Precursor flat urothelial lesions: Molecular landscape, pathogenesis, and biological insights

Flat urothelial lesions represent a diagnostically challenging and clinically significant spectrum in bladder pathology. Distinguishing urothelial carcinoma in situ (CIS) from precursor lesions such as dysplasia remains problematic due to overlapping morphologic features, marked interobserver variability, and unresolved questions about biological behavior and progression risk. These challenges pose a substantial risk of underdiagnosis of neoplastic lesions-misclassified as reactive or benign-or overtreatment of precursors overcalled as CIS. As a result, intermediary lesions-particularly dysplasia-remain controversial and marginally addressed in major guidelines, including the 2022 WHO classification. Recent molecular studies, including next-generation sequencing and proteogenomics, have uncovered defining genomic alterations in flat lesions-such as prevalent TERT promoter mutations across the intraurothelial neoplasia spectrum, alongside variable TP53, FGFR3, and chromatin-remodeling gene changes-that help better define biological behavior and refine diagnostic categories. This review synthesizes recent molecular profiling data within the framework of established urothelial carcinogenesis pathways, offering insights into the biology and progression of flat lesions. It examines evolving classification systems, ongoing challenges in diagnostic reproducibility, and clinical implications. Ancillary modalities, including immunohistochemistry (e.g., CK20, p53, CD44) and emerging molecular tests, are appraised for their utility and constraints. Finally, the review highlights emerging computational tools-particularly artificial intelligence-based analysis of histopathology slides, which shows considerable promise in enhancing diagnostic accuracy-and concludes with evidence-based recommendations aimed to optimize the management of flat urothelial lesions.