Prognostic implications of aberrations in p16/pRb pathway in urothelial bladder carcinomas: A multivariate analysis including p53 expression and proliferation markers

Objective: To assess the prognostic value of the expression of two negative regulators of the cell cycle, namely CDKN2/INK4a gene product (p16) and re tinoblastoma gene product (pRb), in urinary bladder cancer in relation to c linicopathological parameters, proliferative fraction and p53 protein accum ulation. Methods: Paraffin sections from 139 patients with urothelial carcinomas wer e stained immunohistochemically with antibodies to p16 (F12), pRb (PMG3-245 ), p53 (DO1), PCNA (PC10) and Ki-67 (MIB-1). Results: Diminished p16 and pRb expression occurred in 29 and 74% of cases, respectively, being associated with advanced stage but not with histologic al grade, papillary status or proliferation rate. In most cases (53%) with some fault in the p16/pRb pathway, only one gene was affected. A double-neg ative p16/pRb phenotype was comparatively uncommon (25%) and was usually se en in T3-T4 tumours. In survival analysis (either univariate or multivariat e) aberrant p16 expression was an adverse prognostic parameter only in T3-T 4 tumours. In contrast, the abnormal p16/pRb and p53/p16 phenotypes were li nked to a diminished overall and disease-free survival (univariate analysis ); p53/p16 abnormal expression was also found to be an independent predicto r of reduced survival in muscle-invasive tumours, while proliferation marke rs were the only parameters with independent significance in superficial (T a-T1) tumors. Conclusion: Our results suggest that lack of p16 immunoexpression, when com bined with p53 accumulation plays an important role in determining the clin ical outcome in muscle-invasive urothelial carcinomas. Copyright (C) 2001 S . Karger AG, Basel.