Carbonic Anhydrase IX in Bladder Cancer A Diagnostic, Prognostic, and Therapeutic Molecular Marker

BACKGROUND: The objective of this study was to evaluate the role of carbonic anhydrase IX (CAIX) in urothelial carcinoma of the bladder. METHODS: A tissue microarray was constructed that contained 724 tissue samples from 340 patients. Immunohistochernical staining was performed using the antibody MN-75, the percentage of positive cells was evaluated, and their association with tumor (T) classification, grade, and survival was assessed. RESULTS: All normal urothelial tissue samples were negative for CAIX expression, whereas 71% of bladder cancers expressed CAIX. CAIX expression was higher in noninvasive (Ta) versus invasive (T1-T4) tumors (P < .001), in low-grade versus high-grade bladder cancer (P < .001), and in metastases versus the corresponding primary tumor (P = .032). For patients with nonmuscle invasive carcinoma who underwent transurethral resection (TUR), higher CAIX expression was associated with poorer recurrence-free survival (P = .001). In addition, for patients with T1 tumors who underwent TUR, higher CAIX expression conveyed a 6.5-fold higher risk of progression into muscle-invasive disease (P = .006). In patients who underwent cystectomy, higher CAIX expression was associated with worse overall survival (P = .003). Multivariate Cox models revealed that CAIX expression was the strongest, independent prognostic factor of recurrence-free survival (hazard ratio, 2.29; P = .001) and overall survival (hazard ratio, 1.9: P < .001). CONCLUSIONS: CAIX was expressed differentially in noninvasive versus invasive tumors, in low-grade versus high-grade bladder cancer, and in primary tumors versus metastases. The current results indicated that CAIX is a strong predictor of recurrence, progression, and overall survival of patients with bladder cancer; and the integration of CAIX expression into conventional prognostic models significantly improved their predictive accuracy. The data suggest a tripartite role of CAIX as a diagnostic, prognostic, and therapeutic molecular marker in bladder cancer. Cancer 2009;115:1448-58. (C) 2009 American Cancer Society.