Application of transcriptomic bladder-cancer subtypes to upper-tract urothelial carcinoma (UTUC) across international cohorts reveals racial differences and translational limitations

Background and Objectives: Management of UTUC follows bladder cancer (BC) guidelines but could be refined. Molecular subtyping has yielded valuable insights into tumor biology and therapy response/resistance for muscle-invasive (MI) and non-MI (NMI) BC and could have similar value for UTUC. Like NMIBC, UTUC is predominantly luminal-papillary (LumP) in subtype, which has spurred more granular UTUC-specific classification schemes. Here, we investigated whether MIBC and NMIBC subtyping could be translated to UTUC. Methods: Histologically confirmed FFPE UTUC nephroureterectomy specimens were retrospectively collected from Cedars-Sinai Medical Center (Los Angeles, USA) and Kindai University (Osaka, Japan). RNA-seq was performed on 126 tumors, which were classified using consensus-MIBC and UROMOL2021-NMIBC frameworks. Event-free survival (EFS) was estimated by Kaplan-Meier analysis, excluding cases with prior or concurrent BC. Results: Of 126 UTUCs, 69 (54.8%) were NMI and 55 (47.3%) MI. The LumP subtype was most common (57%), enriched in NMI-UTUC (75%) versus MI-UTUC (36%), mirroring NMIBC vs. MIBC. Cedars-Sinai tumors were mainly NMI (59%), while Kindai tumors were mostly MI (58%), suggesting population differences. LumP enrichment in Cedars-Sinai (80% of NMI vs. 33% of MI) contrasted with more balanced distributions in Kindai (5/10 NMI, 7/15 MI), indicating potential race-specific variation.Within LumP-UTUC, all four UROMOL classes were represented, whereas non-LumP UTUCs were mostly UROMOL 2b. Stratification by LumP vs. other revealed opposing (but not significant) survival trends in NMI- and MI-UTUC: LumP had poorer 5-year EFS in NMI-UTUC but better outcomes in MI-UTUC. Further stratification of LumP NMI-UTUC by UROMOL class showed no significant EFS differences, although Class 2b tumors had comparably poor outcomes to LumP MI-UTUC. Pathologic T stage remained the strongest prognostic factor (EFS: Ta > T1 > T2 > T3/4; p < 0.05). Conclusions: LumP prevalence in UTUC is largely driven by NMI tumors, recapitulating NMIBC biology. Subtype and stage distributions vary between Western and Asian cohorts, implying race-related molecular diversity. While BC-derived classifiers can categorize UTUC, their clinical interpretation does not directly translate. Tumor stage outweighs molecular subtype as the principal determinant of outcome.