Urologic Oncology: Seminars and Original Investigations
Seminar articleUrine markers for detection and surveillance of bladder cancer
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:
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The quantitative BTA TRAK and the qualitative point-of-care BTA (bladder tumor antigen) stat test (both by Polymedco Inc., Cortlandt Manor, NY).
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The quantitative immunoassay NMP22 and the qualitative, point-of-care test NMP22 BladderChek (Matritech Inc., Newton, MA).
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The UroVysion Bladder Cancer Kit (Vysis Inc., Downers Grove, IL), a multiple marker FISH test.
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The uCytTM test, an immunocytochemical assay (Scimedx Inc., Denville, NJ).
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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
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Both authors contributed equally.