Increased proliferation as independent predictor of disease recurrence in initial stage pTa urothelial bladder cancer

Abstract

Objectives: To investigate the predictive impact of the proliferation biomarker Ki-67 on the clinical course of patients with initial stage pTa urothelial carcinoma of the bladder (UCB). Methods: We retrospectively analyzed all patients treated by transurethral resection of bladder tumors (TUR-B) for UCB between 1992-2004 in a single-center. Disease recurrence (≥pTa UCB) and absent tumor in histopathology, assessed by TUR-B with a non-malignant result for endoscopic suspect bladder lesion displayed endpoints. Immunohistochemical (IHC) analysis of formalin-fixed and paraffin-embedded tissue blocks was performed with an immunostainer using a primary antibody for Ki-67. Semiquantitative evaluation of Ki-67 was performed by three reviewers. Increased proliferation was defined with a cut-off value of ≥50. Uni- and multivariable binary regression analyses were applied to address prediction of disease recurrence. Results: 215 patients (84 male, median age 69 years at first diagnosis) were evaluable and included to the study. 89 patients stayed disease-free (41), 126 patients showed recurrence (59). Recurrence rates of patients with Ki-67 expression <10, 10-24, 25-49 and ≥50 were 14.8 vs. 30.8 vs. 63.9 and 80.7, respectively (p<0.001). In Kaplan-Meier analysis patients with increased proliferation ≥50 showed a statistically significant worse 10-year recurrence-free survival (19 vs. 57, p<0.001). Multivariable regression analysis revealed instillation treatment (p=0.001) and high proliferation of Ki-67 (p<0.001) to be independent predictors of recurrence in stage pTa UCB. Conclusions: High proliferation with Ki-67 expression ≥50 was strongly associated with worse recurrence-free survival in patients with initial stage pTa UCB. Stage pTa UCB patients with increased Ki-67 expression should undergo a strictly follow-up regime comparable to stage pT1 bladder carcinoma, while at least patients with Ki-67 expression <10 might be feasible for more liberate follow-up regime after evaluation of our data in randomized, prospective and multicenter studies.