Specifically, we analyzed 175 consecutive patients with papillary HG-NMIBC treated at our tertiary referral center. All transurethral resections of bladder tumors (TURBTs) were performed by a highly experienced surgeon, and all specimens underwent review by two dedicated uropathologists. Patients were managed according to guideline-based protocols, including re-TURBT when indicated and Bacillus Calmette–Guérin (BCG) induction with maintenance whenever feasible. We compared patients managed exclusively at our institution from the first diagnosis (Group A) with those initially treated in community hospitals and subsequently referred to our center (Group B). To minimize confounding, we applied propensity score overlap weighting and evaluated disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS).
Our findings demonstrated meaningful differences in both early pathological outcomes and long-term oncological control. At re-TURBT, patients in Group A showed higher rates of complete tumor clearance (pT0: 59% vs. 36%) and lower rates of residual high-grade disease (31% vs. 52%) compared with referred patients. Although causality cannot be claimed, these results suggest that the quality and consistency of early surgical management may substantially influence subsequent staging and treatment trajectories.
With a median follow-up of 54 months, long-term outcomes favored patients centralized from diagnosis. The 5-year DFS was 75% in Group A compared with 51% in Group B (HR 0.36, p<0.001), with similarly improved PFS and CSS. After propensity score adjustment, these associations remained significant, supporting the robustness of the observed relationship between early pathway centralization and oncological outcomes. Overall, only 12% of patients underwent radical cystectomy during follow-up, reflecting durable bladder preservation in most cases.
At the same time, we observed substantial biological heterogeneity despite optimized management. Multivariable analyses identified prior multiple TURBTs, multifocality, lymphovascular invasion, and concomitant carcinoma in situ as independent predictors of relapse. Using these factors, we developed a Cox-derived scoring system that stratified patients into distinct risk groups with markedly different DFS and cystectomy-free survival. These findings emphasize that while pathway optimization improves the quality of care, it cannot fully offset adverse tumor biology.
Our results have several clinical implications. First, they reinforce the central role of the initial TURBT as a prognostic and therapeutic determinant in HG-NMIBC. Second, they support the potential value of early referral and centralized management for patients with high-risk disease. Third, they highlight the importance of early identification of unfavorable pathological features to guide intensified surveillance and timely consideration of treatment escalation, including radical cystectomy or alternative bladder-sparing strategies in selected patients.
This study should be interpreted in light of its limitations. Its retrospective, single-center design limits causal inference and may reduce generalizability. Referral patterns and delays prior to centralization may have influenced outcomes despite extensive statistical adjustment. Moreover, approximately 15% of patients did not complete adequate BCG therapy, reflecting real-world barriers to guideline adherence.
Nonetheless, our findings provide a pragmatic benchmark of outcomes achievable when HG-NMIBC patients are managed from diagnosis within a coordinated, experienced, and multidisciplinary pathway. By integrating high-quality surgery, expert pathology review, standardized intravesical therapy, and structured follow-up, such pathways may help optimize long-term disease control.
By emphasizing the interaction between surgical expertise, care organization, and tumor biology, this study supports a more systematic and centralized approach to HG-NMIBC management. Ultimately, improving outcomes in this population requires not only effective therapies but also consistent implementation of evidence-based care from the earliest stages of disease.
Written by: Pietro Scilipoti,1 Giuseppe Rosiello,2 Alfonso Santangelo,1 Alessandro Viti,1 Mattia Longoni,1 Angelo Occhi,1 Michele Brancaccio,1 Giovanni Tremolada,1 Andrea Folcia,1 Paolo Zaurito,1 Mario de Angelis,1 Pierre I. Karakiewicz,3 Alexandre Mottrie,4 Roberta Lucianò,5 Maurizio Colecchia,5 Andrea Salonia,1 Alberto Briganti,1 Marco Moschini,1 Francesco Montorsi1
- Division of Experimental Oncology/Unit of Urology, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
- Division of Experimental Oncology/Unit of Urology, IRCCS Ospedale San Raffaele, Milan, Italy.
- Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada.
- Department of Urology, Onze-Lieve-Vrouwziekenhuis, Aalst, Belgium; ORSI Academy, Melle, Belgium.
- Department of Pathology, Pathology Unit, IRCCS Ospedale San Raffaele, Milan, Italy.