Two Types of Ovarian Cortical Inclusion Cysts: Proposed Origin and Possible Role in Ovarian Serous Carcinogenesis

Ovarian cortical inclusion cysts (CICs) have been long regarded as a possible site of origin of epithelial ovarian carcinoma. It has been proposed that they develop from invagination of ovarian surface epithelium (OSE) which then undergoes metaplasia to form mullerian-type tissue and then undergoes neoplastic transformation. Recent studies have challenged this view, at least for high-grade serous carcinoma, proposing that the latter arise from occult carcinomas in the fallopian tube. Although there is compelling evidence supporting this view, it does not account for the origin of all high-grade serous carcinomas. We have postulated that a subset of high-grade serous carcinoma may develop from CICs, but that they are derived from implantation of tubal epithelium when the OSE is disrupted at ovulation. If true, it would be expected that the number of CICs would increase with age and that CICs would not be present before menarche. To test this hypothesis we examined ovaries removed at autopsy for the presence of CICs and correlated their presence with age. In addition, we used immunohistochemistry for PAX8 (mullerian marker) and calretinin (mesothelial marker). CICs were defined as either ciliated (tubal-type, PAX8-positive) or flat (OSE-type, calretinin-positive). As it has been argued that steroid hormones convert mesothelial-derived OSE to mullerian-type tissue, we performed immunohistochemistry for estrogen and progesterone receptors. CICs lined by tubal-type epithelium were found only in postmenarchial women and 20/21 (95%) were PAX8-positive; none of the 5 flat cysts expressed PAX8 but 4/5 (80%) expressed calretinin. Estrogen receptor was expressed in 1 of 21 (5%) ciliated CICs, whereas it was negative in all 5 flat CICs. Progesterone receptor was expressed in 14 of 21 (66%) ciliated CICs, and in none of the 5 flat cysts. The findings suggest that there are 2 types of CICs, 1 from OSE and 1 from tubal epithelium that probably develop at the time of ovulation.