Upper tract urothelial carcinoma (UTUC) is a rare and challenging-to-treat malignancy. In most patients it is a sporadic tumor entity, less commonly it falls on the spectrum of Lynch syndrome, an autosomal dominant familial tumor syndrome. Localized UTUC with high-risk features as well as the metastatic disease scenario might require systemic therapy. Platinum-based combination chemotherapy is currently the recommended management option. However, the introduction of immune checkpoint inhibitors into the therapeutic armamentarium has led to a paradigm shift in treatment standards. Immunotherapy has been shown to be safe and effective in treating at least metastatic UTUC, although UTUC-specific high-level evidence is still lacking. Recent technological advances and noteworthy research efforts have greatly improved the general understanding of the biological landscape of UTUC. According to the main findings, UTUC represent a particular subtype of urothelial carcinoma frequently associated with activated FGFR3 signaling, a luminal–papillary phenotype and a T-cell-depleted microenvironment. This improved knowledge promises precision oncology approaches that match treatment decision strategies and genomic profile to ultimately result in better clinical outcomes. The aim of this review was to summarize the main currently available evidence on immune checkpoint inhibition and clinical genomics in UTUC.

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Introduction: Adjuvant therapy has no defined role for patients with positive surgical margins (PSMs) following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). The aim of our study was to describe loco-regional recurrence-free survival (LRFS), metastatic-free survival (MFS), recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) and identify predictors of each endpoint in patients with PSMs following RC for MIBC. Methods: A collaborative retrospective cohort study was conducted on 394 patients with PSMs who underwent RC for MIBC between January 2000 and December 2018 at 10 tertiary referral centers. Patients receiving perioperative radiotherapy were excluded from the study. Kaplan–Meier curves were used to estimate patient survival. Cox regression analysis was used to identify predictors of survival. Results: Median age at surgery was 70 years (IQR 62–76) with 129 (33%) and 204 (52%) patients had pT3 and pT4 tumors, respectively. Nodal metastasis (pN+) was identified in 148 (38%). Soft tissue PSMs were found in 283 (72%) patients, urethral PSMs in 65 (16.5%), and ureteral PSMs were found in 73 (18.5%). The median follow-up time was 44 months (95% CI 32–60). Median LRFS, MRFS, RFS, CSS, and OS were 14 (95% CI 11–17), 12 (95% CI 10–16), 10 (95% CI 8–12), 23 (95% CI 18–33), and 16 months (95% CI 12–19), respectively. On multivariable Cox regression analysis, the pT3–4 stage, pN+ stage, and multifocal PSMs were independent predictors of LRFS, MRFS, RFS, and OS. Adjuvant chemotherapy improved all oncological outcomes studied (p < 0.05). The number of lymph nodes removed was independently associated with better LRFS, MRFS, and RFS. Advanced age at diagnosis was independently associated with worse OS. Conclusion: Patients with PSMs following RC have poor outcomes since half of them will recur within a year and will die of their disease. Among all PSMs types, patients with multifocal PSMs harbor the worst prognosis. We observed a benefit of adjuvant chemotherapy, but clinical trials evaluating innovative adjuvant strategies for these patients remain an unmet need.

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Although lymphonodal dissection is well-accepted for muscle-invasive bladder cancer management, its role is still debated during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). The aim of this study was to summarize the current knowledge concerning the indication, anatomical template, prognostic, and therapeutic roles of lymph node dissection (LND) performed at the time of RNU. Quality control markers, such as the number of lymph nodes (LN) removed, lymph node density, and safety of the different surgical approaches, were assessed. We performed a narrative review using the PubMed and ClinicalTrials.gov databases. We identified and analyzed articles based on the practice and the role of lymph node dissection for non-metastatic UTUC. There are no clear guidelines regarding the indication of LND for UTUC, but aggressive tumors may beneficiate from lymphadenectomy since lymph node invasion is a clear independent poor prognostic factor, allowing for adjuvant treatments. It seems that an extended lymphadenectomy may provide therapeutic advantages as a higher number of nodes removed may be related to the removal of undetected LNs micrometastases and a subsequent improvement in recurrence rate and cancer-specific survival. Clear anatomical templates are thus needed based on the location and the laterality of the primary tumor.

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