Observations on the origin of ovarian cortical inclusion cysts in women undergoing risk-reducing salpingo-oophorectomy

AIMS: Evidence suggests that up to 70% of high-grade serous ovarian carcinomas (HGSCs) arise potentially from fallopian tube fimbriae, and that many of the remaining cases arise from within the ovary in cortical inclusion cysts (CICs) with a Mullerian phenotype (Mullerian-CICs). It has been proposed that Mullerian-CICs arise either from metaplasia of mesothelial ovarian surface epithelium (OSE) entrapped within the ovary after ovulation or from normal tubal cells entrapped postovulation. However, this proposal is controversial. We therefore conducted a study of CICs in women, most of them BRCA1/2 mutation carriers, undergoing risk-reducing salpingo-oophorectomy at our institution from 2000 to 2014. METHODS AND RESULTS: We used immunohistochemistry for PAX8, a Mullerian marker, and calretinin, a mesothelial marker to classify CIC cells. In 499 CICs from 59 women, 72.3% were positive for PAX8 (PAX8+ ): ≥10% of CIC cells positive; 43.5% positive for calretinin (calretinin+ ). The proportion of PAX8+ CICs increased from 62.9% in premenopausal to 80.5% in postmenopausal patients. The proportion of calretinin+ CICs decreased from 52.6% to 35.6%, respectively. There was significant overlap of PAX8 and calretinin positivity: 82 (16.4%) CICs were PAX8+ /calretinin+ ; 43 (40.2%) of these 82 demonstrated PAX8+ /calretinin+ in the same cells. CONCLUSIONS: These results, and the increased ratio of PAX8+ to calretinin+ CICs from premenopausal to postmenopausal, show that many PAX8+ CICs probably arise from metaplasia of OSE-derived CICs. The proportion of PAX+ /calretinin- CICs arising from OSE-derived CICs is unclear, but our results strongly support the proposal that many Mullerian-CICs arise from OSE via metaplasia.