Reproducibility and Prognostic Performance of the 1973 and 2004 World Health Organization Classifications for Grade in Non-muscle-invasive Bladder Cancer: A Multicenter Study in 328 Bladder Tumors

Abstract

Background: Histologic grade is an important prognosticator in patients with non-muscle-invasive bladder cancer (NMIBC). Currently, 2 classifications for grade are widely used; the World Health Organization (WHO) 1973 and the WHO 2004. We compare inter-observer variability of both classifications and investigate which histologic criteria cause this variability. Furthermore, the prognostic value of both classifications was assessed.

Patients and methods: Three pathologists reviewed 328 bladder tissue samples of 232 patients with NMIBC in a blinded manner. WHO 1973 grade, WHO 2004 grade, histologic criteria of both classifications, and T-category were evaluated. Reproducibility was analyzed using the weighted Fleiss κ, association between criteria scores and grade with the χ² test, and time-to-recurrence and time-to-progression with the log-rank test and Cox regression.

Results: Reproducibility of both classifications was poor. The WHO 2004 showed better reproducibility (κ = 0.35; 95% confidence interval (CI), 0.29-0.42) compared with the WHO 1973 as a 3-tiered (κ = 0.24; 95% CI, 0.19-0.28), but not as a 2-tiered (G1 + G2 vs. G3) classification (κ = 0.36; 95% CI, 0.29-0.42). Reproducibility of individual criteria was poor (κ range, -0.05 to 0.25). All criteria were associated with grade (P < .05). After a median follow-up of 60 months, 33 of 232 and 112 of 232 patients developed progression and recurrence, respectively. In 1 out of the 3 pathologists, progression was predicted by both the WHO 1973 grade and the WHO 2004 grade in multivariable analysis. Recurrence was not predicted by grade (multivariable).

Conclusions: Reproducibility of the WHO 2004 and WHO 1973 classification for grade are poor. Scoring of individual criteria is poorly reproducible, suggesting that descriptions of these criteria for grade are not specific. The prognostic value of both the WHO 1973 and the WHO 2004 differ per pathologist.

Keywords: Inter-observer variability; Neoplasm grading; Observer variation; Prognosticator; Urinary bladder neoplasm.