Emerging biomarkers for the diagnosis and monitoring of urothelial carcinoma

Abstract

Urothelial carcinoma (UC) arises extensively from the renal pelvis, ureter, urinary bladder, and urethra. UC represents a clinical and social challenge because of its incidence, post-treatment recurrence rate, and prognosis. Combinations of urine cytology, cystoscopy, and conventional imaging such as computed tomography are currently used for diagnosis and monitoring modalities of UC. Both the poor diagnostic accuracy of urine cytology and poor cost performance of cystoscopy and conventional imaging modalities emphasize the urgent need for advancement in clinical guidance for UC. Urine- and blood-based biomarkers for detection of UC of the bladder and upper urinary tract represent a considerable research area. Biomarkers can help to improve UC diagnosis with the aim of replacing cystoscopy and other imaging examinations in future and may enable individualizing risk stratification regarding therapy and follow-up. Over the decades, numerous studies have focused on the potential application of biomarkers for UC, including urine, circulating tumor DNA, RNAs, proteins, and extracellular vesicles. Although some biomarkers such as ImmunoCyt/uCyt+, UroVysion, NMP-22, bladder tumor antigen, CxBladder, and Xpert Bladder Cancer are currently available in clinical practice, few biomarkers achieve high sensitivity and specificity. Emerging biomarkers are continuously developed and reported in medical journals. However, there is a significant lack on following external validation using different cohorts. The positive results are needed to be confirmed by more studies with large-scale cohorts and long follow-up periods to prove the true value of novel biomarkers, followed by their adoption in clinical practice. The present paper provides an overview of the evidence based on high-impact studies regarding urine- and blood-based biomarkers and their clinical applications in bladder cancer and upper tract UC.

Urinary Biomarkers in Bladder Cancer: Where Do We Stand and Potential Role of Extracellular Vesicles

“…These include circulating tumor cells (CTCs), proteins, metabolites, circulating nucleic acids, namely cell-free tumor DNA (ctDNA), messenger RNA (mRNA), micro RNA (miRNA), or long non-coding RNA (lncRNA). Most of these biomarkers may be found free or within extracellular vesicles (EVs) shed by tumor cells or by other elements of the tumor microenvironment [ 56 , 57 ] ( Figure 1 ). There is a growing interest on the liquid biopsy concept, since (i) the biomarkers found have extensive potential for diagnosis and monitoring of disease stage and recurrence; (ii) prediction of therapeutic response/resistance and disease prognosis, with minimally invasive procedures, and (iii) helping therapeutic clinical reasoning based on identified molecular changes [ 56 , 57 , 58 ].…”

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study

“…As urine is in direct contact with the inner part of the bladder, cells from the epithelium, including scammed cells from bladder tumors, can exfoliate and be detected in urine and used to evaluate and monitor the presence of neoplasia in a noninvasive approach (Botezatu et al, 2000;Zwarthoff, 2008;Ralla et al, 2014;Critelli et al, 2016;Togneri et al, 2016). Over the years, many different noninvasive assays have been developed in order to search genetic and protein alterations known to be involved in the development, progression, and recurrence of bladder cancer, both in serum and urine samples, with the purpose to diagnose and monitor bladder cancer (Soloway et al, 1996;Fradet and Lockhard, 1997;Pode et al, 1999;Kruger et al, 2003;Tetu et al, 2005;Moonen et al, 2007;Halling and Kipp, 2008;Serizawa et al, 2011;Goodison et al, 2012;Kinde et al, 2012;Kinde et al, 2013;Allory et al, 2014;Bansal et al, 2014;Hurst et al, 2014;Ralla et al, 2014;Wang et al, 2014;Ellinger et al, 2015;Yafi et al, 2015;Springer et al, 2018;Miyake et al, 2018). Some of these tests presented values of sensitivity and specificity higher than urinary cytology and achieved FDA approval for bladder cancer diagnosis.…”

Significant reduction of indeterminate (atypical) diagnosis after implementation of The Paris System for Reporting Urinary Cytology: A single‐institution study of more than 27,000 cases

“…Urothelial carcinoma (UC), which accounts for 90% of bladder cancers, is the most common malignancy involving the urinary tract. Because of high recurrence rates, a lengthy disease course, and intensive surveillance strategies, the management of UC is very expensive 1 . Cystoscopic examination with tissue sampling is the gold‐standard procedure for diagnosing urinary tract neoplasms.…”