Grade is an important determinant of progression in non-muscle-invasive bladder cancer. Although the World Health Organization (WHO) 2004/2016 grading system is recommended, other systems such as WHO1973 and WHO1999 are still widely used. Recently, a hybrid (three-tier) system was proposed, separating WHO2004/2016 high grade (HG) into HG/grade 2 (G2) and HG/G3 while maintaining low grade. We assessed the prognostic performance of HG/G3 and HG/G2. Three independent cohorts with 9712 primary (first diagnosis) Ta-T1 bladder tumors were analyzed. Time to progression was analyzed with cumulative incidence functions and Cox regression models. Harrell's C-index was used to assess discrimination. Time to progression was significantly shorter for HG/G3 than for HG/G2 in multivariable analyses (cohort 1: hazard ratio [HR] = 1.92; cohort 2: HR = 2.51, and cohort 3: HR = 1.69). Corresponding progression risks at 5 yr were 18%, 20%, and 18% for HG/G3 versus 7.3%, 7.5%, and 9.3% for HG/G2, respectively. Cox models using hybrid grade performed better than models with WHO2004/2016 (all cohorts; p < 0.001). For the three cohorts, C-indices for WHO2004/2016 were 0.69, 0.62, and 0.75, while, for hybrid grade, C-indices were 0.74, 0.68, and 0.78, respectively. Subdividing the HG category into HG/G2 and HG/G3 stratifies time to progression and supports the recommendation to adopt the hybrid grading system for Ta/T1 bladder cancers.

Department of Clinical Sciences Danderyd Hospital Karolinska Institute Stockholm Sweden

Department of Surgical Sciences Uppsala University Uppsala Sweden; Northern Registry Centre Department of Diagnostics and Intervention Umeå University Umeå Sweden

Department of Surgical Sciences Uppsala University Uppsala Sweden; School of Cancer and Pharmaceutical Sciences King's College London London UK

Department of Urology Ninewells Hospital Dundee UK

Department of Urology Queen Elizabeth University Hospital Glasgow UK

Department of Urology Queen Elizabeth University Hospital Glasgow UK; School of Cancer Sciences University of Glasgow Glasgow UK

Department of Urology Victoria Hospital Kirkcaldy UK

Edinburgh Bladder Cancer Surgery Department of Urology Western General Hospital Edinburgh UK

Edinburgh Bladder Cancer Surgery Department of Urology Western General Hospital Edinburgh UK; Department of Urology University Hospital Ayr Ayr UK

Edinburgh Bladder Cancer Surgery Department of Urology Western General Hospital Edinburgh UK; European Association of Urology Non Muscle Invasive Bladder Cancer Guidelines Panel Arnhem The Netherlands; University of Edinburgh Edinburgh UK

European Association of Urology Guidelines Office Board Arnhem The Netherlands

European Association of Urology Non Muscle Invasive Bladder Cancer Guidelines Panel Arnhem The Netherlands

European Association of Urology Non Muscle Invasive Bladder Cancer Guidelines Panel Arnhem The Netherlands; Pathology Tenon Hospital AP HP Sorbonne University Paris France

European Association of Urology Non Muscle Invasive Bladder Cancer Guidelines Panel Arnhem The Netherlands; Urology Caritas St Josef Medical Center University of Regensburg Regensburg Germany

European Association of Urology Non Muscle Invasive Bladder Cancer Guidelines Panel Arnhem The Netherlands; Urology Città della Salute e della Scienza University of Torino School of Medicine Torino Italy

European Association of Urology Non Muscle Invasive Bladder Cancer Guidelines Panel Arnhem The Netherlands; Urology Pitié Salpétrière Hospital AP HP GRC n°5 ONCOTYPE URO Sorbonne University Paris France

European Association of Urology Non Muscle Invasive Bladder Cancer Guidelines Panel Arnhem The Netherlands; Urology Teaching Hospital Motol and 2nd Faculty of Medicine Charles University Praha Prague Czech Republic; Urology Comprehensive Cancer Center Medical University Vienna Vienna General Hospital Vienna Austria

Institution of Translational Medicine Lund University Malmö Sweden

Institution of Translational Medicine Lund University Malmö Sweden; European Association of Urology Non Muscle Invasive Bladder Cancer Guidelines Panel Arnhem The Netherlands; Department of Urology Skåne University Hospital Malmö Sweden

Laboratory Medicine Program University Health Network Princess Margaret Cancer Center University of Toronto Toronto Canada

Surgical Oncology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands; Urology Amsterdam University Medical Centers Vrije Universiteit Amsterdam The Netherlands

Surgical Oncology University Health Network Princess Margaret Cancer Center University of Toronto Toronto Canada

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