Increased Proliferation as Independent Predictor of Disease Recurrence in Initial Stage pTa Urothelial Bladder Cancer

Johannes Breyer; Sanzhar Shalekenov; Atiqullah Aziz; Bastiaan W G van Rhijn; Johannes Bründl; Eva Lausenmeyer; Julius Schäfer; Stefan Denzinger; Christian Giedl; Maximilian Burger; Arndt Hartmann; Matthias Evert; Wolfgang Otto

doi:10.3233/BLC-170103

Increased Proliferation as Independent Predictor of Disease Recurrence in Initial Stage pTa Urothelial Bladder Cancer

Bladder Cancer. 2017 Jul 27;3(3):173-180. doi: 10.3233/BLC-170103.

Affiliations

¹ Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany.
² Department of Urology, University of Hamburg, Hamburg, Germany.
³ Department of Surgical Oncology (Urology), Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁴ Institute of Pathology, University of Regensburg, Regensburg, Germany.
⁵ Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany.

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.

Keywords: Immunohistochemistry; Ki-67; recurrence; urothelial bladder cancer.