Inverted urothelial papilloma: Diagnostic challenges, molecular insights, and clinical implications

Inverted urothelial papilloma (IUP) is a rare benign tumor of the urinary tract, most commonly arising in the bladder and characterized by an endophytic growth pattern. IUP primarily affects middle-aged and older men and typically presents with painless hematuria. IUP was first described in 1927 and recognized as an independent entity by the World Health Organization in 1973. It can be difficult to distinguish from urothelial carcinoma (UC), which can result in misdiagnosis and overtreatment. Genetic analyses have confirmed the benign nature of IUP. Activating mutations in RAS family genes (HRAS, KRAS, NRAS) are frequent in IUP, whereas mutations typical of UC, such as FGFR3, TP53, and TERT promoter alterations, are rare. Macroscopically, lesions are generally small, solitary, and broad-based. Histologically, IUP exhibits two architectural patterns: trabecular and glandular, which both show minimal atypia and low mitotic activity. Differentiating IUP from UC with inverted growth and benign mimickers, such as florid von Brunn's nests or cystitis cystica/glandularis, is challenging, particularly when specimen size is limited. Immunohistochemistry (KRT20, TP53, and Ki-67) may support the diagnosis but does not reliably distinguish IUP from UC in difficult cases. The standard treatment is complete transurethral resection, and recurrence rates are low. The superficial urothelial cells overlying IUP may also harbor RAS mutations, challenging the long-held assumption that these cells are morphologically and genetically normal. Future studies should investigate whether similar genetic alterations in morphologically normal urothelium occur in other urothelial tumors. This could refine understanding of early tumorigenesis and guide improved detection and risk assessment.