Upper Tract Urothelial Carcinoma: Molecular Pathogenesis and Current Treatment Strategies-A Narrative Review

Background: Upper tract urothelial carcinoma (UTUC) is a rare malignancy representing approximately 5-10% of all urothelial cancers. Key risk factors include smoking, chemical exposures, selected metabolic conditions, and hereditary cancer syndromes. This narrative review summarises current knowledge on UTUC molecular pathogenesis, major risk determinants, and contemporary therapeutic strategies. Methods: This study was conducted as a narrative review with a structured literature search. PubMed, Web of Science, Embase, and Scopus were searched using predefined combinations of UTUC-related terms covering molecular pathogenesis, carcinogenic risk factors, and treatment strategies. The review was prepared according to SANRA principles to improve transparency and consistency; however, no formal systematic review methodology or meta-analysis was performed. Results: Available genomic studies indicate that UTUC has a molecular profile distinct from urothelial bladder carcinoma (UBC), with recurrent alterations involving FGFR3, HRAS, KMT2D, CDKN2A, KRAS, MYC, and BRIP1. Smoking, aristolochic acid exposure, Lynch syndrome, and possibly early-onset urolithiasis contribute to carcinogenesis through distinct but incompletely understood mechanisms. Surgical treatment remains the standard of care for high-risk localised disease, whereas perioperative chemotherapy, immunotherapy, and targeted agents are expanding treatment options, particularly in advanced disease. A substantial proportion of the therapeutic evidence, however, is derived from broader urothelial carcinoma populations rather than UTUC-specific studies. Conclusions: UTUC is biologically heterogeneous and shaped by both molecular alterations and environmental exposures. Although substantial progress has been made, important gaps remain in understanding UTUC-specific carcinogenic mechanisms and in defining evidence-based personalised treatment strategies. Better integration of molecular, environmental, and clinical data is needed to improve risk stratification and treatment selection.