Impact of Histological Subtypes/Divergent Differentiation on Clinicopathological and Oncological Outcomes for Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy: A Comprehensive Updated Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVE: Upper tract urothelial carcinoma (UTUC) is associated with poor survival. Recent studies have evaluated whether the presence of histological subtypes or divergent differentiation (HS/DD) is associated with worse UTUC prognosis. Our aim was to assess the relationship between HS/DD and clinicopathological features and oncological outcomes for patients with UTUC undergoing radical nephroureterectomy (RNU) without investigating causal pathways. METHODS: A literature search was conducted in September 2024. Patients with UTUC who underwent RNU were included. The main outcomes were differences in clinicopathological features and oncological outcomes between HS/DD and pure urothelial carcinoma (PUC) groups. KEY FINDINGS AND LIMITATIONS: We included 22 studies involving 14 407 patients in our review. HS/DD was present in 14% of tumours. In comparison to PUC, the HS/DD group had significantly higher rates of ≥pT3 stage, high-grade tumours, lymph node invasion (LNI), lymphovascular invasion (LVI), and receipt of adjuvant chemotherapy. Pooled results revealed that the HS/DD group had significantly worse cancer-specific survival (CSS) (hazard ratio [HR] 1.65, 95% confidence interval CI] 1.39-1.96), overall survival (OS; HR 1.84, 95% CI 1.52-2.22) ,and recurrence-free survival (RFS; HR 1.64, 95% CI 1.43-1.87). Intravesical RFS (IVRFS) and urothelial RFS (URFS) were comparable between the groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our findings suggest that UTUC with HS/DD is associated with more advanced/aggressive features, such as higher pathological stage and grade, LNI, and LVI. HS/DD is associated with significantly worse CSS, OS, and RFS, but does not predict worse IVRFS or URFS. Therefore, HS/DD detection should prompt extensive treatment and closer follow-up. To improve the quality of recommendations and patient care, well-designed studies with central pathological review are needed.