Clear Cell Carcinoma of the Ovary
Clear cell carcinoma (CCC) is an uncommon type of ovarian malignancy. Among the ovarian surface epithelial-stromal tumor category, the incidence of CCC was 4.8% in Whites, 3.1% in Blacks, and 11.1% Asians (1). Clear cell carcinoma can also occur in the endometrium and uterine cervix with similar morphology as their ovarian counterpart. In contrast to CCC of endometrium and cervix, CCC of the ovary frequently shows background of endometriosis or atypical endometriosis. Some cases of CCC of the ovary (especially without background of endometriosis) show adenofibromatous growth pattern.
Clear cell carcinoma has a variety of patterns, often admixed, including tubulocystic, papillary, and solid. The papillae tend to lack the hierarchical branching and prominent nuclear stratification of serous carcinomas, and often have distinctive cores (2). The cores of the papillae are often hyalinized, contain colloid-like material, or appear hollow. Clear cells and hobnail cells are the most common cell types. The clear cells (which are glycogen rich) are rounded or polyhedral and have eccentric nuclei. The hobnail cells contain a bulbous, usually dark nucleus that protrudes into lumens. Flat or cuboidal cells lining small cysts are less common and often impart a deceptively benign appearance. A subset of tumor cells can have oxyphilic rather than clear cytoplasm. Rarely, the entire tumor is composed of cells with oxyphilic cytoplasm (oxyphilic clear cell carcinoma variant). Mitoses are usually less frequent (mean 3-4?mfs/10?hpf) in CCC than in serous or other high-grade ovarian carcinomas. Immunohistochemically, clear cell carcinoma is usually positive for HNF-1 beta (nuclear), Napsin A (cytoplasmic), CK7, Pax-8 and negative for CK20, ER and WT-1 (3). P53 is variable and reported to show strong positivity in up to 34% of endometrial CCC. Molecular studies have identified ARID1A and PIK3CA gene mutations in 60% and 40% of CCCs respectively, which appear to be early events in CCC carcinogenesis (4). A recently published study of the genetic landscape of CCC showed that endometrial CCC constitutes a histologically and genetically heterogeneous group of tumors with varying outcomes (5). A recent Japanese study identified the following genes to be most frequently mutated in ovarian CCC: ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%), and KRAS (16.7%) (6).
Clear cell carcinoma is notorious for having poor response to conventional platinum-based chemotherapy and high risk for recurrence. Primary treatment of ovarian CCC and CCC of the uterus involves surgery with a total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy. Lymphadenectomy adds important prognostic information. The prognosis is heavily related to tumor stage with a recent study showing 5-year survival of 92% in stage I disease and 31% in advanced stage (7).
Contributed by Min Han, MD, PhD and Rohit Bhargava, MD