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Multicenter Validation of Histopathologic Tumor Regression Grade After Neoadjuvant Chemotherapy in Muscle-invasive Bladder Carcinoma

Voskuilen, Charlotte S. MD*; Oo, Htoo Zarni MD, PhD; Genitsch, Vera MD; Smit, Laura A. MD, PhD§; Vidal, Alvaro MD; Meneses, Manuel MD; Necchi, Andrea MD; Colecchia, Maurizio MD#; Xylinas, Evanguelos MD**; Fontugne, Jacqueline MD††; Sibony, Mathilde MD, PhD††; Rouprêt, Morgan MD, PhD‡‡; Lenfant, Louis MD‡‡; Côté, Jean-François MD, PhD§§; Buser, Lorenz MD∥∥; Saba, Karim MD¶¶; Furrer, Marc A. MD##; van der Heijden, Michiel S. MD, PhD***; Daugaard, Mads PhD; Black, Peter C. MD; van Rhijn, Bas W.G. MD, PhD*; Hendricksen, Kees MD, PhD*; Poyet, Cédric MD¶¶; Seiler, Roland MD##

The American Journal of Surgical Pathology: December 2019 - Volume 43 - Issue 12 - p 1600–1610
doi: 10.1097/PAS.0000000000001371
Original Articles

Response classification after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma is based on the TNM stage at radical cystectomy. We recently showed that histopathologic tumor regression grades (TRGs) add prognostic information to TNM. Our aim was to validate the prognostic significance of TRG in muscle-invasive bladder cancer in a multicenter setting. We enrolled 389 patients who underwent cisplatin-based chemotherapy before radical cystectomy in 8 centers between 2010 and 2016. Median follow-up was 2.2 years. TRG was determined in radical cystectomy specimens by local pathologists. Central pathology review was conducted in 20% of cases, which were randomly selected. The major response was defined as ≤pT1N0. The remaining patients were grouped into partial responders (≥ypT2N0-3 and TRG 2) and nonresponders (≥ypT2N0-3 and TRG 3). TRG was successfully determined in all cases, and interobserver agreement in central pathology review was high (κ=0.83). After combining TRG and TNM, 47%, 15%, and 38% of patients were major, partial, and nonresponders, respectively. Combination of TRG and TNM showed significant prognostic discrimination of overall survival (major responder: reference; partial responder: hazard ratio 3.5 [95% confidence interval: 1.8-6.8]; nonresponder: hazard ratio 6.1 [95% confidence interval: 3.6-10.3]). This discrimination was superior compared with TNM staging alone, supported by 2 goodness-of-fit criteria (P=0.041). TRG is a simple, reproducible histopathologic measurement of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Integrating TRG with TNM staging resulted in significantly better prognostic stratification than TNM staging alone.

Departments of *Urology


***Medical Oncology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada

Institute of Pathology

##Department of Urology, University of Bern, Bern

∥∥Institute of Pathology and Molecular Pathology, University Hospital Zurich

¶¶Department of Urology, University Hospital Zürich, University of Zürich, Zürich, Switzerland

Faculty of Medicine, Instituto Oncológico FALP, Santiago, Chile

Departments of Medical Oncology

#Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

**Department of Urology, Hôpital Cochin, Paris Descartes University

††Department of Pathology, Institut Curie

Departments of ‡‡Urology

§§Pathology, Sorbonne Université, GRC n°5, ONCOTYPE-URO, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France

C.S.V. and H.Z.O. shared first authorship.

C.P. and R.S. shared senior authorship.

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Charlotte S. Voskuilen, MD, Department of Urology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Plesmanlaan 121 Amsterdam 1066 CX, The Netherlands (e-mail:

Online date: September 12, 2019

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