Dr. Breda notes that the European Association of Urology (EAU) guidelines on upper tract urothelial carcinoma denote low-risk disease as being (i) non-invasive on Computed tomography (CT) imaging, (ii) unifocal disease, (iii) low-grade on biopsy, (iv) negative cytology, and (v) tumor size <2 cm.1 However, risk assessment can be challenging given that CT imaging is not always reliable, 35% of biopsies are inconclusive, 30% of patients have upgrading after nephroureterectomy, and urinary cytology sensitivity for high-grade disease is only 56% (for voided urine).
According to the guidelines, there is strong evidence to use diagnostic ureteroscopy and biopsy if imaging and cytology are not sufficient for the diagnosis and/or risk-stratification of the tumor. Work from Dr. Breda’s group assessed whether CT imaging can replace ureteroscopy, finding that among 244 patients undergoing ureteroscopy for suspicion of upper tract urothelial carcinoma 48% of patients had different characteristics compared to CT imaging (CT sensitivity: 47%).2 Dr. Breda notes that there are several opportunities for improving risk assessment and diagnosis:
However, Dr. Breda highlights that when it comes to biomarkers for upper tract urothelial carcinoma we are currently “borrowing from” bladder urothelial carcinoma, including CellDetect, AnticipateX, CX Bladder, Bladder EpiCheck, UroVysion FISH, Micro-RNA Tests, and MCM5. Recently, it has been shown that miR-129-2 and miR-663a were differentially methylated in urothelial carcinoma compared with other genitourinary tract malignancies. In a study by Padrao et al.,3 they found that promoter methylation levels of both microRNAs were significantly higher in urothelial carcinoma tissue samples compared with normal urothelium. Furthermore, in the urine, the assay was able to distinguish urothelial carcinoma from other genitourinary tract carcinomas with 87.7% sensitivity and 84% specificity, resulting in 86% overall accuracy. A subsequent study looked at methylation of CDH1/VIM/RASSF1A/HSPA2/GDF15/TMEFF2 among 98 upper tract urothelial carcinoma patients compared to 113 control voided urine samples.4 The resulting sensitivity, specificity, PPV, NPV, and AUC are as follows when compared to FISH and cytology:
Dr. Breda notes that EpiCheck is an ideal biomarker in that it uses a panel of DNA methylation biomarkers (KCNJ2, CDKN2A, IRF4, Olig2, ADCYAP1, NPR3, HOXA9, DNM3, PXDN, MSC, intergenic regions on chromosomes 1, 6, 15, 16), requires only a small amount of urine (10 mL), and has no interference by hemoglobin, red/white blood cells or ethanol in the urine. It also is able to be stored in the refrigerator for up to 5 days. After preparation using the Bladder EpiCheck test kit, the DNA undergoes real-time PCR amplification followed by an EpiScore (0-100, positive if >= 60). Dr. Breda’s group is currently performing the first prospective study on urinary biomarkers in upper tract urothelial carcinoma. This study enrolled 80 patients undergoing ureteroscopy who also received an EpiCheck study, results of which are forthcoming (in press).
Dr. Breda concluded his presentation with several take-home messages:
- Achieving a correct diagnosis is crucial to assess the patient’s risk
- Ureteroscopy remains decisive in determining treatment of upper tract urothelial carcinoma
- The merger of new technologies and urinary biomarkers are helping the urologist to break through the limits of the standard techniques
- Development of biomarker tests seems to be the future in the diagnostic assessment of urothelial cancer
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 18th Meeting of the EAU Section of Oncological Urology (ESOU21), January 29-31, 2021
References:
- Roupret M, Babjuk M, Capoun O, et al. European Association of Urology Guidelines on Upper Tract Urothelial Carcinoma: 2020 Update. Eur Urol 2020 Jun 24:S0302-2838(20)30427-9.
- Gallioli A, Territo A, Mercade A, et al. The Impact of Ureteroscopy following computerized tomography urography in the management of upper tract urothelial carcinoma. J Urol 2021 Feb;205(2):392-399.
- Padrao NA, Monteiro-Reis S, Torres-Ferreira J, et al. MicroRNA promoter methylation: A new tool for accurate detection of urothelial carcinoma. Br J Cancer. 2017 Feb 28;116(5):634-639.
- Guo RQ, Xiong GY, Yang KW, et al. Detection of urothelial carcinoma, upper tract urothelial carcinoma, bladder carcinoma, and urothelial carcinoma with gross hematuria using selected urine-DNA methylation biomarkers: A prospective, single-center study. Urol Oncol 2018 Jul;36(7):342.e15-e23.