Cumulative alterations of p27Kip1-related cell-cycle regulators in the development of endometriosis-associated ovarian clear cell adenocarcinoma

Aims: To identify the key cell-cycle dysregulations in the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA). Methods and results: Expression of p27Kip1-interacting cell-cycle regulators, such as p27Kip1 itself, Skp2, cyclin-dependent kinase subunit 1 (Cks1), cyclin A and cyclin E, and Ki67 labelling index (LI), were analysed by immunohistochemistry in 23 CCAs with 36 endometriotic or atypical endometriotic lesions adjacent to CCA from a cohort of 23 patients, and in 31 cases of solitary endometriosis. The cell-cycle regulators examined were overexpressed (Skp2, Cks1, cyclin A and cyclin E; P < 0.01, each) or down-regulated (p27Kip1, P = 0.044) significantly more frequently in the CCAs than in the adjacent endometriosis. The frequency of Skp2 overexpression was significantly higher in atypical endometriosis than in endometriosis, and the frequency of Skp2 and cyclin A overexpression was significantly higher in CCA than in atypical endometriosis (P < 0.01, each). Mean Ki67 LI increased from endometriosis (8.4%) through atypical endometriosis (21.4%) to CCA (46.9%), with statistical significance between each component (P < 0.01, each). The frequency of cell-cycle regulator expression and mean Ki67 LIs were not significantly different between solitary endometriosis and endometriosis adjacent to CCA. Conclusions: Alteration of the p27Kip1-interacting cell-cycle regulators appeared strongly involved in the progression of endometriosis-associated ovarian clear cell carcinogenesis through increasing cell proliferative activity.