Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non–muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review

Context: Tumour grade is an important prognostic indicator in non-muscle invasive bladder cancer (NMIBC). Histopathological classifications are limited by inter-observer variability (reproducibility) which may have prognostic implications. EAU 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, overall and cancer-specific survival. For reproducibility, the primary outcome was inter-observer variability between pathologists. Secondary outcome was intra-observer variability (repeatability) by the same pathologist.
Evidence synthesis: Of 3,593 articles identified, 20 studies were included in the prognostic review; 3 were eligible for the reproducibility review. Increasing tumour grade in both classifications was associated with higher disease progression and recurrence rates. Progression rates in G1 patients were similar to those in low grade patients; progression rates in G3 patients were higher than in high grade patients. Survival data was limited. Reproducibility of the 2004/2016 system was marginally better than 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 sub-optimal. The 1973 system identifies more aggressive tumours. Intra- and inter-observer 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.