Impaired p63 Expression Associates with Poor Prognosis and Uroplakin III Expression in Invasive Urothelial Carcinoma of the Bladder

Purpose: p63 is proposed to play roles in normal development and differentiation of stratified epithelia including urothelium. We recently reported that impaired p63 expression is a common feature of high-grade invasive urothelial carcinomas and associates with reduced β-catenin. On the basis of these facts, we proposed that impaired p63 expression contributes to biological aggressiveness of urothelial neoplasms. Uroplakin (UP) III expression was also evaluated to investigate a possible association between loss of p63 expression and terminal urothelial differentiation. Experimental Design: Expression of p63, β-catenin, and UP III was immunohistochemically analyzed in 75 cystectomy specimens of high-grade invasive bladder carcinoma. p63 expression was semiquantified and compared with pathological parameters, expression of β-catenin and UP III, and cancer-specific survival. Results: Lower p63 expression was significantly associated with higher Tumor-Node-Metastasis (TNM) stage ( P = 0.0004), lymph-node metastasis ( P = 0.013), and reduced β-catenin expression ( P = 0.003). By univariate analysis, lower p63 expression, along with TNM stage and lymph-node status, were significantly associated with a poor prognosis ( P = 0.0005), whereas reduced β-catenin was not. By multivariate analysis, the prognostic effect of p63 expression was independent of TNM stage and lymph-node status with marginal statistical significance ( P = 0.074). UP III expression was restricted to a subset of p63-negative carcinoma cells, including even anaplastic carcinoma cells. Conclusions: Impaired p63 expression characterizes biological aggressiveness of high-grade invasive urothelial carcinomas. Moreover, loss of p63 expression is a prerequisite for UP III expression. Our data suggest that p63 plays critical roles in tumor progression and biochemical terminal differentiation of urothelial neoplasms.