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Urinary Tumor Markers for Bladder Cancer - CAM 268

Description
Bladder cancer is defined as a malignancy that develops from the tissues of the bladder. It is the most common cancer of the urinary system. The cancer typically arises from the urothelium, although it may originate in other locations such as the ureter or urethra.

Tumor biomarkers are proteins detected in the blood, urine, or other body fluids that are produced by the tumor itself or in response to it. Urinary tumor markers may be used to help detect, diagnose, and manage some types of cancer including bladder cancer.

Background
URINARY BLADDER CANCER
Urinary bladder cancer, a relatively common form of cancer in the United States, results in significant morbidity and mortality. Bladder cancer (urothelial carcinoma), typically presents as a tumor confined to the superficial mucosa of the bladder. The most frequent symptom of early bladder cancer is hematuria; however, urinary tract symptoms (i.e., urinary frequency, urgency, dysuria) may also occur.

Diagnosis
The 2012 guidelines from the American Urological Association on the evaluation of microscopic hematuria, which were reviewed and affirmed in 2016, have recommended cystoscopic evaluation of adults older than age 40 years with microscopic hematuria and for those younger than age 40 years with microscopic hematuria and risk factors for developing bladder cancer.1 Confirmatory diagnosis of bladder cancer is made by cystoscopic examination, considered to be the criterion standard, and biopsy. At initial diagnosis, approximately 70% of patients have cancers confined to the epithelium or subepithelial connective tissue. Non-muscle-invasive disease is usually treated with transurethral resection, with or without intravesical therapy, depending on the depth of invasion and tumor grade. However, a 50% to 75% incidence of recurrence has been noted in these patients, with 10% to 15% progressing to muscle invasion over a 5-year period. Current follow-up protocols include flexible cystoscopy and urine cytology every 3 months for 1 to 3 years, every 6 months for an additional 2 to 3 years, and then annually thereafter, assuming no recurrence. 

While urine cytology is a specific test (from 90% to 100%), its sensitivity is lower, ranging from 50% to 60% overall, and it is considered even lower for low-grade tumors. Therefore, interest has been reported in identifying tumor markers in voided urine that would provide a more sensitive and objective test for tumor recurrence.

Adjunctive testing to urine cytology has used a variety of nuclear and cytoplasmic targets, and a range of molecular pathology and traditional (e.g., immunohistochemistry) methods. 

Commercially available tests cleared by the U.S. Food and Drug Administration clearance as well as laboratory-developed tests are summarized in the Regulatory Status section.

Regulatory Status
On April 16, 1997, the FDA approved the Bard BTA stat™ Test, created by Bard Diagnostic Sciences Inc. From the FDA site: “the BTA stat test is an in vitro diagnostic immunoassay indicated for the qualitative detection of bladder tumor associated antigen in urine of persons diagnosed with bladder cancer. This test is indicated for use as an aid in the management of bladder cancer patients in conjunction with cystoscopy”.

On April 15, 1998, the FDA approved the BTA TRAK™ Test, created by Bard Diagnostic Sciences Inc. From the FDA site: “the BTA TRAK test is an in vitro diagnostic immunoassay indicated for the quantitative detection of bladder tumor associated antigen in human urine. This test is indicated for use as an aid in the management of bladder cancer patients in conjunction with cystoscopy”.

On July 2, 1996, the FDA approved the MATRITECH NMP22™ TEST KIT, created by Alere Scarborough Inc. From the FDA site: “THE MATRITECH NMP22 TEST KIT IS AN ENZYME IMMUNOASSAY (EIA) FOR THE IN VITRO QUANTITATIVE DETERMINATION OF NUCLEAR MATRIX PROTEIN NMP22 IN STABILIZED VOIDED URINE”.

On July 30, 2002, the FDA approved the NMP22 BladderChek, created by Matritech Inc. From the FDA site: “The Matritech NMP22 BladderChek Test is indicated for professional and prescription home use as an aid in monitoring bladder cancer patients, in conjunction with standard diagnostic procedures”. This assay is qualitative.

On Jan. 24, 2005, the FDA approved the UROVYSION BLADDER CANCER KIT. From the FDA site: “The UroVysion Bladder Cancer Kit (UroVysion Kit) is designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer”.

On Feb. 23, 2000, the FDA approved the ImmunoCyt, created by Diagnocure Inc. From the FDA site: “ImmunoCyt is a qualitative direct immunofluorescence assay intended for use in conjunction with cytology to increase overall sensitivity for the detection of tumor cells exfoliated in the urine of patients previously diagnosed with bladder cancer. ImmunoCyt is indicated for use as an aid in the management of bladder cancer in conjunction with urinary cytology and cystoscopy” (FDA, 2018).

All of the FDA-approved tests apart from ImmunoCyt are approved for both diagnosis and surveillance of bladder cancer whereas ImmunoCyt is only approved for surveillance (Darwiche, Parekh, & Gonzalgo, 2015)

Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy:
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request

  1. Urinary biomarkers (bladder tumor antigen (BTA) test, nuclear matrix protein (NMP22) test, or fluorescence in situ hybridization (FISH) UroVysion Bladder Cancer test) is considered MEDICALLY NECESSARY.

    • as an adjunct in the diagnostic exclusion of bladder cancer for patients who have an atypical or equivocal cytology

    • as an adjunct in the monitoring of high-risk, non-muscle invasive bladder cancer

  2. The use of fluorescence immunocytology (ImmunoCyt/uCyt) is considered MEDICALLY NECESSARY as an adjunct to cystoscopy or cytology in the monitoring of persons with bladder cancer.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

  1. Urinary biomarkers (bladder tumor antigen (BTA) test, nuclear matrix protein (NMP22) test, or fluorescence in situ hybridization (FISH) UroVysion Bladder Cancer test) are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for screening of bladder cancer, evaluation of hematuria, and diagnosing bladder cancer in symptomatic individuals, and all other indications.

  2. The use of fluorescence immunocytology (ImmunoCyt/uCyt) is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in the evaluation of hematuria, diagnosing bladder cancer, or for screening for bladder cancer in asymptomatic persons and all other indications.

  3. Any other urinary tumor markers for bladder cancer not mentioned above is considered NOT MEDICALLY NECESSARY.

Policy Guidelines
Please see the Codes table for details.

Rationale
In 2020 in the United States, there were more than 81,000 cases and 17,900 deaths due to bladder cancer (NCCN, 2019; R. L. Siegel, Miller, & Jemal, 2017; Rebecca L. Siegel, Miller, & Jemal, 2020). According to the American Cancer Society, an estimated 83,730 new cases of bladder cancer will be diagnosed in the United States in 2021 with 17,200 deaths from bladder cancer (ACA, 2021). Bladder cancer is the sixth most common cancer in the United States, affects men four times more frequently than women, and is typically diagnosed in individuals above the age of 40, with 73 the median age at diagnosis (DeGeorge, Holt, & Hodges, 2017; NCCN, 2019). Bladder cancer risk factors include smoking, a family history of the disease, pelvic radiation, obesity, diabetes, and chronic infection of the urinary tract.

Bladder cancer commonly presents as painless hematuria (blood in urine) and may be gross (visible) or microscopic. Gross hematuria tends to increase the likelihood of bladder cancer, but hematuria as a whole may be transient or due to non-cancer related causes (Perazalla, 2020). Other common symptoms of bladder cancer include pain or irritative and obstructive voiding symptoms such as urge incontinence, dysuria, straining, or nocturia. These symptoms are often mistaken for another condition such as kidney stones, can be temporary, and are not necessarily specific for bladder cancer (Y. Lotan, Choueiri, Toni, 2020). In fact, hematuria is the most common symptom of bladder cancer, but a study reported a 13% prevalence rate of bladder cancer out of 6728 patients with hematuria (DeGeorge et al., 2017; Sutton et al., 2018). Approximately 70%-75% of patients present with superficial tumors (50 – 70% of which can recur but are usually not life threatening), and 25%-30% present as invasive tumors with a high risk of metastasis (Chou & Dana, 2010; Kaufman, Shipley, & Feldman, 2009).

Cystoscopy (white light) is the gold standard for a diagnosis of bladder cancer. This procedure involves a bladder examination and urine sample for cytology. Any lesions are observed and recorded. Cystoscopy does not detect all malignancies or visualize the upper urinary tract. Furthermore, although cystoscopy is minimally invasive, it may be uncomfortable and promote anxiety, which can lead to suboptimal compliance with management recommendations. Fluorescent cystoscopy is somewhat more efficient at detecting tumors than white light cystoscopy; although, it comes with its own set of issues such as higher false-positive rates and costs (Y. Lotan, Choueiri, Toni, 2017, 2020; Mitra, Birkman, Penson, & Cote, 2019). Cytology, or the analysis of cells in urine, is often completed in addition to cystoscopy analysis.

Although cystoscopy has long been the gold standard for a diagnosis of bladder cancer, its high cost and unpleasant burden has led to the search for a non-invasive test that can match the high specificities and sensitivities set by cystoscopy. Urinary biomarkers including “Cell-free proteins and peptides, exosomes, cell-free DNA, methylated DNA and DNA mutations, circulating tumor cells, miRNA, lncRNA, rtRNA and mRNAs” have now been identified for bladder cancer diagnostic purposes (Lopez-Beltran et al., 2019). Urine is exposed to urothelial tissue in many different locations, and therefore has the potential to contain several biomarkers associated with cancer. Validation of these biomarkers could lessen the use of cystoscopy as well as increase the overall sensitivity for bladder cancer identification (D'Costa, Goldsmith, Wilson, Bryan, & Ward, 2016). However,, because of the lower disease prevalence in a screening population, even in those at increased risk, the use of biomarkers for screening is not cost effective or recommended (Y. Lotan et al., 2009). Despite the promise of urine biomarkers, cystoscopy remains the procedure of choice both for initial diagnosis and for surveillance in previously treated patients.

Epigenetic changes may also play an important role in bladder cancer tumorigenesis. These changes are becoming more prevalent as identification rates increase due to improvements in high-throughput DNA sequencing technologies. Epigenetic changes can “regulate [the] gene expression outcome without changing the underlying DNA sequence” with alterations based on DNA methylation, nucleosome positioning, microRNA regulation and histone medications (Li, Duymich, Weisenberger, & Liang, 2016). All of these epigenetic-based changes are distorted in each human cancer type. “A substantial portion (76%) of all primary bladder tumors displays mutations in at least one chromatin regulatory gene. These mutations cause epigenetic dysregulation in bladder cancers (Li et al., 2016).”

Numerous other urinary biomarkers have been proposed as contributors to management of bladder cancer.

Other nuclear matrix proteins aside from NMP22 have been investigated. NMP52, BLCA-4, and BLCA-1 have all been studied as potential markers. Initial data for these markers appears promising, but most likely requires further evaluation (Mitra et al., 2019).

Cytokeratins, protein components of the cell structure, have also been identified as possible markers. Cytokeratins (“CK”), -8, -18, -19, and -20 have been considered for use in bladder cancer evaluation. However, further data is needed (Mitra et al., 2019).

Other markers that have been considered as potential indicators of bladder cancer include the following:

Telomerase is an enzyme that adds telomeres to the ends of chromosomes. This enzyme is only expressed in proliferating cells such as cancer cells, thereby lending credence to its use as a cancer marker. Despite its high sensitivity, its clinical application is limited, as the current assay used to detect telomerase is “significantly” affected by sample collection and processing (Mitra et al., 2019).

Hyaluronic acid is a polysaccharide thatpromotes tumor progression and metastasis. It is cleaved by hyaluronidase, which creates smaller fragments of the polysaccharide that further promote tumor angiogenesis. This pair of markers has been found to detect low-grade and low-stage disease with higher sensitivities than other markers, but requires further data for evaluation (Mitra et al., 2019).

Fibrin degradation products may also be useful in detection of cancer. High levels of vascular endothelial growth factor can increase the permeability of surrounding cellular structures, which cause serum proteins to “leak”. These proteins are eventually degraded to fibrin, and then to fibrin degradation products (Mitra et al., 2019).

Survivin­ is an apoptosis inhibitor. Survivin is frequently elevated in cancers, but virtually undetectable in normal tissues. However, no commercial assays for survivin exist as of time of writing (Mitra et al., 2019).

Finally, miRNA markers have been considered for use in bladder cancer management. These markers are small sequences of non-coding RNA that contribute to gene expression regulation. MiRNAs-126, -200c, -143, and -222 have all been considered to have “promising” results (Mitra et al., 2019).

Proprietary Testing
The two most studied urinary biomarkers are bladder tumor antigen (BTA) and nuclear matrix protein 22 (NMP22). The BTA test is designed to detect complement factor H-related protein (hCFHrp) which is elevated in cancer cells. This test is available in both a quantitative and qualitive version, and its manufacturer-recommended cut-off is 14U/mL (Mahnert et al., 1999; Mitra, Birkman, & Penson, 2017). Similarly, the NMP22 test is designed to detect a protein that is more highly available in cancer cells than normal cells. In this case, cancer cells release more NMP22 into the urine following apoptosis than normal cells do. The NMP22 tests are also available in a quantitative and qualitative version, and its FDA-approved cut-off is 10U/mL (Grossman, Messing, Soloway, & et al., 2005; Mitra et al., 2017; Mitra et al., 2019; Zuiverloon, de Jong, & Theodorescu, 2017). A number of proprietary tests exist revolving around one of these two biomarkers; these tests include Abbott’s “Alere NMP22 BladderCheck” and Quest’s Bladder Tumor Antigen DetectR (Abbott, 2020; Quest, 2020).

The FDA has approved two additional tests for urinary biomarkers. One is UroVysion, which is designed to detect chromosomal alterations that are distinctive of bladder cancer. This test is a fluorescent in situ hybridization (FISH) assay that uses DNA probes to detect alterations (such as aneuploidies) on chromosomes 3, 7, and 17 or loss of the 9p21 locus. The second test is known as ImmunoCyt (or uCyt+) that uses a similar fluorescent technique to detect certain glycoproteins that are expressed solely on cancerous cells (Mitra et al., 2017; Mitra et al., 2019).

Recently, Pangea Laboratory has created a laboratory developed test termed Bladder CARETM which measures the methylation status of specific DNA biomarkers in urine for the detection of bladder cancer via an at-home collection kit. This non-invasive test has not been approved by the FDA, is purported to be more cost-effective, and uses an epigenetic-based detection approach. Specifically, the methylation of bladder cancer DNA biomarkers are measured (Pangea, 2019a). As little as 5 ng of urine DNA from a 100 mL urine sample is required, and it has a limit detection of 0.1% leading to the identification of a single cancerous cell in a sample of 1,000 normal cells (Pangea, 2019a). The authors claim that Bladder CARETM has a sensitivity of 94% and specificity of 86%, allowing for the identification of 88% of low-grade bladder cancer cases; these results are based on a study completed by Pangea Laboratory and Zymo Research which analyzes urine samples from 182 patients (97 with bladder cancer and 85 healthy controls) (Pangea, 2019b).

Another test, termed the Bladder EpiCheck test, has been developed by the Israeli company Nucleix. This non-invasive epigenetic urine test helps to detect bladder cancer with a panel of 15 DNA methylation biomarkers. Nucleix reports a sensitivity of 92%, a specificity of 88% and a negative predictive value of 99% for the Bladder EpiCheck test; these results are based on a multi-center clinical study with 353 bladder cancer patients (Nucleix, 2015). Similar results have been reported by D'Andrea et al. (2019). However, this test is not available in the United States (Nucleix, 2015).

Another test, termed “UBC® Rapid” has been developed by the Swedish company ODL Biotech. This point-of-care test measures soluble fragments of cytokeratins 8 and 18 in urine samples. The test can produce results within 10 minutes and may be tested with hematuria-containing samples (IDL_Biotech, 2020). Ecke et al. (2018) performed a validation of this test, which encompassed 242 patients with bladder cancer (134 non-muscle-invasive low-grade tumors, 48 non-muscle-invasive high-grade tumors, 60 muscle-invasive high-grade tumors), 62 patients with non-evidence of disease [NED], and 226 healthy controls. The authors found a sensitivity of 38.8% for non-muscle-invasive low-grade bladder cancer, 75% for non-muscle-invasive high-grade bladder cancer and 68.3% for muscle-invasive high-grade bladder cancer. Specificity over the entire cohort was 93.8% (Ecke et al., 2018).

The URO17 assay by Protean Biodiagnostics, an immunohistochemistry-based test that detects the presence of the oncoprotein keratin 17 in bladder cancer and urogenital cancer. Unlike other urine-based test URO17 can detect patients with visible or invisible hematuria, which allows for early diagnosis. URO17 can also detect recurrent bladder cancer in patients under surveillance for relapse (NICE, 2021). The test has 100% sensitivity and 96% specificity for detecting bladder cancer from urine samples (Protean_Biodiagnostics, 2021).

Nonagen Bioscience released Oncuria, an in-vitro multiplex immunoassay, which detects protein biomarkers associated with bladder cancer in the urine. This non-invasive test detects ten proteins from a single urine sample in patients with hematuria with suspicion of bladder cancer. Biomarker levels are combined in a weighted algorithm to aid in the prediction of responding to Bacillus Calmette-Guerin (BCG) therapy in patients with intermediate to high-risk, early-stage bladder cancer (Nonagen_Bioscience, 2021).

Analytical Validity
Recently, Piao et al. (2019) have developed a way to differentiate patients with bladder cancer from patients with a nonmalignant hematuria without bladder cancer by measuring urinary cell-free microRNA expression. This study shows that the non-invasive measurement of urinary microRNA-6124 and microRNA-4511 can be used as a diagnostic tool with a sensitivity of > 90% (Piao et al., 2019). This testing method will help to reduce the number of unnecessary cystoscopies in patients with hematuria that are being evaluated for bladder cancer.

The performance of an epigenetic-based bladder cancer detection tool has been evaluated by Fantony et al. (2017); the urine-based TWIST1/NID2 methylation assay has been analyzed for the detection of urothelial carcinoma via the addition of urine cytology. This multi-institutional study analyzed data from 172 patients. The authors note that “The AUC [area under the curve] for cytology alone with equivocal cytologies positive was 0.704, and improved to 0.773 with the addition of the DNA methylation assay (p < 0.001) (Fantony et al., 2017).” The authors conclude by stating that this TWIST1/NID2 methylation assay is a sensitive diagnostic tool that adds value to urine cytology for the detection of urothelial carcinoma, which is the most common type of bladder cancer.

Soubra and Risk (2015) found the sensitivity of fluorescent cystoscopy to be 0.92 and the sensitivity of white light cystoscopy to be 0.71; the specificity of fluorescent cystoscopy was lower at 0.57, and the specificity of white light cystoscopy was identified at 0.72. Furthermore, fluorescent cystoscopy’s sensitivity for carcinoma in situ (which is difficult to visualize) was measured at 0.924, while white light cystoscopy’s sensitivity for carcinoma in situ was much lower at 0.605, but these differences tended to decrease on higher grade lesions (Soubra & Risk, 2015). Cytology is also a common analytic technique in addition to cystoscopy. Its overall sensitivity is low at 0.34 and its sensitivity for grade 1 and 2 tumors is even lower at 0.12 and 0.26, respectively (Yair Lotan & Roehrborn, 2003).

Breen et al. (2015) compared the sensitivity and specificity values of four diagnostic tests (cytology, NMP22, UroVysion, and CxBladder); CxBladder was found to have the highest sensitivity at 74% and cytology was identified with the highest specificity at 95%. The authors report comparable sensitivity values for cytology, NMP22, and UroVysion at 46%, 45.9% and 47.7% respectively (Breen et al., 2015). It is important to note that even though CxBladder is reported to have the highest sensitivity, the specificity (81.7%) is the lowest; the other tests were reported to have superior specificities with NMP22 at 88%, and UroVysion at 87.7% (Breen et al., 2015).

Sathianathen, Butaney, Weight, Kumar, and Konety (2018) published a study focusing on biomarkers in patients presenting with hematuria. This study encompassed BTA, NMP22, FISH, and uCyt+, as well as a fifth biomarker known as AssureMDx. Sensitivities ranged from 0.67 (BTA) to 0.95 (AssureMDx, second highest was uCyt+ at 0.83) while specificities ranged from 0.68 (BTA) to 0.93 (quantitative NMP22). However, this data is consistent with the previously published meta-analysis that covered all settings, not just hematuria (Chou et al., 2015). Cytology was also found to have superior specificity to all studied biomarkers; although, biomarkers tended to have better sensitivity. The authors concluded that, due to the high heterogeneity and small sample size, more studies were needed to validate biomarkers to replace diagnostic evaluation of hematuria (Sathianathen et al., 2018).

Although many studies emphasize the high validity of biomarkers such as NMP22 and BTA, these studies often have a large proportion of high-grade tumors which inflate the specificity and sensitivity; hence, the problem of identifying low-grade cancers remains. There may be changes at the genetic level in a low-grade cancer, but the proteins tested in the urine may still be relatively normal (D'Costa et al., 2016). Another issue is the conflicting results for the validity of the biomarkers. For example, the sensitivity of the quantitative NMP22 test has been found to range from as low as 0.26 to 1.00 with its specificity ranging from 0.49 to 0.98. Similarly, the BTA STAT test’s sensitivity and specificity have been found to range from 0.29 to 0.91 and from 0.54 to 0.86 respectively (Zuiverloon et al., 2017). For comparison, a study found the sensitivity and specificity of flexible cystoscopy (out of 778 hematuria patients) to be 0.98 and 0.938, respectively (Sutton et al., 2018).

Dudley et al. (2019) have developed a novel high-throughput sequencing method that uses urine derived tumor DNA (utDNA) known as utDNA CAPP-Seq (uCAPP-Seq) to detect bladder cancer. This technique was used to analyze samples from 118 patients with early-stage bladder cancer and 67 healthy adults. “We detected utDNA pretreatment in 93% of cases using a tumor mutation-informed approach and in 84% when blinded to tumor mutation status, with 96% to 100% specificity (Dudley et al., 2019).” These results show that utDNA can be used to diagnose early-stage bladder cancer with high sensitivity and specificity.

Hirasawa et al. (2021) studied the diagnostic performance of Oncuria™, a multiplex immunoassay urinalysis test for bladder cancer. Urine samples from 362 subjects with suspicion of bladder cancer were measured using Oncuria™ for ten biomarkers (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA). Results of the test were confirmed by cystoscopy and tissue biopsy. "The Oncuria™ test achieved a strong overall diagnostic performance, achieving an overall AUC of 0.95, sensitivity and specificity values of 93% and 93%, respectively, and a negative predictive value (NPV) and positive predictive value (PPV) of 99% and 65%, respectively. The Oncuria™ test shows promise for clinical application in the non-invasive diagnosis and surveillance bladder cancer, and potentially for screening at-risk, asymptomatic individuals (Hirasawa et al., 2021).”

Clinical Utility and Validity
A meta-analysis of 57 studies detailed the accuracy of several biomarkers for the diagnosis and surveillance of bladder cancer. These included the six FDA-approved tests (quantitative and qualitive NMP22, quantitative and qualitative BTA, FISH, and uCyt+) as well as a laboratory developed test that does not require FDA approval termed CxBladder. Sensitivities ranged from 0.57 (qualitative NMP22) to 0.82 (CxBladder); however, the CxBladder cohort was only comprised of one study. The specificities ranged from 0.74 (quantitative BTA) to 0.88 (qualitative NMP22). Sensitivity increased as a tumor progressed (higher grade or stage) with low accuracy for lower stage or grade tumors. A cytologic evaluation performed with a biomarker assessment increased sensitivity as well but missed about 10% of cases. Ultimately, the authors concluded that urinary biomarkers reported many false-positive results and failed to identify a large percentage of patients with bladder cancer (Chou et al., 2015). The authors also noted that this was the first study which focused on the measurement of clinical outcomes based on urinary biomarkers.

The ideal marker will be “easier, better, faster, and cheaper” (Schmitz-Dräger et al., 2015). Overall, although there have been numerous promising studies for the clinical utility of these urinary biomarkers, the biomarkers do not yet measure up to the standards set by cystoscopy as the primary method of diagnosis. Most of the biomarkers are yet to be well-validated and the ones that are, such as NMP22 and BTA, fall short of cystoscopy’s standards (D'Costa et al., 2016). Furthermore, because of the lower disease prevalence in a screening population, even in those at increased risk, the use of biomarkers for screening is not cost effective or recommended (Y. Lotan et al., 2009). Although the cost of tests is non-clinical, it is still a crucial issue; the BTA and NMP22 tests are relatively inexpensive at $25 but ImmunoCyt costs around $80 and the CxBladder and UroVysion cost $325 and $800, respectively (Zuiverloon et al., 2017). For comparison, a cystoscopy cost around $210 in 2016, and a cystoscopy with a biopsy cost about $370 (Halpern, Chughtai, & Ghomrawi, 2017). These biomarkers to date have not been highly recommended within any clinical guidelines. Therefore, the authors concluded that biomarkers have not had significant effect on clinical decision-making (Schmitz-Dräger et al., 2015). The majority of studies performed on these biomarkers did not focus on their ability to predict the course of cancer (D'Costa et al., 2016) but some biomarkers may play a role in the diagnosis or surveillance of bladder cancer in the future (Schmitz-Dräger et al., 2015). Even this may be a difficult barrier to cross; Meleth et al. (2014) prepared an assessment for the Agency for Healthcare Research and Quality that stated “although UroVysion is marketed as a diagnostic rather than a prognostic test, limited evidence from two small studies (total n = 168) supported associations between test result and prognosis for risk of recurrence (Meleth et al., 2014).” The authors went on to note that no studies that established clinical utility were found.

D'Andrea et al. (2019) analyzed 357 urine samples from patients at five different centers under surveillance for non-muscle-invasive bladder cancer to investigate the clinical utility of the Bladder EpiCheckTM non-invasive urine test. A specificity of 88% was identified with this test, a negative predictive value of 94.4% for the detection of any cancer, and a negative predictive value of 99.3% for the detection of high grade cancer; the use of the Bladder EpiCheckTM test helped to improve the cancer recurrence predictive value by a difference of 16-22% (D'Andrea et al., 2019). This high-performing diagnostic test may help in the surveillance of non-muscle-invasive bladder cancer.

Tan et al. (2018) completed a systematic review to identify the diagnostic sensitivity and specificity of urinary biomarkers for the diagnosis of bladder cancer. The authors report that multi-target biomarker panels were more accurate than single biomarker targets, and that both the sensitivity and specificity of urinary biomarkers were higher in primary diagnostic scenarios compared to patients under surveillance (Tan et al., 2018). The authors note that “few biomarkers achieve a high sensitivity and negative predictive value,” with single biomarkers reporting a sensitivity of 2-94% and specificity of 46-100%, and multi-target biomarkers reporting a sensitivity of 24-100% and specificity of 48-100% (Tan et al., 2018).

Mossanen et al. (2019) performed a cost analysis to characterize the costs of managing non-muscle-invasive bladder cancer (NMIBC). The authors created a Markov model with four health states: no evidence of disease, recurrence, progression and cystectomy, and death. Patients were stratified into three risk categories of low, intermediate, and high. The authors found that “cumulative costs of care over a 5-year period were $52,125 for low-risk, $146,250 for intermediate-risk, and $366,143 for high-risk NMIBC”. The authors identified that the primary driver of cost was “progression to muscle-invasive disease requiring definitive therapy”, which was found to contribute 81% and 92% to overall cost for intermediate and high-risk disease, respectively. Progression of disease was found to contribute 71% to overall cost for low-risk disease. The authors concluded that although protracted surveillance cystoscopy does contribute to management cost, progression of disease was the dominant factor in increasing cost of care (Mossanen et al., 2019).

Vasdev et al. (2021) studied the role of URO17™ biomarker in the diagnosis of bladder or urothelial cancer in new hematuria patients. Urine samples from 71 subjects were stained using the URO17™ immunobiomarker and results were compared to the biopsy and histology. URO17™ was shown to have an overall sensitivity of 100%, specificity of 92.6%, positive predictive value of 0.957, and negative predictive value of 1. URO17™ investigation was positive in every case of urothelial malignancy. According to the authors, URO17™ test can help improve "diagnostic capabilities in primary care, reduce the number of referrals to Urology department, and reduce the number of unnecessary invasive procedures for new patients with a suspected urinary bladder cancer" (Vasdev et al., 2021).

National Comprehensive Cancer Network
The NCCN has stated that “Urine molecular tests for urothelial tumor markers are now available. Many of these tests have a better sensitivity for detecting bladder cancer than urinary cytology, but specificity is lower. Considering this, evaluation of urinary urothelial tumor markers may be considered during surveillance of high-risk non-muscle-invasive bladder cancer. However, it remains unclear whether these tests offer additional information that is useful for detection and management of non-muscle-invasive bladder tumors. Therefore, the panel considers this to be a category 2B recommendation (NCCN, 2018, 2019, 2020, 2021).”

The NCCN previously stated that an FDA-approved urinary biomarker test such as fluorescence in situ hybridization (FISH) or nuclear matrix protein 22 may be considered in monitoring for recurrence (NCCN, 2018). However, updated NCCN (2019, 2020); (NCCN, 2021) guidelines no longer address these biomarker tests.

National Academy of Clinical Biochemistry Laboratory Medicine
The NACB Laboratory Medicine Practice Guidelines do not recommend use of any FDA‒approved urinary tumor marker tests for the diagnosis of bladder tumors or for monitoring bladder cancer patients. The guideline states that “There are no prospective clinical trial data that establish the utility of any of the FDA cleared markers or the proposed markers for increasing survival time, decreasing the cost of treatment or improving the quality of life of bladder cancer patients (NACB, 2010).” The NACB is now known as the AACC, or American Association for Clinical Chemistry, and have not since released any further updates on this topic (NACB, 2010).

American Urological Association (AUA)
The AUA’s guidelines on the diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults do not recommend use of urine markers (NMP22, BTA-stat, UroVysion) as part of routine evaluation (Davis et al., 2012).

The AUA and Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU) published a guideline on microhematuria in 2020. In it, they remark that “Clinicians should not use urine cytology or urine-based tumor markers in the initial evaluation of patients with microhematuria”, stating that “insufficient evidence exists that routine use would improve detection of bladder cancer.” However, the guideline states that “Clinicians may obtain urine cytology for patients with persistent microhematuria after a negative workup who have irritative voiding symptoms or risk factors for carcinoma in situ.” (Barocas et al., 2020)

The AUA and Society of Urologic Oncology (SUO) joint guidelines on Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer (NMIBC) do not recommend using urinary biomarkers to replace cystoscopy when monitoring NMIBC (grade B), although a clinician can use biomarkers to evaluate a patient’s response to Bacillus Calmette-Guerin (BCG) therapy or a separate cytology such as FISH or ImmunoCyt. However, a urinary biomarker should not be used for monitoring a patient with a normal cystoscopy and a history of low-risk cancer (Chang et al., 2016). This 2016 guideline was amended in 2020, but no relevant changes were identified.

The 2021 American Urologic Association (AUA) annual meeting included a guideline amendment update for non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) to the 2020 guidelines. According to the update, a clinical should not use urinary biomarkers in place of cystoscopy. “In a patient with a history of low-risk cancer and a normal cystoscopy, a clinician should not routinely use a urinary biomarker or cytology during surveillance. In a patient with NMIBC, a clinician may use biomarkers to assess response to intravesical BCG (UroVysion® FISH) and adjudicate equivocal cytology (UroVysion® FISH and ImmunoCyt™)” (AUA/SUO, 2020). The panel does acknowledge the uptake of Cxbladder in clinical practice; however, there is a lack of high quality evidence in the potential replacement of cystoscopy with Cxbladder (AUA, 2021).

Similarly, the joint guidelines between the AUA, the SUO, the American Society of Clinical Oncology (ASCO), and the American Society for Radiation Oncology (ASTRO) regarding non-metastatic muscle-invasive bladder cancer note that molecular biomarkers may be important for staging cancer and deciding a course of treatment soon. Nevertheless, at this time the biomarkers have not been properly validated (Chang et al., 2017).

U.S. Preventive Services Task Force (USPSTF)
The USPSTF concluded in 2011 that there was insufficient evidence to evaluate screening for bladder cancer in asymptomatic adults, assigning a grade I to this recommendation. Since then, there have been no further guidelines published on this topic by the USPSTF (Moyer, 2011).

In 2021, the USPSTF published the following statement regarding bladder cancer screening in adults: “Literature scans conducted in November 2021 in the MEDLINE and PubMed databases and the Cochrane Library showed a lack of new evidence to support an updated systematic review on the topic at this time (USPSTF, 2019, 2021).”

3rd International Consultation on Urological Diseases & Société Internationale d’Urologie (ICUD-SIU)
With a level of evidence of 3 and a grade of “B”, the ICUD-SIU recommends, “examination of urine cytology must be a part of the expectant management or active surveillance protocol.” Concerning the surveillance strategies for NMIBC, “Surveillance strategies following a negative 3 months surveillance cystoscopy should be: (1) for low risk disease, cystoscopy 6–9 months later and annually thereafter; consider cessation following five recurrence-free years. No upper tract imaging necessary unless hematuria present; (2) for intermediate risk, cystoscopy with cytology every 3 – 6 months for 2 years; then every 6 – 12 months during years 3 and 4; then annually for lifetime. Upper tract imaging every 1–2 years; (3) for high risk, cystoscopy with cytology every 3 months for 2 years; then every 6 months during years 3 and 4; then annually for lifetime [Level of evidence: 3; Grade C] (Monteiro et al., 2018).”

National Cancer Institute
In the 2020 update to the NCI’s Bladder and Other Urothelial Cancers Screening (PDQ®) — Health Professional Version, the NCI states that “There is inadequate evidence to determine whether screening for bladder and other urothelial cancers has an impact on mortality… Based on fair evidence, screening for bladder and other urothelial cancers would result in unnecessary diagnostic procedures with attendant morbidity (NCI, 2018, 2020, 2021).”

European Association of Urology (EAU)
The EAU has published guidelines on non-muscle-invasive bladder cancer (NIBC). Regarding urinary molecular marker tests, the EAU has stated that “Driven by the low sensitivity and low negative predictive value of urine cytology, numerous urinary tests have been developed. None of these markers have been accepted for diagnosis or follow-up in routine practice or clinical guidelines (M. Babjuk et al., 2017).” Further, as an exploratory measure after hematuria or after other bladder cancer symptoms have been identified, the EAU states that “It is generally accepted that none of the currently available tests can replace cystoscopy. However, urinary cytology or biomarkers can be used as an adjunct to cystoscopy to detect missed tumours, particularly CIS (carcinoma in situ). In this setting, sensitivity for high-grade tumours and specificity are particularly important (M. Babjuk et al., 2017).” Finally, the EAU states that currently, there is no urinary marker with the ability to replace cystoscopy.

An update to these guidelines was published in 2020. In it, the EAU concluded that “Cystoscopy is necessary for the diagnosis of bladder cancer” and that “Urinary cytology has high sensitivity in high-grade tumours including carcinoma in situ.” The EAU remarks that “There is no known urinary marker specific for the diagnosis of invasive BC (bladder cancer)” (Witjes et al., 2020).

An update to guidelines on non-muscle-invasive bladder cancer (NIBC) was published in 2022. The EAU concluded that urinary molecular marker tests cannot replace cystoscopy in routine practice, "but the knowledge of positive test results (microsatellite analysis) can improve the quality of follow-up cystoscopy." Diagnosis ultimately depends on “cystoscopy examination of the bladder and histological evaluation of sampled tissue” (Marko Babjuk et al., 2022).

Table of Terminology

Term

Definition

AACC

American Association for Clinical Chemistry

AMH

Asymptomatic microhematuria

ASCO

American Society of Clinical Oncology

ASTRO

American Society for Radiation Oncology

AUA

American Urological Association

AUC

Area under the curve

BC

Bladder cancer

BCG

Bacillus calmette-guerin

BLCA-1

Bacillus collagen-like protein of anthracis

BLCA-4

Bacillus collagen-like protein of anthracis

BTA

Bladder tumor antigen

CFHrp

Complement factor h-related protein

CIS

Carcinoma in situ

CK

Cytokeratins

CLIA ’88

Clinical laboratory improvement amendments of 1988

CMS

Centers for Medicare and Medicaid

CXCR2

C-X-C motif chemokine receptor 2

DNA

Deoxyribonucleic acid

EAU

European Association of Urology

EIA

Enzyme immunoassay

FDA

United States Food and Drug Administration

FISH

Fluorescence in situ hybridization

hCFHrp

Complement factor h-related protein

ICUD-SIU

International Consultation on Urological Diseases & Société Internationale d’Urologie

LDTs

Laboratory-developed tests

MRI

Magnetic resonance imaging

NACB

National Academy of Clinical Biochemistry Laboratory Medicine

NCCN

National Comprehensive Cancer Network

NCI

National Cancer Institute

NED

Non-evidence of disease

NID2

Nidogen 2

NMIBC

Non-muscle invasive bladder cancer

NMP22

Nuclear matrix protein 22

NMP52

Nuclear matrix protein 52

PCR

Polymerase chain reaction

SUFU

Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction

SUO

Society of Urologic Oncology

TWIST1

Twist-related protein 1

uCyt+

ImmunoCyt test

USPSTF

U.S. Preventive Services Task Force

UT

Urine derived tumor

utDNA

Urine derived tumor deoxyribonucleic acid

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Coding Section 

Code

Number

Description

CPT

86294

Immunoassay for tumor antigen, qualitative or semiquantitative (e.g., bladder tumor antigen)

 

86316

Immunoassay for tumor antigen, other antigen, quantitative (e.g., CA 50, 72-4, 549), each

 

86386

Nuclear Matrix Protein 22 (NMP22), qualitative

 

88120

Cytopathology, in situ hybridization (e.g., FISH), urinary tract specimen with morphometric analysis, 3 – 5 molecular probes, each specimen; manual

 

88121

Cytopathology, in situ hybridization (e.g., FISH), urinary tract specimen with morphometric analysis, 3 – 5 molecular probes, each specimen; using computer-assisted technology

 

88346

Immunofluorescence, per specimen; initial single antibody stain procedure

 

88350

Immunofluorescence, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)

 

0012M

Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm reported as a risk score for having urothelial carcinoma
Proprietary test: Cxbladder™ Detect
Lab/manufacturer: Pacific Edge Diagnostics USA, Ltd

 

0013M

Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm reported as a risk score for having recurrent urothelial carcinoma
Proprietary test: Cxbladder™ Monitor
Lab/manufacturer: Pacific Edge Diagnostics USA, Ltd

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

07/21/2022 Interim review to updating coding.

04/07/2022 

Annual review, no change to policy intent. Adding "As" to criteria 1a for clarity. Updating coding, rationale and references. Adding table of terminology. 

11/08/2021 

Updated the policy with the 5th criteria. No other changes made. 

04/01/2021 

Annual review, no change to policy intent. Updating coding, description, rationale and references. 

04/14/2020 

Annual review, no change to policy intent. 

9/30/2019 

Adding ICD-10 codes to Coding Section. No other changes made. 

04/02/2019 

Major revision for clarity and specificity. No change to policy intent. 

04/17/2018 

Interim review, no change to policy intent. Changing review month. 

10/23/2017

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references.

04/26/2017 

Updated category to Laboratory. No other changes. 

05/10/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

01/04/2016 

Updated cpt codes. No other changes made. 

05/11/2015 

Annual review, no change to policy intent. Updated background, description, guidelines, rationale and references. Added coding. 

05/08/2014

Annual review.  Updated background, policy guidelines, rationale and references.
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