Objectifying grade in Ta-T1 urothelial carcinomas of the bladder using proliferative and quantitative markers: A multicentre study in 310 bladder tumors

Purpose: Histological grade is an important prognostic factor in patients with non-muscle-invasive bladder cancer (NMIBC). However, interobserver variability is high. Previous studies have suggested that quantification of histological features is useful to objectify grading. We evaluated whether quantification of the mean nuclear area of the 10 largest nuclei (MNA-10), degree of aneuploidy (DNA index or DI) and mitotic activity index (MAI) are of diagnostic value for NMIBC grade. Additionally, prognostic value of the 3 measures was assessed.

Material and methods: A consensus grade was determined by 3 uropathologists in 310 NMIBC tissues according to the World Health Organization (WHO) 1973 and the WHO2004. Logistic regression with forward selection was used to determine the optimal combination of measures (MNA-10, DI, and MAI) to diagnose grade 3 (G3) or high-grade (HG) NMIBC (WHO1973 and WHO2004, respectively).

Results: In 310 tumors of 215 patients at least 1 of the measures (MNA-10, DI, or MAI) had been determined. The combination of MNA-10 and MAI was selected as the most diagnostic combination and resulted in a sensitivity of 94% (95% confidence interval [CI]: 87-100) at a specificity of 72% (95% CI: 66-78) for G3 tumors. For the diagnosis of HG tumors sensitivity was 92% (95% CI: 86-97) at a specificity of 76% (95% CI: 70-93).

Conclusions: Determination of MNA-10 and MAI is promising for diagnosing G3 and HG bladder tumors. These findings warrant further studies on the diagnostic and prognostic value of proliferative and quantitative features in bladder cancer patients.