Field cancerization in urothelial carcinoma: molecular alterations and clinical implications

Abstract

Urothelial carcinoma (UC) is a common malignancy of the urinary tract and is characterized by frequent recurrence, particularly in patients with non-muscle-invasive disease. Recurrence has traditionally been explained by residual tumor cells, intraluminal seeding, or the outgrowth of disseminated clones. However, molecular studies have shown that urothelium that appears normal under routine histological examination may already harbor cancer-related alterations. These findings support the concept of field cancerization, whereby prolonged exposure to carcinogens, chronic inflammation, and other injurious stimuli produces a biologically altered urothelial field before overt malignancy becomes visible. In this review, we searched PubMed and Web of Science for relevant studies published up to January 2026. We focused on investigations of peritumoral tissue or histologically normal-appearing urothelium that reported molecular abnormalities associated with UC development or recurrence. Available evidence from sequencing, methylation profiling, spatial mapping, and multi-omics studies indicates that field changes may involve somatic mutations, copy-number alterations, epigenetic dysregulation, metabolic reprogramming, and remodeling of the local immune and stromal microenvironment. These changes may create a permissive background for clonal expansion, multifocal tumor development, and recurrence after treatment. Although the clinical definition and spatial extent of the urothelial field remain unsettled, molecular characterization of apparently uninvolved urothelium may help refine risk assessment beyond conventional histopathology. In particular, perioperative urinary tumor DNA testing may assist in identifying molecular residual disease and support more individualized surveillance or adjuvant treatment decisions.