The prognostic value of histopathological grade in muscle-invasive urothelial carcinoma (MIBC) to predict disease-specific survival (DSS) is understudied. While grading systems like WHO1973 and WHO2004 are established in non-muscle-invasive bladder cancer (NMIBC), their relevance in MIBC remains controversial. This study assessed the prognostic impact of histopathological grade on DSS in a multicenter cohort.

We included 1,123 cN0M0 MIBC patients treated with upfront radical cystectomy (1987–2020) at nine centers. Tumors were graded using WHO1973 (G1 + G2 combined as G1/2 due to low numbers vs. G3), WHO2004 (low-grade [LG] vs. high-grade [HG]), and a hybrid three-tier system. Slides were locally reviewed by uro-pathologists. DSS was analyzed using Kaplan-Meier and Cox models, adjusting for age, stage, lympho-vascular invasion, surgical margins, lymph-node status, adjuvant chemotherapy, treatment center, and era of cystectomy.

Among all cases, 74 (6.6%) were G1/2 and 1,049 (93.4%) G3; 27 (2.4%) were LG and 1,096 (97.6%) HG. Median follow-up was 5.3 years (IQR 2.9–8.5). Univariable analyses showed significantly better DSS for LG and G1/2 tumors across grading systems. However, multivariable models showed no independent association between grade and DSS.

Although LG and G1/2 MIBC tumors demonstrated superior DSS in univariable analyses, the lack of independent prognostic significance in multivariable models questions the relevance of histopathological grade in MIBC. Further studies should explore the clinical utility of grade, define new grading schemes including features of epithelial-mesenchymal transition or tumor microenvironment, and explore alternative prognostic (bio)markers.