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Multicenter Study
. 2025 Nov;136(5):882-890.
doi: 10.1111/bju.16828. Epub 2025 Jun 25.

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

Matteo Ferro  1 , Michele Catellani  2 , Roberto Bianchi  1 , Giuseppe Fallara  1 , Marco Tozzi  1 , Martina Maggi  1 , Francesco Chierigo  1 , Alessandro Uleri  3   4 , Luigi Filippo Da Pozzo  5   2 , Ludovica Cella  3   6 , Rodolfo Hurle  6 , Mauro Savino Di Stasi  7 , Enrico Checcucci  8 , Pierluigi Bove  9 , Francesco Maiorino  9 , Mihai Dorin Vartolomei  10   11 , Emanuele Montanari  12 , Giancarlo Albo  12 , Elisa De Lorenzis  12 , Luca Boeri  12 , Giovanni Liguori  13 , Francesca Vedovo  13 , Beat Roth  11 , Gian Maria Busetto  14 , Ugo Falagario  14 , Riccardo Mastroianni  15 , Massimo Madonia  16 , Alessandro Tedde  16 , Pasquale Di Tonno  17 , Giuseppe Lucarelli  17 , Saverio Forte  17 , Giorgio Ivan Russo  18 , Arturo Lo Giudice  18 , Fabrizio Verweij  19 , Marco Racioppi  20 , Francesco Pio Bizzarri  20 , Alessandro Crestani  21 , Marco Rinaldi  21 , Maria Angela Cerruto  22   23 , Francesco Claps  24 , Andrea Conti  25   26 , Sisto Perdonà  27 , Fabrizio Dal Moro  28 , Fabio Zattoni  29 , Ciro Imbimbo  30 , Felice Crocetto  29 , Achille Aveta  27 , Savio Domenico Pandolfo  29 , Angelo Porreca  30 , Giuseppe Carrieri  14 , Luca Carmignani  25   26 , Cosimo De Nunzio  31 , Giuseppe Simone  15 , Luigi Cormio  14 , Marco Borghesi  32 , Alessandro Antonelli  22 , Francesco Porpiglia  8 , Bernardo Rocco  20 , Biagio Barone  33 , Roberto Contieri  27
Affiliations
Multicenter Study

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

Matteo Ferro et al. BJU Int. 2025 Nov.

Abstract

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.

Keywords: Ta sub‐staging; four‐tier hybrid; grading system; non‐muscle‐invasive bladder cancer; progression; recurrence.

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