Urine-Based Approaches for Screening, Diagnosis, and Surveillance of Urothelial Carcinoma

Background: Urothelial carcinoma (UC) is characterized by high recurrence rates and the need for long-term surveillance. Cystoscopy remains the diagnostic gold standard but is invasive, costly, and burdensome for patients. Urine, as a tumor-proximal and non-invasive biospecimen, represents an attractive source for biomarkers enabling screening, diagnosis, risk stratification, and follow-up. Objective: This review summarizes current and emerging urine-based diagnostic approaches for UC, ranging from conventional cytology to advanced molecular technologies, and discusses their clinical utility, limitations, and future perspectives. Methods: A narrative review of the literature was conducted focusing on urine-based diagnostics for UC, including urinary cytology, FDA-approved and investigational protein and DNA/RNA biomarkers, next-generation sequencing (NGS), cell-free DNA (cfDNA), exosomes, and microRNAs. Evidence from clinical validation studies, meta-analyses, and translational research was evaluated. Results: Urinary cytology remains highly specific for high-grade disease but has limited sensitivity for low-grade tumors. Protein- and DNA-based biomarkers have improved sensitivity but often lack sufficient specificity for standalone use. Recent advances in NGS-based assays enable comprehensive detection of tumor-specific genomic alterations in urinary cfDNA, offering high sensitivity for both initial diagnosis and disease monitoring. Exosomes and microRNAs represent promising biomarkers reflecting tumor biology, though standardization and large-scale validation are ongoing challenges. Overall, multimodal approaches combining cytology with molecular assays appear most promising for clinical implementation. Conclusions: Urine-based diagnostics are rapidly evolving toward integrated liquid biopsy platforms capable of transforming UC management. While several assays show strong potential to reduce reliance on cystoscopy, robust prospective validation, cost-effectiveness analyses, and clinical integration strategies are required before widespread adoption.