A 27-year-old women presented with abdominal pain and early satiety. Subsequent imaging demonstrated a 12 cm right ovarian mass. Her admission labs were all within the normal range, except for her serum calcium, which was modestly elevated. The patient underwent a unilateral salpingo-oophorectomy with salpingectomy with the following findings:
The correct answer is ...
Small cell carcinoma of the ovary, hypercalcemic type
Small cell carcinoma of the ovary, hypercalcemic type (SSCOHT), is a rare but aggressive ovarian tumor. It affects younger women, with an average age of diagnosis of 24. While the majority of patients will have hypercalcemia (>60%), a minority of patients will not have significant hypercalcemia prior to diagnosis. Symptomatic hypercalcemia is relatively uncommon. The clinical outcomes for SSCOHT are poor, with survival of early (stage I) disease as low as 33% and overall survival estimated to be 10% to 20%.
Histologically, these tumors can have a range of morphologies, including diffuse, trabecular, and nested architectures. So called ‘follicle-like’ spaces are often present, although they will be absent in some cases, such was the case in the current patient. Cytologically, the constitutive cells are usually small with scant cytoplasm, vesicular chromatin, and small nucleoli. A population of larger cells is also often present, characterized by abundant cytoplasm and with an eccentrically placed nuclei and prominent nucleoli. Rarely, large cells will make up the majority of the cellularity. Cells with prominent rhabdoid character are often present, which may be a useful finding. Mitotic activity is brisk, and necrosis is often present. A minority of cases will demonstrate mucinous epithelium, typically in the form of cystic spaces.
SCCOHT typically are immunoreactive for WT1, CD10, calretinin and EMA, and are negative for inhibin and SF1. Despite its name, neuroendocrine markers are positive in only a small minority of cases. Most significantly, the vast majority of SSCOHT show loss of SMARCA4. SMARCA4, also known as BRG1, is a member of SWItch/Sucrose Non-Fermentable (SWI/SNF) complex of proteins and is lost in many malignant neoplasms, including SMARCA4 deficient undifferentiated carcinomas of endometrium, SMARCA4 deficient thoracic sarcomas, and a subset of epithelioid sarcomas with retained SMARCB1/INI1. Loss of expression of this marker in combination with the above immunostains is useful in confirming the diagnosis.
The differential diagnosis for SSCOHT is broad, and immunohistochemical techniques greatly assist in narrowing the differential diagnosis. Granulosa cell tumors, both adult-type and juvenile-type, may show morphologic overlap and may present in a similar patient demographic. Markers of sex cord stromal differentiation, such as inhibin, SF1, and FOXL2 will be positive in granulosa cell tumors but would be negative in SSCOHT. A primary pulmonary-type small cell carcinoma would also be a consideration.
Morphologically, pulmonary-type small cell carcinoma will lack the characteristic follicle-like spaces, lack a large cell component, are often positive for TTF1, and more likely to be positive for neuroendocrine markers. They are usually negative for WT1 and demonstrate retained SMARCA4. Ovarian involvement by a hematopoietic neoplasm is sometimes a consideration due to morphologic similarities. Careful and thorough sampling should reveal a more conventionally epithelial component, and immunohistochemistry will readily differentiate these lesions. Metastatic tumors from extra-ovarian primaries should also be considered and excluded, including small cell carcinomas of pulmonary origin, endometrial carcinomas (including SMARCA4 deficient undifferentiated/dedifferentiated carcinomas), and melanoma, among others.
Mark Hopkins, M.D.
Fellow, Surgical Pathology
Maryam Shahi, M.D.
Senior Associate Consultant, Anatomic Pathology
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science