BACKGROUND: Prognostic tools in pathological-node (pN) patients after radical cystectomy (RC) are needed. OBJECTIVES: To evaluate the prognostic impact of lymph node (LN)-density on disease-specific survival (DSS) in patients with bladder cancer (BC) undergoing RC with pelvic lymph node dissection. METHODS: We analyzed a multi-institutional cohort of 1169 patients treated with upfront RC for cT1-4aN0M0 urothelial BCat nine centers. LN-densitywas calculated as the ratio of the number of positive LNs×100% to the number of LNs removed. The optimal LN-density cut-off value was defined by creating a time-dependent receiver operating characteristic (ROC) curve in pN patients. Univariable and multivariable Cox' regression analyses were used to assess the effect of conventional Tumor Nodes Metastasis (TNM) nodal staging system, LN-density and other LN-related variables on DSS in the pN-positive cohort. RESULTS: Of the 1169 patients, 463 (39.6%) patients had LN-involvement. The area under the ROC curve was 0.60 and the cut-off for LN-density was set at 20%, 223 of the pN-positive patients (48.2%) had a LN-density ≥ 20%. In multivariable models, the number of LN-metastases (HR 1.03, p = 0.005) and LN-density, either as continuous (HR 1.01, p = 0.013) or as categorical variable (HR 1.37, p = 0.014), were independently associated with worse DSS, whereas pN-stage was not. CONCLUSIONS: LN-density ≥ 20% was an independent predictor of worse DSS in BC patients with LN-involvement at RC. The integration of LN-density and other LN-parameters rather than only conventional pN-stage may contribute to a more refined risk-stratification in BC patients with nodal involvement.

Department of Medical Oncology Claudius Regaud Institute Toulouse University Cancer Center Oncopole Toulouse France

Department of Medicine Surgery and Health Sciences Urological Clinic University of Trieste Trieste Italy

Department of Pathology Institut Curie Paris France

Department of Pathology University Health Network Princess Margaret Cancer Center University of Toronto Toronto ON Canada

Department of Pathology University of Trieste Trieste Italy

Department of Surgery and Surgical Oncology University Health Network Princess Margaret Cancer Center University of Toronto Toronto ON Canada

Department of Surgical Oncology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Translational Research and New Technologies Unit of Urology University of Pisa Pisa Italy

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology and Pediatric Urology University Hospital Erlangen Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Department of Urology Caritas St Josef Medical Center University of Regensburg Regensburg Germany

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology Erasmus MC Cancer Institute University Medical Center Rotterdam The Netherlands

Department of Urology Hôpital Foch UVSQ Paris Saclay University Suresnes France

Department of Urology Hospital Universitario La Ribera Valencia Spain

Department of Urology Leiden University Medical Center Leiden The Netherlands

Department of Urology Reinier de Graaf Hospital Delft The Netherlands

Department of Urology Turku University Hospital and University of Turku Turku Finland

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

Institute of Pathology University Hospital Erlangen Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Molecular Oncology Team Institut Curie CNRS UMR144 PSL Research University Paris France

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