Prognostic impact of combined loss of RB1, p53 and p21 in muscle-invasive bladder cancer

Benedikt Ebner; Lennert Eismann; Julian Hermans; Marc Kidess; Nikolaos Pyrgidis; Marie Semmler; Yannic Volz; Alexander Buchner; Michael Chaloupka; Marie-Lisa Eich; Philipp Weinhold; Christian G Stief; David Horst; Gerald B Schulz; Simon Schallenberg

doi:10.1016/j.prp.2025.155960

Prognostic impact of combined loss of RB1, p53 and p21 in muscle-invasive bladder cancer

Pathol Res Pract. 2025 Apr 8:270:155960. doi: 10.1016/j.prp.2025.155960. Online ahead of print.

Authors

Affiliations

¹ Department of Urology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address: Benedikt.Ebner@med.uni-muenchen.de.
² Department of Urology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
³ Institute of Pathology, University Hospital Cologne, Cologne, Germany.
⁴ Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
⁵ Institute of Pathology, University Hospital Cologne, Cologne, Germany; Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

PMID: 40215668
DOI: 10.1016/j.prp.2025.155960

Abstract

Introduction: Muscle-invasive bladder cancer (MIBC) represents a genetically heterogeneous disease with limited prognostic markers. This study aimed to validate the prognostic relevance of combined alterations in cell cycle regulators RB1, p53, and p21 in a broad cohort of MIBC patients undergoing radical cystectomy (RC).

Material and methods: We analyzed formalin-fixed paraffin-embedded material from MIBC patients who underwent RC at the Department of Urology, University Hospital, Ludwig-Maximilians-University Munich. Tissue microarrays (TMAs) from 251 MIBC patients (pT2-pT4) were constructed, incorporating triplicate cores from tumor center and front. Immunohistochemical expression of RB1, p53, and p21 was assessed using a four-grade scoring system. Prognostic associations with overall survival (OS) and cancer-specific survival (CSS) were evaluated using multivariable Cox regression, Kaplan-Meier curves, and log-rank tests.

Results: We assessed 4518 stainings from 251 patients. Single marker analysis revealed no significant association between the loss of RB1, p53, or p21 and OS or CSS. However, the loss of two or three markers was significantly associated with worse OS (HR 3.49, 95 % CI 1.28-9.50; p = 0.01) and CSS (HR 11.2, 95 % CI 1.46-86.04; p = 0.02).

Conclusions: RB1, p53, and p21 are insufficient as single prognostic markers in MIBC but demonstrate significant prognostic relevance when analyzed in combination. These findings underscore the need for multi-marker approaches in prognostic modeling and personalized treatment strategies for MIBC.

Keywords: MIBC; Muscle-invasive bladder cancer; P21; P53; Prognostic markers; RB1; Urothelial carcinoma.