Abnormal expression of multiple proteins predicts cancer-specific mortality in patients with high-grade non-muscle-invasive bladder cancer treated with transurethral resection

High-grade non-muscle-invasive bladder urothelial carcinoma leads to various outcomes. It can cause death even after radical cystectomy and is treated only by transurethral resection (TUR). In the present study, we aimed to determine whether the molecular markers E-cadherin, coxsackie adenovirus receptor (CAR), S100A4 and uroplakin III are associated with clinicopathological outcomes in patients with high-grade non-muscle invasive bladder cancer (NMIBC) treated with TUR. Immunohistochemical staining was performed on serial sections from specimens obtained from 77 patients. Expression patterns were stratified according to the number of abnormally expressed markers: 0-1 or =2. The median follow-up time was 56 months (range, 3-287). The results from the present study indicated that expression of E-cadherin, CAR, S100A4 and uroplakin III was abnormal in 16, 17, 27 and 61% of tumors, respectively. Results of the log-rank test revealed that patients with abnormal expression of multiple molecular markers had a significantly increased risk of bladder cancer-specific mortality (P=0.016). The 5-year cancer-specific survival rates were 91 and 66% for patients with 0-1 and =2 molecular markers, respectively. No individual marker was associated with disease prognosis. Multivariate models that included clinicopathological outcomes and classified molecular markers indicated that abnormal expression of multiple molecular markers and lack of bacillus Calmette-Guerin (BCG) instillation are predictors of cancer-specific death (P=0.046 and 0.029, respectively). Abnormal expression of multiple molecular markers is a strong predictor of mortality in bladder cancer patients undergoing TUR, suggesting that high-grade non-muscle-invasive cancer is characterized by a variety of pathophysiological pathways. A combination of molecular markers may be useful in a minimally invasive modality for determining prognosis.