CONTEXT: Tumour grade is an important prognostic indicator in non-muscle-invasive bladder cancer (NMIBC). Histopathological classifications are limited by interobserver variability (reproducibility), which may have prognostic implications. European Association of Urology NMIBC guidelines suggest concurrent use of both 1973 and 2004/2016 World Health Organization (WHO) classifications. OBJECTIVE: To compare the prognostic performance and reproducibility of the 1973 and 2004/2016 WHO grading systems for NMIBC. EVIDENCE ACQUISITION: A systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library. Studies were critically appraised for risk of bias (QUIPS). For prognosis, the primary outcome was progression to muscle-invasive or metastatic disease. Secondary outcomes were disease recurrence, and overall and cancer-specific survival. For reproducibility, the primary outcome was interobserver variability between pathologists. Secondary outcome was intraobserver variability (repeatability) by the same pathologist. EVIDENCE SYNTHESIS: Of 3593 articles identified, 20 were included in the prognostic review; three were eligible for the reproducibility review. Increasing tumour grade in both classifications was associated with higher disease progression and recurrence rates. Progression rates in grade 1 patients were similar to those in low-grade patients; progression rates in grade 3 patients were higher than those in high-grade patients. Survival data were limited. Reproducibility of the 2004/2016 system was marginally better than that of the 1973 system. Two studies on repeatability showed conflicting results. Most studies had a moderate to high risk of bias. CONCLUSIONS: Current grading classifications in NMIBC are suboptimal. The 1973 system identifies more aggressive tumours. Intra- and interobserver variability was slightly less in the 2004/2016 classification. We could not confirm that the 2004/2016 classification outperforms the 1973 classification in prediction of recurrence and progression. PATIENT SUMMARY: This article summarises the utility of two different grading systems for non-muscle-invasive bladder cancer. Both systems predict progression and recurrence, although pathologists vary in their reporting; suggestions for further improvements are made.

Academic Urology Unit University of Aberdeen Scotland UK

Academic Urology Unit University of Aberdeen Scotland UK; Department of Urology Aberdeen Royal 12 Infirmary Aberdeen Scotland

Department of Medicine Health Science Centre McMaster University Hamilton Ontario Canada

Department of Pathology Hôpitaux Universitaires de l'Est Parisien HUEP Assistance Publique Faculty of Medicine Pierre et Marie Curie Institut Universitaire de Cancerologie GRC5 University Paris 6 Paris France

Department of Surgical Sciences Urology University of Turin Turin Italy

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

Department of Urology Fundació Puigvert Universitat Autònoma de Barcelona Barcelona Spain

Department of Urology General Teaching Hospital and 1st Faculty of Medicine Charles University in Praha Praha Czech Republic

Department of Urology Groupe Hospitalier Pitié Salpêtrière Assistance Publique Hopitaux de Paris Faculty of Medicine Pierre et Marie Curie Institut Universitaire de Cancérologie GRC5 University Paris 6 Paris France

Department of Urology Hospital Universitario Fundación de Alcorcón Madrid Spain

Department of Urology Medizinische Universität Graz Graz Austria

Department of Urology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Urology Royal Free London NHS Foundation Trust London UK

Department of Urology Royal Surrey County Hospital Guildford UK

Department of Urology Vienna General Hospital Medical University of Vienna Vienna Austria

EAU Guidelines Office Board European Association of Urology The Netherlands

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

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