Although the increased incidence of bladder cancer (BC) has softened in recent years, proposed to be due in part to smoking cessation strategies, BC remains a significant healthcare problem with high recurrence rates.1,2 Currently, there is inadequate evidence that screening for BC in the asymptomatic population promotes improved overall morbidity or mortality.3 Despite this current state of the science, there is great interest in bettering the gold standard for early diagnosis—cystoscopy, cytology, and imaging—as these are expensive, uncomfortable, and not suggested for low-risk individuals or for those without hematuria.4
Background
Bladder cancer is projected to be the fourth most common cancer diagnosed in American men in 2012, with an expected incidence of over 55,000 cases; for women, the incidence is estimated to be just under 18,000 new cases. More than 10,000 men are expected to die of the disease in 2012, with an estimated 4000 women succumbing as well. BC occurs 4 times more commonly in men than in women, and in twice as many white men as African American men.5 Efforts should be made to promote smoking cessation, as smoking is the most wellestablished risk factor for BC. Other risk factors include work-related exposures to dyes, rubber, and leather, as well as exposure to paints, solvents, and arsenic; certain previous infections of the bladder; older age; and a positive personal or family history of BC.1,3,5,6 It has been hypothesized that BC risk is related to the concentration of carcinogens in urine and the amount of time urothelial tissues are exposed to such causative agents. Therefore, increasing hydration as well as nocturia may be protective.1
Screening/Early Detection
There are currently no guidelines for BC screening of asymptomatic adults. The American Cancer Society reviews its data annually and continues to recommend against screening for BC in patients at average risk.1,3,5 The US Preventive Services Task Force, upon review of the evidence of benefits versus harms of screening for BC in low-risk, asymptomatic individuals, and further based on their statement from 2004, states that the evidence is insufficient to recommend screening.3 Healthcare professionals, nonetheless, need to individualize their approach to care. Healthcare professionals need to consider the potential harms of screening for BC, including the possibility of false-positive results, which may lead to unnecessary diagnostic procedures. This can be the source of great stress and anxiety for patients. On the other hand, early detection of disease and, if possible, the identification of more aggressive cancers that require immediate interventions may have an important effect on morbidity and mortality. Therefore, screening some individuals may prove beneficial. However, current data do not provide certainty that earlier, less toxic therapies improve outcomes versus waiting to use more toxic treatment in those with symptomatic or advanced tumors.3
For the asymptomatic individual, incidental microhematuria is often found on routine urinalysis and workup for other planned interventions, such as elective surgeries and annual physical exams. Occult blood found in the urine often prompts the patient to visit a urologist for further workup, generally urine cytology, cystoscopy, and imaging—the gold standard. For those at risk, this gold standard is employed for screening/early detection, minimally every 3 months, depending on interventions. Not only are these tests uncomfortable and embarrassing, but they are not always sensitive enough to detect cancer. Because superficial BC can be missed or may not be of metastatic potential, the standard is not enough to effect positive outcomes. For example, cystoscopy can miss flat tumors or carcinoma in situ, leading to 10% to 30% false-negative results.7 Consequently, the limitations of cytology and the invasiveness of cystoscopy have generated interest and investigation into various noninvasive diagnostic tools.8
In order for a diagnostic tool—ie, a screening method, biomarker, or tumor marker—to be effective, several elements must be in place. First, the disease prevalence must be an obvious healthcare issue, and diagnosing early would seem of benefit. Second, there should be acceptable treatments available. Third, the tool should be minimally invasive or noninvasive and cost-effective, or at least not prohibitively expensive. Fourth, the tool must be useful in the asymptomatic population, with high sensitivity (true positives and no falsenegatives) and high specificity (true negatives and no false-positives), as optimum sensitivity is crucial for screening and high specificity is imperative for disease confirmation. Lastly, the tool must also be acceptable to the population who will be assessed.1,9,10
Approved Markers
Clinical application of markers includes screening, confirmation of diagnosis, classification and staging, prognosis, monitoring response, surveillance, and early detection of disease recurrence.9 However, the definition of markers useful for these applications is broad. Tumor markers are generally substances secreted by the tumor, overexpressed by malignant cells, or secreted by the host in response to malignancies. These can be hormones, proteins, enzymes, receptors, and genomic alterations.9-11 It is hypothesized that the levels of these markers reflect tumor burden, thus increasing with malignancy and progression of disease and decreasing in response to treatment and with remission.
For BC, there are a few US Food and Drug Administration (FDA)-approved markers available for use in the clinical setting, although currently they are utilized by discerning clinicians for complementary use alongside more standard interventions. Nevertheless, the use of these markers is not currently included in algorithms of recommended screening guidelines. Listed below are several FDAapproved markers for screening of BC:
Nuclear matrix protein (NMP22) is a nuclear mitotic apparatus protein, released into urine as BC cells die. It is responsible for chromatid regulation and cell separation during replication. Approximately 70% of BC carcinomas are positive for NMP22. The NMP22 BladderChek (NMP22BC) test kit detects antibodies in voided urine and thus is noninvasive. The overall sensitivity and specificity reported for this test are 50% to 90% and 60% to 90%, respectively. The FDA has approved this test for screening and monitoring of BC; note, however, that it is not currently included in screening guidelines.10-12
In their nonrandomized study (N = 203) comparing the sensitivity and specificity of urine cytology, NMP22BC, and UroVysion fluorescence in situ hybridization (FISH) (see below) in the detection of BC, Kehinde and colleagues concluded that NMP22BC appeared to be more cost-effective, more rapid, and relatively higher in sensitivity and specificity over urine cytology.13 They suggested that NMP22BC should replace urine cytology as the gold standard, although it should be coupled with cystoscopy.
According to Sagnak and colleagues, in their small study (N = 164) looking at patients with asymptomatic hematuria, an ultrasound of the upper urinary tract coupled with the NMP22BC test for lower urinary tract investigation was found to be a better first-line screening tool than urine cytology, as it was more sensitive and less expensive. This combination of noninvasive testing also helped guide next steps, instead of going directly to cystoscopy.4
Two other recent studies evaluated the performance of NMP22BC over urine cytology, due in part to its rapid response and lesser expense. Both Weber and colleagues14 and Smrkolj and colleagues15 concluded that NMP22BC was more sensitive than urine cytology and suggested its use as a replacement for cytology; neither research group was able to suggest its use as a replacement for cystoscopy, however.
Bladder tumor–associated analytes (BTA) are composed of collagen, fibronectin, laminin, and proteoglycan, which are components of basement membrane, released when bladder tumor cells attach to the bladder wall. BTA is elevated in approximately 30% of low-grade and 60% of high-grade tumors. The BTA assay detects H-related protein in voided urine. The overall sensitivity and specificity for this test are reported to be 57% to 83% and 60% to 92%, respectively. The FDA has approved the BTA assay for monitoring of disease, along with cystoscopy.10-12
UroVysion is a multitarget 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 (P16). The FDA has approved this test for both screening and monitoring of BC, as it outperforms urine cytology in sensitivity. The high cost and need for large volumes of urine to detect tumor exfoliation, however, have prevented wider use of this test.10,12
ImmunoCyt combines cytology with immunofluorescence assay. It detects cellular biomarkers for BC in exfoliated urothelial cells for a high molecular weight form of carcinoembryonic antigen and 2 bladder tumor–associated mucins. The test is expensive and requires training to perform. It may perform better than cytology but should be coupled with cystoscopy. It is FDA approved for monitoring BC.10,12
Investigational Urine Markers
Several promising, noninvasive urine tests are currently being investigated for use in various stages of the BC continuum (eg, screening, surveillance, monitoring). The high rate of disease recurrence in BC requires lifelong surveillance, generally with cystoscopy (painful, embarrassing, expensive), along with urine cytology (not very sensitive). Thus, the use of noninvasive markers will significantly improve disease management. Whether these markers can and will move into the cancer screening arena, ongoing investigation will reveal. Listed below are a few of the urine markers being investigated2,7,12,16,17:
Conclusions
Bladder cancer is a major healthcare concern, both in the United States as well as worldwide. More than 70,000 individuals are expected to be diagnosed in the United States this year. To date, there are no agreed-upon guidelines, based on evidence, for screening of the asymptomatic population. Problematic as well is the invasiveness of diagnostics, once workup is begun. Even microhematuria, often an incidental finding, requires further investigation. The current gold standard for diagnosis of BC is urine cytology, cystoscopy, and imaging.
Many tumor markers and biomarkers are being investigated for diagnosing and following BC in a noninvasive way. The FDA has approved a number of these markers, which utilize voided urine, but currently, none has been incorporated into screening guidelines. Large randomized clinical trials are required to provide greater evidence on sensitivity and specificity for new markers and combinations of interventions for asymptomatic populations at variable risks. Better data for stratifying risk will enable im - proved algorithms for directing interventions. Until reliable markers or combinations of interventions are validated, cystoscopy remains the gold standard.
References
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