Discordant Response in Pelvic Lymph Nodes and Cystectomy Specimens After Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer

Background: Radical cystectomy with pelvic lymph node dissection (PLND) remains the standard treatment for muscle-invasive bladder cancer (MIBC). Neoadjuvant chemother- apy (NAC) improves survival, and recent immunochemotherapy trials have reported complete pathological responses in up to 60% of patients, increasing interest in bladder-sparing strategies. However, the ability to accurately identify patients without residual pelvic lymph node metastases after NAC remains limited. Objective: To evaluate the association between pathological response in the bladder and pelvic lymph node status after NAC in patients with MIBC undergoing radical cystectomy (RC) and PLND. Design, setting, and participants: This retrospective, multi-institutional cohort study included 751 patients with MIBC treated with NAC followed by RC and PLND between 2000 and 2021 across 26 institutions. Intervention: Neoadjuvant chemotherapy followed by RC and PLND. Outcome measurements and statistical analysis: The primary outcome was residual lymph node involvement (ypN+). Multivariable logistic regression was used to identify factors associated with ypN+. Results and limitations: Overall, 175 patients (23%) achieved a complete pathological response in the bladder (ypT0), 102 (14%) were downstaged to non–muscle-invasive dis- ease (ypTa/ypTis/ypT1), and 185 (25%) had residual lymph node involvement. On multi- variable analysis, cN+ disease before NAC was associated with higher odds of ypN+ (OR 1.97, 95% CI 1.32–2.94), whereas ypT0 (OR 0.11, 95% CI 0.05–0.21) and ypTa/ypTis/ypT1 (OR 0.24, 95% CI 0.12–0.47) were associated with lower odds of ypN+. Notably, 5% of ypT0 and 10% of downstaged patients harboured residual lymph node metastases. Limitations include potential selection bias and centre-level variability in surgical and pathological assessment, which may affect the generalizability of the findings. Conclusions: Current clinical and radiological variables cannot reliably exclude residual pelvic lymph node disease, even in patients achieving ypT0-1. Novel imaging techniques and liquid biomarkers require validation before bladder-sparing approaches can be safely expanded.