Beyond the label ‘high‐grade’: histological heterogeneity as a prognostic marker in Ta non‐muscle‐invasive bladder cancer

OBJECTIVE: To evaluate whether the proportion of a high-grade (HG) component within primary non-muscle-invasive bladder cancer (NMIBC) influences recurrence and progression outcomes beyond the current World Health Organization (WHO) recommended threshold of ≥5% to designate a tumour as HG. PATIENTS AND METHODS: We conducted a retrospective cohort study of patients diagnosed with primary pathological T stage (pT)a HG NMIBC. All cases underwent centralised genitourinary pathological re-review to quantify the percentage of the HG component. Patients were stratified using pre-defined HG cut-offs (5%, 10%, 25%, 50%, and 100%). Recurrence-free survival and progression-free survival (PFS) were assessed using Kaplan-Meier analyses and multivariable Cox proportional hazards models, adjusting for established clinicopathological factors. Subgroup analyses were performed according to intravesical Bacillus Calmette-Guérin (BCG) treatment. RESULTS: From 466 patients identified in our database, 362 underwent centralised pathologic re-review, and a total of 321 patients with confirmed pTa urothelial carcinoma were included in the study. The median follow-up was 61.3 months. The overall incidence of recurrence and progression, defined as progression to pathological stage ≥T1, was 35.5% and 9.4%, respectively. Increasing HG proportion was not significantly associated with recurrence after multivariable adjustment, whereas age and tumour multiplicity independently predicted recurrence risk. In contrast, higher HG percentage thresholds (≥10%, ≥25%, ≥50%, and 100%) were associated with progressively worse PFS, most pronounced in exploratory subgroups without BCG. The 5% threshold did not significantly discriminate outcomes. CONCLUSION: The overall burden of HG differentiation seems to provide better prognostic significance than the mere presence of mixed histology in HG pTa tumours. Using higher HG percentage thresholds might improve the identification of patients at risk of progression and enhance risk stratification beyond existing WHO criteria. Prospective studies are needed to confirm if including HG percentage in clinical decision-making can lead to better personalised treatment for NMIBC.