Multi-Center Assessment of Lymph-Node Density and Nodal-Stage to Predict Disease-Specific Survival in Patients with Bladder Cancer Treated by Radical Cystectomy

Erik J van Gennep; Francesco Claps; Peter J Bostrom; Shahrokh F Shariat; Yann Neuzillet; Alexandre R Zlotta; Carlo Trombetta; Markus Eckstein; Laura S Mertens; Rossana Bussani; Maximilian Burger; Joost L Boormans; Bernd Wullich; Arndt Hartmann; Roman Mayr; Nicola Pavan; Riccardo Bartoletti; M Carmen Mir; Damien Pouessel; John van der Hoeven; Theo H van der Kwast; Yves Allory; Tahlita C M Zuiverloon; Yair Lotan; Bas W G van Rhijn

doi:10.3233/BLC-230086

Multi-Center Assessment of Lymph-Node Density and Nodal-Stage to Predict Disease-Specific Survival in Patients with Bladder Cancer Treated by Radical Cystectomy

Bladder Cancer. 2024 Jun 18;10(2):119-132. doi: 10.3233/BLC-230086. eCollection 2024.

Authors

Erik J van Gennep^{1

2}, Francesco Claps^{1

2

3}, Peter J Bostrom^{4

5}, Shahrokh F Shariat^{6

7

8

9

10}, Yann Neuzillet^{1

11

12}, Alexandre R Zlotta⁴, Carlo Trombetta³, Markus Eckstein¹³, Laura S Mertens¹, Rossana Bussani¹⁴, Maximilian Burger¹⁵, Joost L Boormans¹⁶, Bernd Wullich¹⁷, Arndt Hartmann¹³, Roman Mayr¹⁵, Nicola Pavan³, Riccardo Bartoletti¹⁸, M Carmen Mir¹⁹, Damien Pouessel^{11

20}, John van der Hoeven²¹, Theo H van der Kwast²², Yves Allory^{11

23}, Tahlita C M Zuiverloon¹⁶, Yair Lotan⁶, Bas W G van Rhijn^{1

4

15}

Affiliations

¹ Department of Surgical Oncology (Urology), Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
² Department of Urology, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Medicine, Surgery and Health Sciences, Urological Clinic, University of Trieste, Trieste, Italy.
⁴ Department of Surgery (Urology) and Surgical Oncology, University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.
⁵ Department of Urology, Turku University Hospital and University of Turku, Turku, Finland.
⁶ Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁷ Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
⁸ Department of Urology, Weill Cornell Medical College, New York, NY, USA.
⁹ Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
¹⁰ Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
¹¹ Molecular Oncology Team, Institut Curie, CNRS, UMR144, PSL Research University, Paris, France.
¹² Department of Urology, Hôpital Foch, UVSQ-Paris-Saclay University, Suresnes, France.
¹³ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
¹⁴ Department of Pathology, University of Trieste, Trieste, Italy.
¹⁵ Department of Urology, Caritas St Josef Medical Center, University of Regensburg, Regensburg, Germany.
¹⁶ Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.
¹⁷ Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
¹⁸ Department of Translational Research and New Technologies, Unit of Urology, University of Pisa, Pisa, Italy.
¹⁹ Department of Urology, Hospital Universitario La Ribera, Valencia, Spain.
²⁰ Department of Medical Oncology, Claudius Regaud Institute, Toulouse University Cancer Center (IUCT) Oncopole, Toulouse, France.
²¹ Department of Urology, Reinier de Graaf Hospital, Delft, The Netherlands.
²² Department of Pathology, University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.
²³ Department of Pathology, Institut Curie, Paris, France.

Abstract

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.

Keywords: Bladder cancer; lymph node density; radical cystectomy; survival; urothelial neoplasm.