尿液脫落細胞作為尿路上皮癌潛在生物標誌物

查舫宇¹、張瑛芝^2,3、黃昭淵¹、洪健華^1,4

¹台大醫院泌尿部²;中央研究院基因體研究中心; ^2,3美國史丹佛大學化學工程學系;

⁴國立臺灣大學醫學工程學系

Urinary Exfoliated Cells as a Potential Biomarker for Urothelial Carcinoma

Fang-Yu Cha¹、Ying-Chih Chang^2,3, Chao-Yuan Huang¹, Jian-Hua Hong^1,4

¹Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan

University, Taipei, Taiwan.; ²Genomics Research Center, Academia Sinica, Taipei, Taiwan; ³Department of Chemical Engineering, Stanford University, USA;⁴Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.

Purpose: Cells that have exfoliated from the urothelial epithelium are known as urinary exfoliated cells (UECs). According to the hypothesis of implantation and regional carcinogenesis, cancer cells found in UECs are thought to be significantly involved in the development and recurrence of disease. In the past, their detection has often relied on their cellular morphology or immunofluorescence labeling as a means of tumor detection. Clinical evidence shows that up to 20-50% of urothelial carcinoma (UC) cases that receive radical nephroureterectomy or cystectomy experience bladder recurrence, indicating that UECs may carry information from primary tumor cells and promote carcinogenesis.

Material and Methods: The current study collected self-voided urine from 21 UC patients before and after radical nephroureterectomy or cystectomy, as well as from 7 healthy controls, in order to identify and analyze cellular characteristics in urine samples. After centrifugation, UECs (Pan CK+/CD45-/DAPI+) were identified by multiplex immunofluorescence. Two-tailed Fisher's exact test were used for analyzing categorical variables, and Mann-Whitney U test for comparing the test results between recurrent and non-recurrent patients, or between cancer patients and healthy controls. The study also compared the differences among different stages of UC patients and normal controls using Kruskal-Wallis test. In terms of tumor survival, log rank test and Cox's proportional hazards model were used to evaluate the disease-free survival. All calculated P values were two-tailed. Statistical significance was defined as P < 0.05.

Results: UEC levels were higher in late stages of UC compared to early stages and healthy controls, indicating a possible link between UECs and urothelial cancer. Patients who had a significant reduction in UECs three months after surgery compared to preoperative levels (more than 75% decline) had longer recurrence-free survival (HR 0.091, 95% CI 0.0009-0.912, p=0.0415).

Conclusions: The current study found that UECs are significantly higher in UC patients than healthy controls, particularly in advanced stages. Patients with a significant reduction of UECs after surgery had longer recurrence-free survival. UECs may serve as a biomarker to distinguish between disease recurrence.