Lab: Bladder/Urothelial Tumor Markers

LCD Information Document Information Source LCD ID N/A LCD ID L33420 Original ICD-9 LCD ID Not Applicable LCD Title Lab: Bladder/Urothelial Tumor Markers Proposed LCD in Comment Period N/A Source Proposed LCD N/A Original Effective Date For services performed on or after 10/01/2015 Revision Effective Date For services performed on or after 03/04/2021 Revision Ending Date N/A Retirement Date N/A Notice Period Start Date N/A Notice Period End Date N/A CPT codes, descriptions, and other data only are copyright 2025 American Medical Association. All Rights Reserved. Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of CPT, and the AMA is not recommending their use. The AMA does not directly or indirectly practice medicine or dispense medical services. The AMA assumes no liability for data contained or not contained herein. CPT is a registered trademark of the American Medical Association. 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Issue Issue Description Issue - Explanation of Change Between Proposed LCD and Final LCD CMS National Coverage Policy Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. Title XVIII of the Social Security Act, §1862(a)(7) states Medicare will not cover any services or procedures associated with routine physical checkups. 42 CFR §411.15 Particular Services Excluded From Coverage 42 CFR §410.32 Diagnostic X-ray Tests, Diagnostic Laboratory Tests, and Other Diagnostic Tests: Conditions 42 CFR §410.33 Independent Diagnostic Testing Facility CMS Internet-Only Manual, Pub 100-08, Medicare Program Integrity Manual, Chapter 3, §3.4.1.3 Diagnosis Code Requirements Coverage Indications, Limitations, and/or Medical Necessity INDICATIONSGross painless hematuria is often the first manifestation of an urothelial tumor. Since the degree of hematuria bears no relation to the seriousness of the underlying disease, the microscopic finding of blood in the urine is a serious symptom until significant pathology has been excluded. At this time, there is no published consensus from the following national organizations: National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), American Urological Association (AUA) and the International Bladder Cancer Consensus Group (IBCCG) regarding the management of persistent asymptomatic microscopic hematuria. Due to insufficient supporting data, the AUA’s 2001 best practices policy could not recommend routine use of voided urinary markers in the evaluation of patients with microscopic hematuria.3Recommended surveillance schedules for patients with a previous negative evaluation for unexplained microscopic hematuria include annual urinalysis and voided urinary cytology until the hematuria resolves, or for up to 3 years if microscopic hematuria persists. The AUA has been silent regarding practice guidelines due to the paucity of prevalence studies on asymptomatic microscopic hematuria. Cystoscopy in conjunction with bladder tumor markers is the standard practice to evaluate patients with symptoms suggesting bladder cancer and to monitor treated patients for recurrence or progression. Although cystoscopy is considered the “gold standard”, studies have shown that up to 20% of tumor can be missed. Urinary cytology has close to a 90%-100% specificity, but only 10%-50% sensitivity for low grade urinary cancer (UC) detection. Due to this deficit, clinicians have sought noninvasive tumor markers detectable in urine. Upwards of 50% of patients have recurrence of bladder cancer within 5 years. After initial diagnosis and treatment, patients with UC are frequently monitored every 3 months for the first 2 years, every 4 months for the third, year then usually twice a year for the fourth year. Annual monitoring is recommended during years 5 through 15. Diagnostic and Surveillance Tests BTA TRAK® - a quantitative determination of human complement factor H-related protein Nuclear matrix protein 22 (NMP-22) – detects nuclear mitotic apparatus protein believed to be released during apoptosis; a quantitative assay, which is either positive of negative NMP-22® BladderChek® – a CLIA-waved assay, point of care test with an immunochromographic qualitative format taking 20 minutes to perform The UroVysion® Bladder Cancer Kit is fluorescence in situ hybridization (FISH) DNA probe technology. It is designed to detect aneuploidy for chromosomes 3, 7, 17 and loss of the 9p21 locus. This assay involves visualization of nucleic acid sequences within cells by creating short sequences of fluorescently labeled, single-strand DNA probes that match target sequences. The probes bind to complementary strands of DNA to identify the targeted chromosome(s) location. It is used to detect chromosomal abnormalities in voided urine to assist not only in bladder cancer surveillance but also in the initial identification of bladder cancer. Scientific studies demonstrate the sensitivity of BTA and NMP-22® are superior to urinary cytology.1 Studies affirm the adjunctive value of BTA stat® and NMP-22® in suspected and known bladder cancer in conjunction with cystoscopy. However, false positive results occur more frequently in the presence of hematuria, nephrolithiasis, recent GU instrumentation, inflammation and other urological malignancies. Administration of bacillus Calmette-Guerin (BCG) within 2 years of testing decreases specificity to 28%. The DNA probe assay has high sensitivity (81%) and specificity (96%) for high grade tumors, but lower sensitivity (36-57%) for low grade and stage tumors. The assay specificity approaches that of cytology, and can be utilized in patients recently treated with intravesical BCG. This can result in a positive UroVysion® test with a negative study for UC. This assay has also been shown to be useful in predicting tumor recurrence following BCG therapy. At present the IBCCG has recommended that tumor markers be used in conjunction with cystoscopy. They also concluded that routine screening for bladder cancer is not cost-effective.3 The US Preventive Services Task Force concluded bladder tumor markers do not have a proven role in screening of asymptomatic patients for early detection of bladder cancer.3 NCCN, ASCO, and AUA are silent regarding the utilization of these bladder tumor markers. Surveillance Tests BTA (bladder tumor antigen) stat® - a qualitative CLIA-waved test that identifies a human complement factor H-related protein produced by several human bladder cell lines The ImmunoCyt™ test is cleared for monitoring bladder cancer recurrence only in conjunction with cytology and cystoscopy. The assay uses fluorescent labeled antibodies to 3 markers (carcinoembryonic antigen, and mucins LDQ10 and M344) commonly found on malignant exfoliated urothelial cells. The ImmunoCyt™ assay has also been shown to be more sensitive than urine cytology. LIMITATIONSCystoscopy in conjunction with bladder tumor markers is standard practice to evaluate patients with symptoms suggesting bladder cancer and to monitor treated patients for recurrence or progression. Exceptions, such as high grade bladder cancers s/p radical cystectomy, do exist which preclude cystoscopy prior to testing. Testing indications, limitations and frequency do not apply to urine cytology.Bladder cancer tumor markers performed by any technology, immunoassay, molecular or FISH testing, are not covered for screening of all patients with hematuria. Bladder tumor markers are not expected to be performed until other diagnostic studies fail to identify the etiology of the hematuria. Urine cytology is not considered a bladder tumor marker.All other bladder cancer marker assays, including but not limited to the following, regardless of the methodology are considered investigational and not covered by Medicare: BCLA-4 BLCA-1 Hyaluronic acid Hyaluronidase Lewis X antigen Microsatellite markers Quanticyt Soluble FAS TATI (tumor associated trypsin inhibitor) Soluble e-cadherin Survivin Telomerase UBC™ Rapid Test (urinary bladder cancer test for cytokeratins 8 and 18) Summary of Evidence N/A Analysis of Evidence (Rationale for Determination) N/A

INDICATIONS Gross painless hematuria is often the first manifestation of an urothelial tumor. Since the degree of hematuria bears no relation to the seriousness of the underlying disease, the microscopic finding of blood in the urine is a serious symptom until significant pathology has been excluded. At this time, there is no published consensus from the following national organizations: National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), American Urological Association (AUA) and the International Bladder Cancer Consensus Group (IBCCG) regarding the management of persistent asymptomatic microscopic hematuria. Due to insufficient supporting data, the AUA’s 2001 best practices policy could not recommend routine use of voided urinary markers in the evaluation of patients with microscopic hematuria. 3 Recommended surveillance schedules for patients with a previous negative evaluation for unexplained microscopic hematuria include annual urinalysis and voided urinary cytology until the hematuria resolves, or for up to 3 years if microscopic hematuria persists. The AUA has been silent regarding practice guidelines due to the paucity of prevalence studies on asymptomatic microscopic hematuria. Cystoscopy in conjunction with bladder tumor markers is the standard practice to evaluate patients with symptoms suggesting bladder cancer and to monitor treated patients for recurrence or progression. Although cystoscopy is considered the “gold standard”, studies have shown that up to 20% of tumor can be missed. Urinary cytology has close to a 90%-100% specificity, but only 10%-50% sensitivity for low grade urinary cancer (UC) detection. Due to this deficit, clinicians have sought noninvasive tumor markers detectable in urine. Upwards of 50% of patients have recurrence of bladder cancer within 5 years. After initial diagnosis and treatment, patients with UC are frequently monitored every 3 months for the first 2 years, every 4 months for the third, year then usually twice a year for the fourth year. Annual monitoring is recommended during years 5 through 15. Diagnostic and Surveillance Tests BTA TRAK ® - a quantitative determination of human complement factor H-related protein Nuclear matrix protein 22 (NMP-22) – detects nuclear mitotic apparatus protein believed to be released during apoptosis; a quantitative assay, which is either positive of negative NMP-22 ® BladderChek ® – a CLIA-waved assay, point of care test with an immunochromographic qualitative format taking 20 minutes to perform The UroVysion ® Bladder Cancer Kit is fluorescence in situ hybridization (FISH) DNA probe technology. It is designed to detect aneuploidy for chromosomes 3, 7, 17 and loss of the 9p21 locus. This assay involves visualization of nucleic acid sequences within cells by creating short sequences of fluorescently labeled, single-strand DNA probes that match target sequences. The probes bind to complementary strands of DNA to identify the targeted chromosome(s) location. It is used to detect chromosomal abnormalities in voided urine to assist not only in bladder cancer surveillance but also in the initial identification of bladder cancer. Scientific studies demonstrate the sensitivity of BTA and NMP-22 ® are superior to urinary cytology. 1 Studies affirm the adjunctive value of BTA stat ® and NMP-22 ® in suspected and known bladder cancer in conjunction with cystoscopy. However, false positive results occur more frequently in the presence of hematuria, nephrolithiasis, recent GU instrumentation, inflammation and other urological malignancies. Administration of bacillus Calmette-Guerin (BCG) within 2 years of testing decreases specificity to 28%. The DNA probe assay has high sensitivity (81%) and specificity (96%) for high grade tumors, but lower sensitivity (36-57%) for low grade and stage tumors. The assay specificity approaches that of cytology, and can be utilized in patients recently treated with intravesical BCG. This can result in a positive UroVysion ® test with a negative study for UC. This assay has also been shown to be useful in predicting tumor recurrence following BCG therapy. At present the IBCCG has recommended that tumor markers be used in conjunction with cystoscopy. They also concluded that routine screening for bladder cancer is not cost-effective. 3 The US Preventive Services Task Force concluded bladder tumor markers do not have a proven role in screening of asymptomatic patients for early detection of bladder cancer. 3 NCCN, ASCO, and AUA are silent regarding the utilization of these bladder tumor markers. Surveillance Tests BTA (bladder tumor antigen) stat ® - a qualitative CLIA-waved test that identifies a human complement factor H-related protein produced by several human bladder cell lines The ImmunoCyt ™ test is cleared for monitoring bladder cancer recurrence only in conjunction with cytology and cystoscopy. The assay uses fluorescent labeled antibodies to 3 markers (carcinoembryonic antigen, and mucins LDQ10 and M344) commonly found on malignant exfoliated urothelial cells. The ImmunoCyt™ assay has also been shown to be more sensitive than urine cytology. LIMITATIONS Cystoscopy in conjunction with bladder tumor markers is standard practice to evaluate patients with symptoms suggesting bladder cancer and to monitor treated patients for recurrence or progression. Exceptions, such as high grade bladder cancers s/p radical cystectomy, do exist which preclude cystoscopy prior to testing. Testing indications, limitations and frequency do not apply to urine cytology. Bladder cancer tumor markers performed by any technology, immunoassay, molecular or FISH testing, are not covered for screening of all patients with hematuria. Bladder tumor markers are not expected to be performed until other diagnostic studies fail to identify the etiology of the hematuria. Urine cytology is not considered a bladder tumor marker. All other bladder cancer marker assays, including but not limited to the following, regardless of the methodology are considered investigational and not covered by Medicare: BCLA-4 BLCA-1 Hyaluronic acid Hyaluronidase Lewis X antigen Microsatellite markers Quanticyt Soluble FAS TATI (tumor associated trypsin inhibitor) Soluble e-cadherin Survivin Telomerase UBC ™ Rapid Test (urinary bladder cancer test for cytokeratins 8 and 18)