新型泌尿上皮癌生物標記檢驗

蔡秉軒、曾聖修、陳仲均、陳品鍵、蔡曜州

佛教慈濟醫療財團法人台北慈濟醫院 外科部 泌尿科

Urine biomarkers enables the detection of urothelial carcinoma

Pin-Hsuan Tsai, Shen-Shiou Tseng, Chung-Chun Chen, Nicholas Pin-Jian Tan, Yao-Chou Tsai

Divisions of Urology, Department of Surgery, Taipei Tzu Chi Hospital, New Taipei, Taiwan

Purpose: To evaluate the clinical diagnostic performance of a urine gene test — integrating NRN1 gene methylation and somatic mutations in the TERT promoter and FGFR3 gene — for the detection of urothelial carcinoma (UC), including bladder cancer (BC) and upper tract urothelial carcinoma (UTUC), and to compare its performance against conventional urine cytology.

Materials and Methods: In this prospective single-center study conducted at Taipei Tzu Chi Hospital (May 2023 – December 2025), a total of 182 consecutive patients presenting with lower urinary tract symptoms (LUTS), hematuria, or incidentally detected hydronephrosis were enrolled. Urine specimens (60–80 mL) were analyzed using a real-time PCR-based kit detecting NRN1 methylation and TERT/FGFR3 mutations. A continuous Integrated Molecular Score (IMS) was derived from raw Ct values for receiver operating characteristic (ROC) analysis. Diagnostic performance metrics — sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) — were calculated with 95% confidence intervals. Agreement between modalities was assessed via Cohen's kappa coefficient. Pathological diagnosis served as the gold standard, with tumor grading per the 2004 WHO classification and staging per the 2010 AJCC TNM system.

Results: After excluding 37 cases (20.3%) with invalid assay results, 145 patients comprised the evaluable cohort. Of these, 62 patients (42.8%) had pathologically confirmed disease. UC was pathologically confirmed in 32 patients (22.1%; 23 BC, 9 UTUC). The urine gene test detected 31 of 32 malignancies, yielding a sensitivity of 96.9% (95% CI: 84.3–99.5%), specificity of 73.3% (95% CI: 55.6–85.8%), and NPV of 95.7% (95% CI: 79.0-99.2), with substantial agreement with pathology (κ = 0.707). In contrast, voided urine cytology and washing cytology demonstrated sensitivities of only 27.3% and 62.5%, respectively, with 100% specificity each. ROC analysis revealed the highest AUC for the IMS (0.953), significantly outperforming combined cytology (AUC = 0.840). In a head-to-head comparison among 20 patients with concurrent results, the IMS achieved a numerically superior AUC (0.853 vs. 0.840), though the difference did not reach statistical significance (DeLong's test, P = 0.907), likely due to limited sample size. One false-negative case involved obstructive UTUC with hydronephrosis, and false positives were observed in patients with BPH, urolithiasis, and non-urothelial malignancies.

Conclusions: The urine gene test IMS incorporating NRN1 methylation and TERT/FGFR3 mutation analysis demonstrated excellent sensitivity and overall discriminative capacity for UC detection, markedly surpassing conventional cytology. It provides an objective, non-invasive adjunctive diagnostic tool with strong clinical utility, particularly for identifying malignancies missed by cytology. Large-scale multicenter prospective studies with extended follow-up are needed to validate these findings and define the assay's role in routine urological practice.