARCA4 (BRG1) on immunohistochemistry is considered highly sensitive and specific for the diagnosis of SCCOHT (8,9). Interestingly, genetic alteration of SMARCA4 are also frequent present in malignant rhabdoid tumors. Given the morphologic and genetic similarity, some authors propose to rename SCCOHT as 'malignant rhabdoid tumor of the ovary' (10).

The differential diagnosis of SCCOHT includes numerous other tumors that occurs in young women including juvenile and adult granulosa cell tumor, poorly-differentiated or unclassified Steroli-Leydig cell tumor, desmoplastic small round cell tumor, Ewing family of tumors, lymphoma, ovarian small cell carcinoma of pulmonary type, metastatic melanoma, etc. SCCOHT is usually distinguished from these mimickers by its unique clinical presentation, histological appearance, immunophenotype and cytogenetic characteristics, especially the loss of nuclear expression of BRG1.

SCCOHT has a very poor prognosis, with a 33% survival rate when diagnosed at an early stage and a much more dismal prognosis with advanced stage at diagnosis. The traditional management includes surgical resection, followed by multiple adjuvant chemotherapy. The favorable prognostic parameters include increased age at diagnosis, normal serum calcium at presentation, no large cell component and small tumor size (<10 cm) (10).

REFERENCES

1. Dickersin GR, Kline IW, Scully RE. Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer. 1982;49(1):188-97.
2. Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am J Surg Pathol. 1994;18(11):1102-16.
3. Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs. Fourth Edition. 2014
4. Witkowski L, Donini N, Byler-Dann R, et al. The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases. Fam Cancer. 2017;16(3):395-399.
5. Jelinic P, Mueller JJ, Olvera N, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet. 2014;46(5):424-6.
6. Witkowski L, Carrot-Zhang J, Albrecht S, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 2014;46(5):438-43.
7. Ramos P, Karnezis AN, Craig DW, et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet. 2014;46(5):427-9.
8. Conlon N, Silva A, Guerra E, et al. Loss of SMARCA4 Expression Is Both Sensitive and Specific for the Diagnosis of Small Cell Carcinoma of Ovary, Hypercalcemic Type. Am J Surg Pathol. 2016;40(3):395-403.
9. Karanian-Philippe M, Velasco V, Longy M, et al. SMARCA4 (BRG1) loss of expression is a useful marker for the diagnosis of ovarian small cell carcinoma of the hypercalcemic type (ovarian rhabdoid tumor): a comprehensive analysis of 116 rare gynecologic tumors, 9 soft tissue tumors, and 9 melanomas. Am J Surg Pathol. 2015;39(9):1197-205.
10. Witkowski L, Goudie C, Foulkes WD, et al. Small-Cell Carcinoma of the Ovary of Hypercalcemic Type (Malignant Rhabdoid Tumor of the Ovary): A Review with Recent Developments on Pathogenesis. Surg Pathol Clin. 2016;9(2):215-26. .

Contributed by Huina Zhang, MD, PhD and Esther Elishaev, MD