Clear cell carcinoma of the ovary comprises 7.4% of ovarian carcinomas and 2.4% of ovarian epithelial neoplasms. Women typically present between the ages of 40 and 70 with the peak incidence at age 52. Between 1/3 and 2/3 are nulliparous. Presenting symptoms are usually related to an enlarging abdominal mass. Clear cell carcinoma is the most common epithelial ovarian neoplasm to be associated with paraneoplastic hypercalcemia, and rarely hypercalcemia may be a presenting symptom. Fifty percent of cases are FIGO I at the time of diagnosis, and 15% are FIGO II. Four percent of stage I cases are bilateral. The typical gross appearance is that of a large unilocular cyst (15-20 cm) with one or more white, yellow, or light brown solid areas of tumor protruding into the lumen. Variable amounts of hemorrhage and necrosis may be present.
Adequate sampling is needed as portions of the specimen may be benign or show borderline adenofibroma. The most common morphologic patterns are solid and tubulopapillary, and it is common to have several patterns within one tumor. Sheets of clear cells separated by delicate fibrovascular septa characterize the solid pattern. Clear cells and hobnail cells are found in virtually every case of ovarian clear cell carcinoma. Clear cells are typically polyhedral with distinct cell membranes, eccentric rounded or slightly angular nuclei, and abundant clear cytoplasm rich in glycogen. The tubulopapillary pattern is characterized by papillae that are often complex and frequently contain hyalinized cores. Complex tubules and cysts admixed with papillae characterize the tubulocystic pattern. Clear, hobnail, eosinophilic, or columnar cells line the tubules and papillae. The less common oxyphilic clear cell carcinoma is characterized by extensively eosinophilic cytoplasm.
Despite well-described patterns, architectural and cytologic features do not correlate well with prognosis. Overall, microcalcifications are seen in 10-30% of cases, and most contain eosinophilic PAS positive globules. Mixed clear cell/endometrioid carcinomas and clear cell/serous carcinomas are well described.
The differential diagnosis of clear cell ovarian carcinoma commonly includes yolk sac tumor and dysgerminoma. Krukenberg tumor, metastatic renal cell carcinoma, and struma ovarii are less common entities that may cause diagnostic difficulty.
Clear cell carcinomas with a loose edematous pattern can resemble yolk sac tumors. Patient age is important as yolk sac tumors typically occur in a younger age group. Nuclei and papillae of yolk sac tumors are more primitive and lack hyalinized eosinophilic cores. The Schiller-Duval bodies often present in yolk sac tumors are absent in clear cell carcinoma. Positive alpha-fetoprotein immunostaining favors a diagnosis of yolk sac tumor although occasional clear cell carcinomas show positive staining. Leu-M1 is positive in clear cell carcinoma more commonly than in yolk sac tumor, and is often used to help distinguish the two entities.
A dysgerminoma with a diffuse clear cell pattern may be difficult to distinguish from clear cell carcinoma, however cells in dysgerminoma are not polyhedral and almost always contain lymphocytes. Clear cell carcinoma may have a diffuse inflammatory infiltrate, but plasma cells and other inflammatory cell types are typically present. Clear cell carcinoma with loose edematous stroma and clusters of epithelial cells may resemble a Krukenberg tumor. A mucin stain should be negative in clear cell carcinoma in contrast to Krukenberg tumors. Clinical and radiograph findings often help distinguish ovarian clear cell from metastatic renal cell carcinoma. Renal cell typically lacks hobnail cells and has greater vascularity. In addition to LeuM1, clear cell carcinoma typically shows positive immunostaining for keratins, epithelial membrane antigen, BerEP4, and B72.3. CEA is positive in 63% of cases.
ASSOCIATION WITH ENDOMETRIOSIS
The estimated prevalence of endometriosis is 5-15% in women of reproductive age and 3-5% in postmenopausal women. Shinji Ogawa et al investigated 127 women with primary ovarian carcinoma. Endometriosis was diagnosed in 37 of these patients. 70% of the women with clear cell carcinoma had endometriosis. 43% of women with endometrioid and 7% with serous carcinoma had endometriosis (1). Susan Modesitt et al studied 115 women with endometriosis-associated ovarian cancer and cancer arising in extraovarian endometriosis. Clear cell and endometrioid carcinomas were the most common types of malignancy, each comprising 23% of cases. Mixed epithelial patterns were identified in 19% (2). Although percentages vary, research consistently demonstrates that women with clear cell and endometrioid carcinomas have higher rates of endometriosis than the general female population.
Malignant transformation of endometriosis is often sited as a possible link between endometriosis and ovarian carcinoma. Modesitt et al found histologic transition points between benign endometriosis and malignancy in 40% of their cases. Ogawa et al demonstrated this transition in 22 of the 37 cases of concomitant primary ovarian carcinoma and endometriosis. Molecular studies by Jiang et al (loss of heterozygosity, X chromosome inactivation, and p53 mutation) demonstrated that malignant transformation of endometriosis contributed to ovarian cancer in over half of cases studied (3).
Contributed by Amy Davis, MD and Mirka Jones, MD