Predictive Value of Combined Immunohistochemical Markers in Patients With pT1 Urothelial Carcinoma at Radical Cystectomy

Purpose: pT1 urothelial carcinoma of the bladder is a potentially aggressive cancer diathesis with heterogeneous clinical behaviors. We tested whether the combination of immunohistochemical markers could risk stratify cases of pT1 urothelial carcinoma of the bladder at radical cystectomy. Materials and Methods: p53, p21, pRB, p27, survivin and Ki-67 immunohistochemical staining was performed on representative urothelial carcinoma of the bladder specimens of 80 patients with pT1 urothelial carcinoma of the bladder treated with radical cystectomy and bilateral pelvic lymphadenectomy (median followup 61.6 months). Results: p53 expression was altered in 25% of patients, p21 in 46%, pRB in 39%, p27 in 35%, survivin in 49% and Ki-67 in 34%. On multivariable analyses p53, p27 and Ki-67 were independently associated with urothelial carcinoma of the bladder recurrence (HR 3.66, p = 0.033; HR 3.76, p = 0.048 and HR 3.96, p = 0.021, respectively) and disease specific mortality (HR 5.25, p = 0.016; HR 3.68, p = 0.043 and HR 6.23, p = 0.009, respectively). The combination of these 3 biomarkers stratified cases into statistically significantly different risk groups for disease recurrence (p <0.001) and disease specific mortality (p <0.001). The addition of the number of altered markers increased the concordance indices of the base model that included grade, lymph node status, lymphovascular invasion and concomitant carcinoma in situ for disease recurrence and disease specific survival from 54.7% to 71.7% and from 64.3% to 77.5%, respectively. Conclusions: Assessment of p53, p27 and Ki-67 in urothelial carcinoma of the bladder specimens improves the prediction of recurrence-free and urothelial carcinoma of the bladder specific survival in patients with pT1 disease at radical cystectomy. These markers may help stratify the heterogeneous population of patients with pT1 disease into risk groups that can be used to guide clinical decision making regarding observation vs adjuvant therapy.