Impact of Divergent Differentiation and Histological Subtypes on Oncologic Outcomes in Patients Treated with Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

BACKGROUND:Divergent differentiation (DD) and histological subtypes (HS) represent rare but clinically meaningful forms of upper tract urothelial carcinoma (UTUC), but their prognostic impact remains incompletely understood. We assessed the incidence, clinicopathological characteristics, and oncologic outcomes associated with DD-HS in a large multi-institutional cohort of patients undergoing radical nephroureterectomy (RNU) for non-metastatic UTUC. METHODS:We retrospectively analyzed 3,441 patients treated between 1985 and 2022 across 22 institutions. Tumors were classified as pure urothelial carcinoma (PUC), DD, and HS. Clinicopathological features and survival outcomes-including recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)-were compared using the Kaplan-Meier estimator, stratified by pathological stage (organ-confined [OC: ≤pT2N0-Nx] vs. non-organ-confined [NOC: ≥pT3 or ≥pN1]) and multivariable Cox regression. RESULTS:DD-HS were present in 201 patients (5.8%), with DD comprising 139 (69%). Compared to PUC, DD-HS were associated with more advanced T/N stages, higher rates of lymphovascular invasion (40% vs. 20%), multifocality (35% vs. 27%), and concomitant carcinoma in situ (21% vs. 14%) (all P < 0.05). While outcomes for DD were similar to stage-matched PUC, HS showed significantly worse stage-matched RFS (OC: 38% vs. 83%; NOC: 25% vs. 46%) and OS (OC: 44% vs. 75%; all P < 0.01), and remained independently associated with poorer outcomes on multivariable analyses. Limitations include the retrospective design and lack of centralized pathology review. CONCLUSIONS:UTUC with DD-HS represents a biologically heterogeneous population with distinct oncologic outcomes compared with PUC. Further investigation into subtype-specific tumor biology and rigorous pathological characterization is warranted to better define the clinical relevance of individual histological entities and to guide future treatment strategies.