Enhanced prognostic value of four‐tier hybrid grading system in Ta non‐muscle‐invasive bladder cancer

Objectives: To compare the predictive performance of the World Health Organization (WHO) 1973, WHO 2004/2022, the three-tier (low grade [LG]/Grade 1 [G1]–G2, high grade [HG]/G2, and HG/G3), and four-tier (LG/G1, LG/G2, HG/G2, and HG/G3) hybrid grading systems in Ta non-muscle-invasive bladder cancer (NMIBC), by evaluating recurrence-free survival (RFS) and progression-free survival (PFS). Patients and Methods: This retrospective multicentre study included 1233 patients with pTa NMIBC treated with transurethral resection of bladder tumour, eventually followed by intravesical instillations as determined by their physicians, between 2010 and 2023, across 18 Italian hospitals. Pathologists graded resected tissues using the WHO 1973, WHO 2004/2022 classifications, and hybrid three-tier (LG, HG/G2, HG/G3) and four-tier (LG/G1, LG/G2, HG/G2, HG/G3) systems. Kaplan–Meier curves estimated RFS and PFS. Discriminative performance was assessed using Harrell's concordance index (C-index). Results: Among 1233 patients with pTa NMIBC, 890 were classified as LG and 343 as HG according to the WHO 2004/2022 grading system, while 586, 405, and 242 were categorised as G1, G2, and G3, respectively, under the WHO 1973 system. With a median (interquartile range) follow-up of 26 (14–48) months, 418 patients experienced recurrence, including 184 with HG recurrence and 42 who progressed to MIBC. The C-index values for RFS were 0.60, 0.56, 0.57, and 0.61 for the WHO 1973, WHO 2004/2022, hybrid three-tier, and four-tier grading systems, respectively. For progression, the C-index values were 0.80, 0.74, 0.75, and 0.81 across the same systems, underscoring the superior predictive capacity of the four-tier classification. Nonetheless, the low number of MIBC progression events limits the robustness of these analyses. Conclusion: Our findings highlight the superior prognostic accuracy of the four-tier hybrid classification in predicting recurrence and progression in patients with stage Ta NMIBC. By combining strengths from the WHO 1973 and 2004/2022, this hybrid model shows promise as tool for enhancing NMIBC patient management in clinical practice.