Bladder Cancer Molecular Grade (FGFR3/MIB-1) and EORTC Risk Scores Are Predictive in Primary Non–Muscle-Invasive Bladder Cancer Bas W.G. van Rhijn a,b,c, *, Tahlita C.M. Zuiverloon a,d , Andre ´ N. Vis a,b , Franc ¸ ois Radvanyi e , Geert J.L.H. van Leenders d , Bert C.M. Ooms f , Wim J. Kirkels a , Gina A. Lockwood g , Egbert R. Boeve ´ b , Adriaan C. Jo ¨bsis h , Ellen C. Zwarthoff d,1 , Theo H. van der Kwast d,i,1 a Department of Urology, Erasmus MC, Rotterdam, The Netherlands b Department of Urology, Sint Franciscus Hospital, Rotterdam, The Netherlands c Division of Urology, University Health Network, Toronto, Canada d Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands e Laboratoire de Morphogene `se Cellulaire et Progression Tumorale, UMR 144, CNRS, Institut Curie, Paris, France f Department of Pathology, Haaglanden MC, The Hague, The Netherlands g Department of Biostatistics, University Health Network, Toronto, Canada h Department of Pathology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands i Department of Pathology, University Health Network, Toronto, Canada EUROPEAN UROLOGY 58 (2010) 433–441 available at www.sciencedirect.com journal homepage: www.europeanurology.com Article info Article history: Accepted May 31, 2010 Published online ahead of print on June 9, 2010 Keywords: Bladder cancer FGFR3 MIB-1 Grade Recurrence Progression Survival Observer-variability Molecular marker EORTC Abstract Background: The European Organization for Research and Treatment of Cancer (EORTC) risk scores are not validated in an independent patient population. Molecular grade (mG) based on fibroblast growth factor receptor 3 (FGFR3) gene mutation status and MIB-1 expression was proposed as an alternative to pathologic grade in bladder cancer (BCa) [1]. Objective: To validate the EORTC risk score and to determine its relation to mG in a series with long- term follow-up as well as to determine reproducibility of pathologic grade and mG. Design, setting, and participants: In this multicenter study, we included 230 patients with primary non–muscle-invasive BCa (NMIBC). Measurements: Four uropathologists reviewed the slides. FGFR3 mutation status was examined by two assays. MIB-1 was assessed by immunohistochemistry. The EORTC risk scores for recurrence and progression were determined. Multivariable analyses were used to find prognostic factors. Results and limitations: Median follow-up was 8.62 yr (interquartile range: 6.6–11.8). FGFR3 mutations were significantly related to favorable disease parameters, whereas altered MIB-1 was frequently seen with pT1, high grade, and high EORTC risk scores. EORTC risk scores were significant in multivariable analyses for recurrence and progression. In multivariable analyses for progression and disease-specific survival, the mG had independent significance. The addition of mG to the multivariable model for progression increased the predictive accuracy from 74.9% to 81.7% ( p < 0.001; Mantel-Haenszel test). The mG (89%) was more reproducible than the pathologic grade (41–74%). Conclusions: We validated the EORTC risk scores for primary NMIBC in a clinical and biomarker setting. Next to EORTC risk score, mG proved highly reproducible and predictive. Our long-term results justify an independent prospective analysis of mG and EORTC risk scores. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. 1 These authors contributed equally to this paper. * Corresponding author. Division of Urology, University Health Network, University of Toronto, 610 University Avenue, 3-130, Toronto, ON M5G 2M9 Canada. Tel. +1 416 946 2909; Fax: +1 416 598 9997. E-mail address: basvanrhijn@hotmail.com (B.W.G. van Rhijn). 0302-2838/$ – see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2010.05.043