Altered expression of p27Kip1-interacting cell-cycle regulators in the adult testicular germ cell tumors: potential role in tumor development and histological progression

We examined the potential role of cell-cycle dysregulation in the development and histological progression of adult testicular germ cell tumors (TGCTs). Expressions of p27Kip1-interacting cell-cycle regulators (down-regulation of p27Kip1 and overexpression of Skp2, Cks1, cyclin A, and cyclin E) and Ki-67 labeling index (LI) were immunohistochemically examined in histological components of 50 intratubular germ cell neoplasms, unclassified (IGCNUs); 74 seminomas; and 25 embryonal carcinomas, identified from 88 patients. Altered expression of p27Kip1, Skp2, Cks1, cyclin A, and cyclin E was observed in 20%, 12%, 16%, 10%, and 24% of IGCNUs; 26%, 36%, 27%, 89%, and 23% of seminomas; and 48%, 68%, 56%, 100%, and 60% of embryonal carcinomas, respectively. A significant difference in the frequency of Skp2 and cyclin A overexpression was observed between IGCNUs and seminomas. Significantly more frequent alterations of Skp2, Cks1, and cyclin E and p27Kip1 were detected in embryonal carcinomas than in seminomas. Alterations of all cell-cycle regulators were significantly more frequent in embryonal carcinomas than in IGCNUs. The mean Ki-67 LI significantly increased from IGCNU (21.2%) through seminoma (34.7%) to embryonal carcinoma (54.2%). These results suggest that alterations of the p27Kip1-interacting cell-cycle regulators are common in TGCTs and may be involved in their histological progression.