Divergent Differentiation and Histologic Subtypes in Upper Tract Urothelial Carcinoma Demonstrate Distinct Patterns of Extraurothelial Recurrence

Divergent differentiation and histologic subtypes in upper tract urothelial carcinoma is associated with significantly higher extraurothelial recurrence rates despite similar urothelial recurrence rates. These findings support risk-adapted surveillance strategies and early multidisciplinary management in this high-risk subgroup. Upper tract urothelial carcinoma (UTUC) shows lower urinary tract recurrence after nephroureterectomy, with rates of 22–47%. We aimed to evaluate recurrence patterns and survival outcomes in UTUC patients with divergent differentiation and histologic subtypes (DDHSs) compared with pure urothelial carcinoma (UC), with a focus on differentiating urothelial versus extraurothelial recurrences. A retrospective review was conducted of 398 patients who underwent nephroureterectomy for UTUC at a single center (2014–2024). Clinical, pathologic, and treatment data were collected. Patients were stratified by histology (pure UC vs DDHSs). The primary outcomes include urothelial (U-RFS) and extraurothelial (EU-RFS) recurrence-free survival. Multivariable Cox proportional hazards regression was used to evaluate the predictors of recurrence-free survival. A Kaplan-Meier analysis was used to estimate recurrence-free and overall survival. Among 398 patients, 14% had DDHSs. Patients with DDHSs received adjuvant therapy more frequently (33% vs 13%) and presented with more advanced pathologic stage and nodal involvement at nephroureterectomy than those with pure UC. Overall recurrence rates were similar between groups. The Kaplan-Meier analysis demonstrated significantly worse EU-RFS in patients with DDHSs ( p < 0.001), while U-RFS did not differ. On a multivariable Cox analysis, DDHSs (hazard ratio HR 3.18, p = 0.01) and advanced pathologic T stage (HR 4.64, p = 0.047) were independently associated with extraurothelial recurrence. Overall survival was similar between groups. Patients with DDHS UTUC exhibit higher rates of extraurothelial recurrence despite similar rates of urothelial recurrence. These findings underscore the need for intensified surveillance and early systemic therapy consideration in DDHS UTUC patients. We studied patients with upper tract urothelial cancer who had different tumor types. We found that patients with these specific rare tumor types were more likely to have cancer spread outside the urinary tract. These patients may benefit from closer follow-up and additional treatment after surgery.