Urethral cancer management in contemporary practice: A review

Primary urethral carcinoma (PUC) is a very rare and aggressive genitourinary cancer. Its low incidence has limited the availability of clinical trials and robust information, with most evidence derived from retrospective series, population-based registries, and expert consensus. This review synthesizes contemporary knowledge on epidemiology, diagnosis, histopathology, molecular biology, treatment, and future perspectives in PUC. Sex-specific and anatomical differences strongly influence presentation and histology: squamous cell carcinoma predominates in men with distal disease, urothelial carcinoma is more frequent in the prostatic urethra, and adenocarcinoma arises mainly from female periurethral diverticula. Chronic inflammation, strictures, long-term catheterization, and human papillomavirus infection are established etiologic factors. Diagnostic delays are common, particularly in women, underscoring the need for heightened suspicion, early biopsy, and advanced imaging for accurate staging. Surgical resection remains the cornerstone for localized disease, with penile- or urethra-preserving approaches favored in distal tumors to optimize functional outcomes. Radical surgery, including penectomy or anterior exenteration, is often required in proximal or advanced cases but carries significant morbidity. Radiotherapy, historically applied in women and unfit surgical candidates, retains a role in organ preservation when combined with other therapies. Systemic treatment, centered on cisplatin-based regimens, has demonstrated improved survival in advanced disease, with neoadjuvant strategies enhancing resectability. Emerging evidence supports integrating immunotherapy and targeted agents guided by molecular alterations. Multimodal therapy has become the standard in advanced stages, improving survival while enabling functional preservation in selected patients. Prognosis is dictated by stage, nodal status, histology, and surgical margins. Future priorities include international collaborations, harmonized registries, biomarker-driven personalization, and integration of patient-reported outcomes to align oncologic control with quality of life. PUC management today is defined by risk-adapted, multidisciplinary strategies delivered in specialized centers, reflecting both historical lessons and modern advances.