Hybrid grading systems improve progression risk stratification in non‐invasive papillary urothelial carcinoma and support a histomorphological continuum of disease progression

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OBJECTIVE: Histological grading is a key predictor of progression in non-muscle-invasive bladder cancer (NMIBC). The WHO 1973 three-tier system is limited by heterogeneity within the G2 category, whereas the WHO 2004/2016 binary classification reduces prognostic resolution by grouping biologically diverse tumours into broad low-grade (LG) and high-grade (HG) categories. We aimed to evaluate the prognostic performance of hybrid grading systems compared with WHO 2004/2016, while further characterizing the histomorphological continuum of non-invasive papillary urothelial carcinoma. METHODS: Non-invasive papillary urothelial carcinomas (2012-2023; n = 472) were reviewed and reclassified by two urological pathologists according to WHO 2004/2016, hybrid three-tier and four-tier systems, and an investigational five-tier framework (Grades I, IIA, IIB, IIIA, IIIB) integrating architectural, cytological and proliferative features. Primary endpoints were recurrence, grade progression and T1+ stage progression, assessed using ROC analysis, Cox proportional hazards regression and model-performance metrics (AIC, BIC, C-index). RESULTS: Increasing morphological atypia was associated with larger tumour size, greater multifocality and progressively higher progression risk, with events concentrated in Grades IIIA and IIIB. All systems showed limited recurrence discrimination (C-index 0.54-0.56). For T1+ progression, discrimination improved with increasing stratification (AUC 0.754 for WHO 2004/2016 vs. 0.815, 0.828 and 0.827 for the hybrid three-tier, four-tier and five-tier systems, respectively; all P < 0.001). The Hybrid 3-Tier model achieved the most favourable AIC and BIC, while the five-tier model yielded the highest C-index (0.818). CONCLUSIONS: Hybrid grading systems improve progression-risk stratification in non-invasive papillary urothelial carcinoma compared with WHO 2004/2016, with most benefit achieved by the Hybrid 3-Tier framework. These findings support the concept of a histomorphological continuum of progression risk and favour continued refinement of biologically informed hybrid grading for NMIBC risk stratification.

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