Seminar article
Urine markers for detection and surveillance of bladder cancer

https://doi.org/10.1016/j.urolonc.2013.06.001Get rights and content

Abstract

Objectives

Bladder cancer detection and surveillance includes cystoscopy and cytology. Urinary cytology is limited by its low sensitivity for low-grade tumors. Urine markers have been extensively studied to help improve the diagnosis of bladder cancer with the goal of complementing or even replacing cystoscopy. However, to date, no marker has reached widespread use owing to insufficient evidence for clinical benefit.

Material and methods

Pubmed/Medline search was conducted to identify original articles, review articles, and editorials regarding urine-based biomarkers for screening, early detection, and surveillance of urothelial carcinoma of the bladder. Searches were limited to the English language, with a time frame of 2000 to 2013. Keywords included urothelial carcinoma, bladder cancer, transitional cell carcinoma, biomarker, marker, urine, diagnosis, recurrence, and progression.

Results

Although several urinary markers have shown higher sensitivity compared with cytology, it remains insufficient to replace cystoscopy. Moreover, most markers suffer from lower specificity than cytology. In this review, we aimed to summarize the current knowledge on commercially available and promising investigational urine markers for the detection and surveillance of bladder cancer.

Conclusions

Well-designed protocols and prospective, controlled trials are needed to provide the basis to determine whether integration of biomarkers into clinical decision making will be of value for bladder cancer detection and screening in the future.

Introduction

Bladder cancer (BC), a highly aggressive and heterogeneous disease, is the most common malignancy of the urinary tract [1]. The global incidence of BC was approximately 357,000 cases in 2012 [1]. Its high incidence, coupled with its high propensity to recur pose an enormous socioeconomic problem. At any point in time, it is estimated that 2.7 million people have the diagnosis of BC in Western countries [2]. Most BC (75%–85%) presents as non–muscle invasive BC (NMIBC) at first diagnosis (Ta, T1, and carcinoma in situ (CIS)) [3], [4]. Among these NMIBCs, approximately 70% are Ta, 20% are T1, and 10% are CIS lesions [3], [4]. Disease recurrence occurs in up to 80% of patients with NMIBC and is the main problem for patients with Ta NMIBC, whereas disease progression occurs in up to 30% of patients and is the main threat to patients with T1 or CIS [3], [4]. NMIBC is particularly sensitive to nuances in care, and each intervention changes the biological and clinical behavior of the disease. Therefore, an in-depth understanding of risk factors and management is necessary to ensure optimal evidence-based clinical care for each patient with NMIBC.

Owing to the lack of disease-specific symptoms, diagnosis and follow-up of BC remain a challenge. Cystoscopy, the gold standard for the detection of BC, is invasive and relatively expensive, thus limiting its use. Although new cystoscopy technologies, such as fluorescence or narrow-band imaging, are emerging, the invasiveness and added costs of these procedures further underscore the need for better, simpler, and cheaper diagnostic tests in the management of patients with BC [5], [6], [7]. Voided urine cytology is a highly specific, noninvasive adjunct to cystoscopy. It has good sensitivity for detecting high-grade BC, but its sensitivity for detection of low-grade tumors is only 4% to 31% [8], [9]. Furthermore, the performance of cytology is dependent upon the level of expertise of the cytopathologist, it is relatively expensive and it is not readily available in all countries. Thus, a noninvasive, highly sensitive, and specific marker for detecting BC could decrease the morbidity associated with cystoscopy, improve patient quality of life, and decrease costs by substituting a less expensive, noninvasive test for the more expensive endoscopic procedure. The clinical scenarios in which such a test could play a role are in the early diagnosis (voiding symptoms, hematuria, and high-risk populations) of BC and the surveillance of patients with previous occurrence of BC.

In this review, we discuss first these 2 clinical scenarios and then report on the performance of the most known commercially available and investigational urinary markers subdivided into cell and protein markers.

BC screening could be an indication for the use of a noninvasive diagnostic test [10]. Although the mortality/incidence ratio is higher for BC than for prostate cancer, the comparatively low incidence of BC in the general population, along with the low mortality from BC because of a high amount of cases with nonfatal tumors, has been an obstacle to the development of effective screening strategies for BC. Nevertheless, data from a few screening trials and theoretical considerations on cost-effectiveness issues have revitalized this discussion recently [11], [12], [13]. Screening of well-defined high-risk populations with a disease prevalence comparable to tumor entities accepted for screening (e.g. breast cancer or colorectal cancers) may offer a solution to this problem [14]. A recent study, which incorporated data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial used simple decision analytic techniques to identify the best candidates for a screening trial [15]. The authors showed that screening for BC can be optimized by restricting it to a subgroup of patients considered to be at an elevated risk. Using a risk stratification tool improved the detection rates when compared with general population (selected on age) and resulted in approximately 25% of the population being screened to prevent 57 invasive or high-grade BC per 100,000 population (while screening the entire population would prevent only an additional 38 cases). As of now, the main risk factors for BC remain age, gender, smoking history, and intensity, as well as some occupational exposures. Determining whether a population is at sufficient risk to justify screening is as important as developing a diagnostic test.

Surveillance of patients with a history of BC is a key area for the use of new markers. This is largely due to the high prevalence and recurrence rate of the disease [4]. Molecular markers may be able to detect BC before they are visually evident [16], [17]. However, this causes a significant problem in defining negative tests. Currently, there is no reliable way of separating false-positive tests from true-positive tests when patients do not present with a visually detectable tumor. Theoretically, in the surveillance setting, a marker could both reduce the number of cystoscopies and detect disease recurrence or progression earlier than the traditional tests.

Section snippets

NMP22

Nuclear matrix proteins (NMPs) are part of the structural framework of the nucleus and provide support for the nuclear shape. One member of this family, nuclear mitotic apparatus protein 22 (NMP22), is much more prevalent in malignant urothelial cells than in normal cells [18]. Apoptosis is accompanied with a release of NMP22 into the urine, and patients with BC have a significantly elevated concentration of NMP22 compared with their healthy counterparts [18]. The 2 marker tests for BC

UBC tests

UBC-Rapid and UBC-enzyme-linked immunosorbent assay (ELISA) tests are immunological assays available from IDL (IDL Biotech, Borlange, Sweden). Both assays detect cytokeratin 8 and 18 fragments in urine [55]. As cytokeratins are intracellular proteins, their detection in urine is possible only when they are released in urine following cell death. The UBC-Rapid assay is a qualitative point-of-care assay wherein cytokeratin 8 and 18 fragments present in urine react with gold-labeled antibodies

uCyt+TM/ImmunocytTM

The uCyt+TM assay, formerly ImmunocytTM, is a commercially available immunocytological assay based upon microscopical detection of tumor-associated cellular antigens in urine-derived urothelial cells by immunofluorescence (Scimedx Inc., Denville, NJ). It combines cytology with an immunofluorescence assay [69]. It detects cellular markers for BC in exfoliated urothelial cells using fluorescent monoclonal antibodies for a high molecular weight form of carcinoembryonic antigen and 2 bladder tumor

Urovysion

UroVysion (Abbott Molecular, Inc, Des Plaines, IL) is a multitarget fluorescence in situ hybridization (FISH) assay that detects aneuploidy in chromosomes 3, 7, and 17 as well as loss of the 9p21 locus of the P16 tumor-suppressor gene. The FDA both for the detection and surveillance settings has approved this test. The FISH test combines assessment of morphologic changes of conventional cytology with molecular DNA changes. Each probe is a fluorescently labeled, single-stranded DNA fragment

Promising markers

Aurora kinase A (AURKA) is a gene encoding a key regulator of mitosis. AURKA is frequently amplified or overexpressed in cancer cells or both, and the level of AURKA amplification is associated with the level of aneuploidy. AURKA gene amplification has been investigated as a biomarker for the detection of BC [84]. The FISH test for the AURKA gene copy number yielded a specificity of 96.6% and sensitivity of 8 7% [84]. Moreover, a higher degree of gene amplification was associated with

Commercial availability

The FDA-approved tests are as follows:

  • The quantitative BTA TRAK and the qualitative point-of-care BTA (bladder tumor antigen) stat test (both by Polymedco Inc., Cortlandt Manor, NY).

  • The quantitative immunoassay NMP22 and the qualitative, point-of-care test NMP22 BladderChek (Matritech Inc., Newton, MA).

  • The UroVysion Bladder Cancer Kit (Vysis Inc., Downers Grove, IL), a multiple marker FISH test.

  • The uCytTM test, an immunocytochemical assay (Scimedx Inc., Denville, NJ).

  • With the exception of the

Conclusions

Urinary cytology is limited by its low sensitivity for low-grade tumors. Urine markers have been extensively studied; however, to date, no marker has reached widespread use. Although several urinary markers have shown higher sensitivity compared with cytology, most suffer from low specificity. Moreover, many of them are currently evaluated in prospective trials. Combination of different markers is promising concept and seems to represent the future. Another limitation is that each setting

References (89)

  • H. Boman et al.

    Four bladder tumor markers have a disappointingly low sensitivity for small size and low grade recurrence

    J Urol

    (2002)
  • M. Sánchez-Carbayo et al.

    Comparative sensitivity of urinary CYFRA 21-1, urinary bladder cancer antigen, tissue polypeptide antigen, tissue polypeptide antigen and NMP22 to detect bladder cancer

    J Urol

    (1999)
  • M.F. Sarosdy et al.

    Improved detection of recurrent bladder cancer using the Bard BTA stat test

    Urology

    (1997)
  • B.R. Konety et al.

    Urine based markers of urological malignancy

    J Urol

    (2001)
  • S.B. Malkowicz

    The application of human complement factor H-related protein (BTA TRAK) in monitoring patients with bladder cancer

    Urol Clin North Am

    (2000)
  • V.B. Lokeshwar et al.

    Current bladder tumor tests: does their projected utility fulfill clinical necessity?

    J Urol

    (2001)
  • V.B. Lokeshwar et al.

    Bladder tumor markers beyond cytology: international consensus panel on bladder tumor markers

    Urology

    (2005)
  • H.G. Wiener et al.

    Can urine bound diagnostic tests replace cystoscopy in the management of bladder cancer?

    J Urol

    (1998)
  • D. Pode et al.

    Noninvasive detection of bladder cancer with the BTA stat test

    J Urol

    (1999)
  • S. Ramakumar et al.

    Comparison of screening methods in the detection of bladder cancer

    J Urol

    (1999)
  • A. Giannopoulos et al.

    Comparative evaluation of the BTA stat test, NMP22, and voided urine cytology in the detection of primary and recurrent bladder tumors

    Urology

    (2000)
  • M.P. Raitanen et al.

    Human complement factor H related protein test for monitoring bladder cancer

    J Urol

    (2001)
  • M. Babjuk et al.

    Qualitative and quantitative detection of urinary human complement factor H-related protein (BTA stat and BTA TRAK) and fragments of cytokeratins 8, 18 (UBC rapid and UBC IRMA) as markers for transitional cell carcinoma of the bladder

    Eur Urol

    (2002)
  • G.L. Schroeder et al.

    A side by side comparison of cytology and biomarkers for bladder cancer detection

    J Urol

    (2004)
  • M. Babjuk et al.

    Urinary cytology and quantitative BTA and UBC tests in surveillance of patients with pTapT1 bladder urothelial carcinoma

    Urology

    (2008)
  • W.J. Ellis et al.

    Clinical evaluation of the BTA TRAK assay and comparison to voided urine cytology and the Bard BTA test in patients with recurrent bladder tumors

    Urology

    (1997)
  • A.S. Glas et al.

    Tumor markers in the diagnosis of primary bladder cancer. A systematic review

    J Urol

    (2003)
  • B.W.G. van Rhijn et al.

    Urine markers for bladder cancer surveillance: a systematic review

    Eur Urol

    (2005)
  • M. Sánchez-Carbayo et al.

    Initial evaluation of the new urinary bladder cancer rapid test in the detection of transitional cell carcinoma of the bladder

    Urology

    (1999)
  • I.J. Schultz et al.

    Bladder cancer diagnosis and recurrence prognosis: comparison of markers with emphasis on survivin

    Clin Chim Acta

    (2006)
  • S.F. Shariat et al.

    Urine detection of survivin is a sensitive marker for the noninvasive diagnosis of bladder cancer

    J Urol

    (2004)
  • J.M. Myers-Irvin et al.

    Use of the novel marker BLCA-1 for the detection of bladder cancer

    J Urol

    (2005)
  • T.S. Van Le et al.

    Highly specific urine-based marker of bladder cancer

    Urology

    (2005)
  • B.R. Konety et al.

    Clinical usefulness of the novel marker BLCA-4 for the detection of bladder cancer

    J Urol

    (2000)
  • C. Mian et al.

    Immunocyt: a new tool for detecting transitional cell cancer of the urinary tract

    J Urol

    (1999)
  • J.L. Vriesema et al.

    Diagnostic efficacy of the immunocyt test to detect superficial bladder cancer recurrence

    Urology

    (2001)
  • C. Pfister et al.

    Immunocyt test improves the diagnostic accuracy of urinary cytology: results of a French multicenter study

    J Urol

    (2003)
  • E.K. Cha et al.

    Immunocytology is a strong predictor of bladder cancer presence in patients with painless hematuria: a multicentre study

    Eur Urol

    (2012)
  • T. Hajdinjak

    UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic accuracy and comparison with urinary cytology testing

    Urol Oncol

    (2008)
  • O.N. Gofrit et al.

    The predictive value of multi-targeted fluorescent in-situ hybridization in patients with history of bladder cancer

    Urol Oncol

    (2008)
  • M. Skacel et al.

    Multitarget fluorescence in situ hybridization assay detects transitional cell carcinoma in the majority of patients with bladder cancer and atypical or negative urine cytology

    J Urol

    (2003)
  • B.J. Schlomer et al.

    Prospective validation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the bladder

    J Urol

    (2010)
  • Y. Lotan et al.

    Prospective evaluation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the bladder

    J Urol

    (2008)
  • I.S. Sawczuk et al.

    DD23 biomarker: a prospective clinical assessment in routine urinary cytology specimens from patients being monitored for TCC

    Urol Oncol

    (2002)
  • Cited by (0)

    1

    Both authors contributed equally.

    View full text