Clinical utility of a urine-based urothelial cancer test in equivocal upper tract lesions: improving malignancy detection and minimizing unnecessary URS

Background and Objective: Upper tract urothelial carcinoma (UTUC) is a rare but aggressive malignancy that often requires diagnostic ureterorenoscopy (URS), an invasive procedure associated with infection, ureteral injury, and potential tumor seeding. In patients with equivocal imaging, deciding whether to perform URS is challenging and may lead to unnecessary procedures. A non-invasive and accurate diagnostic tool is therefore needed to improve risk stratification. Bladder CARE™, a urine-based epigenetic assay with high accuracy for bladder cancer and UTUC, received FDA Breakthrough Device Designation in December 2023. This study evaluated its diagnostic performance in patients with equivocal upper-tract lesions, with the goal of confirming malignancy and reducing unnecessary URS in selected cases. Material and Methods: Between December 2023 and August 2025, urine samples from 46 patients with suspected UTUC were analyzed using Bladder CARE™. All patients subsequently underwent URS, with nephroureterectomy performed when malignancy was confirmed. Results were classified using the Bladder CARE Index (BCI): positive (> 10), low positive (2.5-10), and negative (< 2.5). Sensitivity, specificity, PPV, and NPV were calculated using histopathology from URS and/or nephroureterectomy as the reference standard. Associations between BCI and tumor grade were also assessed. Results: Patients had a mean age of 70 years (16 female, 30 male); 24 were UTUC-positive and 22 negative. Mean BCI was significantly higher in UTUC-positive cases vs negatives (85.8 vs 1.7). The positive category showed excellent performance (93% sensitivity, 100% specificity, PPV 100%, NPV 95%), supporting its use to avoid URS in appropriately selected patients. Low-positive results also detected a substantial proportion of cancers but with lower certainty (86% sensitivity, 69% specificity), making URS evaluation appropriate for these cases. Bladder CARE™ detected 88% of low-grade and 100% of high-grade tumors, and 90% of Ta and 100% of T1-T3 tumors. Cytology detected only 2 of 19 UTUC cases. Mean BCI values were higher in high-grade vs low-grade tumors (111.7 vs 54.2) and in T1-T3 vs Ta lesions (136.7 vs 56.0), indicating correlation with tumor aggressiveness. Conclusion: Bladder CARE™ demonstrated strong diagnostic accuracy with potential to modify the UTUC management pathway. A positive result may allow direct progression to definitive treatment without diagnostic URS, reducing morbidity and expediting care. The correlation between BCI and tumor grade/stage may further support treatment selection, including kidney-sparing approaches or neoadjuvant therapy. While multicenter validation is needed, this non-invasive assay represents a promising advance in UTUC diagnostics and clinical decision-making.