Ovarian endometrioma subtypes defined by the ratio of ciliated cells: implications for endometriosis origin and carcinoma histologic subtype

Background: The implantation (retrograde menstruation) theory hypothesizes that endometriosis arises when refluxed endometrial cells implant at ectopic sites; however, a fallopian tube epithelial origin has also been proposed. Because endometrium and fallopian tube epithelia differ markedly in their balance of ciliated and secretory cells, we asked whether ciliated-cell proportion defines ovarian endometrioma subtypes and associates with the histologic phenotype of endometriosis-associated ovarian carcinoma. Methods: We analyzed 67 specimens: paired eutopic endometrium and fallopian tube (17 pairs), ovarian endometrioma (n=30), deep (n=6) and peritoneal (n=3) endometriosis, and endometriosis-associated cancers (n=11). Ciliated and secretory differentiation were assessed by immunostaining for forkhead box J1 (FOXJ1) and ezrin (EZR), and 3-mercaptopyruvate sulfurtransferase (MPST), respectively; FOXJ1/paired-box gene 8 (PAX8) co-localization was evaluated by double immunofluorescence. Ovarian endometriomas were classified using an 18.71% FOXJ1-positive cut-off. Results: FOXJ1-positive ciliated cells were abundant in fallopian tube epithelium but scarce in eutopic endometrium, deep endometriosis, and peritoneal endometriosis. Ovarian endometriomas showed a bimodal distribution of FOXJ1-positive frequency and were classified as type 1 (<18.71%, endometrium-like, 19/30) or type 2 (≥18.71%, fallopian tube-like; 11/30). FOXJ1-positive frequency was significantly higher in fallopian tube and type 2 endometrioma than in endometrium, type 1 ovarian endometrioma, and deep and peritoneal endometriosis. In type 2 endometrioma, most FOXJ1-positive ciliated cells co-expressed PAX8, whereas FOXJ1-positive cells lacked PAX8 in fallopian tube epithelium. Clear cell carcinoma was EZR-positive and MPST-negative, whereas endometrioid carcinoma was predominantly MPST-positive with a minor FOXJ1/EZR-positive subset; a mixed carcinoma showed the same component-specific profiles. Conclusions: Ovarian endometriomas comprise two subtypes defined by ciliated-cell proportion, whereas deep and peritoneal endometriosis show low ciliated-cell content comparable to eutopic endometrium. The FOXJ1/PAX8 co-expressing ciliated cells in “fallopian tube-like” type 2 lesions indicate a transitional epithelial phenotype distinct from terminally differentiated fallopian tube epithelium and are compatible with an endometrial origin even for ciliated-cell-rich lesions. Along with the EZR/MPST profiles distinguishing clear cell and endometrioid carcinoma, these findings suggest that differentiation states of endometriotic epithelium may be linked to the histologic phenotype of endometriosis-associated ovarian cancer.