Currentblue cross blue shield - tennesseePolicy N/A

Urinary Tumor Markers for Bladder Cancer

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Defines coverage stance for urinary tumor marker tests for detection and monitoring of bladder cancer for Blue Cross Blue Shield - Tennessee members, including which indications meet or do not meet coverage criteria and limitations (e.g., screening, hematuria evaluation).

Policy Summary

Payerblue cross blue shield - tennessee

PolicyUrinary Tumor Markers for Bladder Cancer

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateJul 1, 2023

Next Review DateN/A

Key ActionDocument the indication and, when requesting authorization, specify that testing is for an adjunctive indication (atypical/equivocal cytology or surveillance of high‑risk NMIBC).

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

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Currentblue cross blue shield - tennesseePolicy N/A

Urinary Tumor Markers for Bladder Cancer

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Policy Summary

Payerblue cross blue shield - tennessee

PolicyUrinary Tumor Markers for Bladder Cancer

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateJul 1, 2023

Next Review DateN/A

Key ActionDocument the indication and, when requesting authorization, specify that testing is for an adjunctive indication (atypical/equivocal cytology or surveillance of high‑risk NMIBC).

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

81,000+U.S. annual bladder cancer cases (approx.)

17,900U.S. annual bladder cancer deaths (approx.)

CystoscopyPreferred procedure

0.57-0.95Biomarker sensitivity range

$25-$800Test cost range

7/1/2023Policy adoption

Coverage Criteria for Urinary Tumor Markers

Covered indications for selected urinary biomarkers

Covered when ALL of the following are met as adjuncts:

Adjunctive use for selected urinary biomarkers: Urinary biomarkers (BTA, NMP22, UroVysion FISH) meet coverage criteria when used as adjuncts BOTH to (a) diagnostic exclusion of bladder cancer for patients with atypical or equivocal cytology, AND (b) monitoring of high-risk, non–muscle-invasive bladder cancer.

Policy indications: see III. Indications and/or Limitations of Coverage.

Covered indication for ImmunoCyt/uCyt+

Covered when ALL of the following are met as adjuncts:

ImmunoCyt/uCyt+ adjunctive use: Fluorescence immunocytology (ImmunoCyt/uCyt) meets coverage criteria when used as an adjunct to cystoscopy or cytology in the monitoring of persons with bladder cancer.

Policy indication: ImmunoCyt/uCyt adjunctive monitoring per III. Indications.

Not medically necessary: screening and non-adjunctive uses

Not covered for other indications:

Not covered uses for urinary biomarkers: Urinary biomarkers (BTA, NMP22, UroVysion FISH) DO NOT meet coverage criteria for screening of bladder cancer, evaluation of hematuria, diagnosing bladder cancer in symptomatic individuals, or other non-specified indications.

Reimbursement policy exclusion statement.

Not covered: other urinary tumor markers

Not covered: other urinary tumor markers: Any other urinary tumor markers for bladder cancer not mentioned (beyond BTA, NMP22, UroVysion, ImmunoCyt/uCyt) DO NOT meet coverage criteria.

Policy exclusion: any other urinary tumor markers not specified above.

Adjunctive/conditional coverage for biomarkers

Covered when ALL of the following are met (guideline-concordant adjunctive use):

Adjunctive biomarker use for NMIBC surveillance: Biomarker testing may be used as an adjunct to cystoscopy (not as a replacement) to assess response to intravesical BCG or to adjudicate equivocal cytology results during surveillance of non–muscle-invasive bladder cancer.

Consistent with AUA/SUO and NCCN guidance that biomarkers can be adjunctive for response assessment or equivocal cytology.

Consideration in high-risk surveillance: Biomarker assessment may be considered during surveillance of high-risk NMIBC, recognizing that additional benefit in changing outcomes is uncertain (NCCN category 2B).

NCCN: category 2B recommendation; guideline uncertainty about outcome benefit.

Not medically necessary / not recommended uses

Not covered / Not recommended for screening or routine substitution when ANY of the following apply:

Population screening: Use of urinary biomarkers for screening asymptomatic adults is unsupported due to inadequate evidence of mortality benefit and is not recommended; screening may lead to unnecessary diagnostic procedures.

Supported by USPSTF and NCI statements regarding insufficient evidence for screening.

Replacement of cystoscopy: Biomarker tests used in place of diagnostic cystoscopy for initial diagnosis or routine surveillance are not appropriate; cystoscopy with histologic confirmation remains necessary for diagnosis and surveillance.

Consistent with EAU/AUA/NCCN positions that biomarkers do not replace cystoscopy.

This policy excludes coverage for routine use of urinary tumor biomarkers outside the limited adjunctive indications described elsewhere. Specifically, BTA, NMP22, and UroVysion (FISH) do not meet coverage criteria for: screening for bladder cancer, evaluation of hematuria, diagnosing bladder cancer in symptomatic individuals, or any other non-specified indications. These tests are therefore considered non-covered when ordered for population screening, hematuria workup, or general diagnostic substitution for standard diagnostic pathways.

Major clinical guidelines and evidence reviews do not support replacing cystoscopy with urine-based biomarkers. The European Association of Urology (EAU) and other guideline bodies state that none of the currently available urinary markers can replace cystoscopy for diagnosis or routine follow-up; biomarkers may at best serve as an adjunct to help detect missed tumors or to clarify equivocal findings, particularly for high-grade disease. Clinicians should continue to use cystoscopy with histologic confirmation as the diagnostic gold standard.

Laboratory-developed tests (LDTs) for urinary biomarkers are not FDA-approved. These assays must be validated locally and performed under applicable regulations: they are regulated by CMS as CLIA high-complexity tests. When an LDT is submitted for coverage consideration, providers should document the CLIA validation and local performance characteristics.

The following urinary biomarker tests are considered not medically necessary when used outside the limited adjunctive indications: BTA, NMP22, UroVysion (FISH), and ImmunoCyt/uCyt. Use of these assays for screening, routine hematuria evaluation, initial diagnosis in symptomatic patients, or any other non-adjunctive purpose does not meet coverage criteria and is subject to denial.

Routine screening of asymptomatic adults with urinary biomarkers and substituting urine markers for cystoscopy in the diagnosis or surveillance of bladder cancer are considered not medically necessary. Evidence reviews (including USPSTF and NCI) find insufficient data to support screening benefit and note potential for unnecessary procedures; accordingly, biomarkers should not be used as a replacement for cystoscopy in either initial diagnosis or routine surveillance.

Tests, Codes, and Cut-offs

Tests mentioned (no codes provided)mixed

Not specified

Document lists test names (BTA, NMP22, UroVysion, ImmunoCyt/uCyt) but does not provide billing codes in this portion.

FDA-cleared urinary biomarker testsmixed

BTA stat	Bard BTA stat™ Test — qualitative bladder tumor associated antigen in urine (FDA-approved)
BTA TRAK	Bard BTA TRAK™ Test — quantitative bladder tumor associated antigen in urine (FDA-approved)
NMP22 Test Kit	MATRITECH NMP22™ TEST KIT — quantitative NMP22 enzyme immunoassay (FDA-approved)
NMP22 BladderChek	NMP22 BladderChek — qualitative assay for monitoring bladder cancer patients (FDA-approved)
UroVysion	UROVYSION BLADDER CANCER KIT — FISH test for aneuploidy and 9p21 locus (FDA-approved)

BTA manufacturer cut-off — 14 U/mL

BTA manufacturer-recommended cut-off14 U/mL

BTA target analyteComplement factor H-related protein (hCFHrp)

Available formatsQuantitative and qualitative versions (e.g., BTA TRAK, BTA stat)

NMP22 FDA-approved cut-off — 10 U/mL

NMP22 FDA-approved cut-off10 U/mL

Test formatsQuantitative and qualitative (including NMP22 BladderChek)

Intended use per FDA

Provider Guidance, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization — Adjunctive Indications

Prior authorization guidance — Coverage is limited to specified adjunctive uses (atypical/equivocal cytology; monitoring high-risk NMIBC). Providers should obtain prior authorization when requesting urinary biomarker testing for these covered adjunctive indications per payer requirements.

Adjunctive uses only: atypical/equivocal cytology or monitoring high-risk non–muscle-invasive bladder cancer (NMIBC).
Document the clinical indication on the authorization request: atypical/equivocal cytology or surveillance of high‑risk NMIBC.

Prior Authorization

Prior Authorization — Non‑Guideline / Non‑Covered Uses

Prior authorization for non-guideline use — Claims intended to replace cystoscopy, used for population screening, evaluation of hematuria, diagnosis in symptomatic individuals, or other non-covered indications are not supported by the evidence and are denial risks. Prior authorization may be required and likely will be denied for these non-guideline uses.

Do not use biomarkers as a substitute for cystoscopy when monitoring NMIBC; requests to replace cystoscopy are not recommended.

Background and Evidence Summary

Bladder cancer arises from the urothelium and is the most common malignancy of the urinary system. It often presents with hematuria and is primarily diagnosed and monitored using cystoscopy with urine cytology. Urinary tumor biomarkers (for example, BTA, NMP22, UroVysion FISH, and ImmunoCyt/uCyt) have been studied as adjuncts to cystoscopy and cytology, but test sensitivity and specificity vary and none have supplanted cystoscopy as the diagnostic standard. As a result, cystoscopy with histologic confirmation remains necessary for definitive diagnosis and routine surveillance.

Clinical society positions and regulatory context emphasize that urinary biomarkers are adjunctive rather than replacement tests. The EAU and related guideline bodies state that no urinary marker currently replaces cystoscopy and that biomarkers may be used only as adjuncts (for example, to help detect missed tumors or to adjudicate equivocal cytology). Additionally, FDA-approved tests have defined indications (with ImmunoCyt approved for surveillance use), while many other assays are laboratory-developed tests subject to CLIA high-complexity validation rather than FDA approval.

Test Definitions and Assay Descriptions

BTA — Bladder tumor antigen description and forms

DefinitionBladder tumor antigen (BTA) detects complement factor H-related protein (hCFHrp) in urine.

Formats availableQuantitative (BTA TRAK) and qualitative (BTA stat) assays

Typical clinical roleUsed as an adjunctive aid in the management of bladder cancer in conjunction with cystoscopy

NMP22 — Nuclear matrix protein 22 description

DefinitionNuclear matrix protein 22 (NMP22) is a protein released into urine from apoptotic cancer cells; elevated levels are associated with bladder cancer.

Formats availableQuantitative enzyme immunoassay and qualitative point-of-care tests (e.g., NMP22 BladderChek)

Policy Revision History

2023-07-01policy_effectiveLatest

Policy adopted and became effective on 2023-07-01 (Adopted Avalon policy recommendation).

Policy Summary

Payerblue cross blue shield - tennessee

PolicyUrinary Tumor Markers for Bladder Cancer

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateJul 1, 2023

Next Review DateN/A

Key ActionDocument the indication and, when requesting authorization, specify that testing is for an adjunctive indication (atypical/equivocal cytology or surveillance of high‑risk NMIBC).

SourceLink

On This Page

Aid in the detection/monitoring of bladder cancer (quantitative EIA and qualitative point-of-care assays)

UroVysion (FISH) — definition and description

DefinitionUroVysion is a fluorescent in situ hybridization (FISH) assay that uses DNA probes to detect chromosomal alterations associated with bladder cancer.

TargetsAneuploidies of chromosomes 3, 7, 17 and loss of the 9p21 locus

Regulatory statusFDA-approved (UROVYSION Bladder Cancer Kit)

ImmunoCyt / uCyt+ — definition and description

DefinitionImmunoCyt (uCyt+) is a fluorescent immunocytology assay that detects specific glycoproteins expressed on malignant urothelial cells.

MethodFluorescent antibody-based detection of tumor-associated glycoproteins on exfoliated urothelial cells

Regulatory statusFDA-cleared (referred to as ImmunoCyt or uCyt+ in FDA summaries)

NMP22 BladderChek — point-of-care qualitative assay description

DescriptionNMP22 BladderChek is a point-of-care, qualitative assay for detection of NMP22 in urine intended as an aid in monitoring bladder cancer patients.

FormatQualitative, point-of-care cassette test (professional and prescription home use per FDA)

Regulatory statusFDA-approved (NMP22 BladderChek)

Population screening, hematuria evaluation, and diagnosis in symptomatic individuals are non‑covered indications and are denial triggers.

Prior Authorization

Government Policy Precedence and Prior Authorization

Follow applicable government prior-authorization rules — If a Local Coverage Determination (LCD), National Coverage Determination (NCD), or state Medicaid policy conflicts with this policy, the government policy takes precedence for that member. Check Medicare/Medicaid coverage and prior-authorization requirements before submitting requests.

When government coverage differs from this policy, apply the applicable LCD/NCD or state Medicaid rule.
Visit the CMS Medicare Coverage Database and applicable state Medicaid websites for current rules and prior‑authorization details.

Documentation Required

Documentation of indication — Providers must document the specific clinical indication on the order and in the medical record (e.g., atypical/equivocal cytology, surveillance of high‑risk NMIBC, assessment of response to BCG). Complete documentation supports prior authorization and claims adjudication.

Include clinical history, prior cystoscopy/cytology results, and reason for biomarker use (adjunctive surveillance vs. equivocal cytology).
For surveillance use, document cancer risk category (high‑risk NMIBC) and any recent treatments such as BCG.

Documentation Required

Regulatory Status and Precedence

Regulatory precedence — Incorporate test regulatory status into coverage decisions. FDA‑approved biomarkers have labeled indications (diagnosis and/or surveillance); where a conflict exists between this policy and an applicable government policy, government policy controls.

Recognize FDA approvals: BTA stat, BTA TRAK, NMP22 Test Kit, NMP22 BladderChek, UroVysion; ImmunoCyt approved for surveillance.
Apply government policies (LCD/NCD/state) over this policy when applicable.

Documentation Required

Test Regulatory / Validation Documentation

Test regulatory and validation documentation — For FDA‑approved assays, include the test name and FDA indication in the request. For laboratory‑developed tests (LDTs), document CLIA high‑complexity validation and the laboratory performing the test.

Submit the assay name and whether it is FDA‑approved/cleared; if an LDT, include CLIA validation documentation and lab CLIA number.
LDTs are regulated under CLIA as high‑complexity tests and are not FDA‑approved; provide validation evidence as required by payer rules.

Note

Adjunctive Use — Do Not Substitute for Cystoscopy

Adjunctive use before substitution — Biomarkers should be used adjunctively with cystoscopy/cytology (e.g., to assess response to BCG or adjudicate equivocal cytology). They should not be used to replace cystoscopy for surveillance or diagnosis.

Use biomarkers to complement, not substitute, standard diagnostic procedures.
Requests seeking to replace cystoscopy with a biomarker test will be evaluated as non‑standard and are likely to be denied.

Step Therapy

Step Therapy / Sequencing

Step therapy — No step therapy requirements are stated in this portion of the policy. Providers should follow any separate payer programs or clinical prior‑authorization pathways if present.

No explicit step therapy or sequencing requirements specified here.
Follow any payer‑specific prior authorization program instructions (e.g., genetic testing prior authorization for Cxbladder).

Clinical/regulatory noteFDA-approved tests available; commonly used as adjuncts to cystoscopy rather than replacements

UroVysion (FISH) — detects chromosomal alterations; FDA-approved

Primary functionDetects chromosomal alterations characteristic of bladder cancer using FISH with DNA probes.

Chromosomal targetsAneuploidy for chromosomes 3, 7, 17 and loss of the 9p21 locus

Regulatory statusFDA-approved (UROVYSION Bladder Cancer Kit)

ImmunoCyt / uCyt+ — fluorescent immunocytology assay description

Assay typeFluorescent immunocytology test detecting tumor-associated glycoproteins on exfoliated urothelial cells.

Clinical useUsed adjunctively with cytology and cystoscopy for monitoring bladder cancer patients

Regulatory statusFDA-cleared (ImmunoCyt / uCyt+)

utDNA CAPP-Seq — urine-derived tumor DNA sequencing assay (preliminary studies)

DefinitionutDNA CAPP-Seq (uCAPP-Seq) is a high-throughput sequencing method that analyzes urine-derived tumor DNA to detect bladder cancer.

Preliminary performanceReported detection rates up to 93% (tumor-informed) and 84% (tumor-blinded) with specificity 96%–100% in a published study (Dudley et al., 2019).

Development statusInvestigational/preliminary studies; not presented as standard FDA-cleared clinical test in this policy context

FDA-approved FISH assay description (UroVysion)

Assay descriptionUroVysion is an FDA-approved fluorescence in situ hybridization (FISH) assay that detects chromosomal aneuploidy and loss of the 9p21 locus in urine specimens.

Intended useAid in detection of bladder cancer using urine specimens from persons with hematuria suspected of having bladder cancer

TechnologyFISH with DNA probes specific to chromosomes 3, 7, 17 and 9p21

UroVysion — FISH kit detecting aneuploidy for chromosomes 3,7,17 and loss of 9p21

Analytical targetDetects aneuploidy for chromosomes 3, 7, and 17 and loss of the 9p21 locus via FISH in urine specimens.

Kit nameUROVYSION Bladder Cancer Kit (FDA-approved)

Clinical contextUsed as an adjunctive test in evaluation for bladder cancer; detects chromosomal alterations distinctive of bladder cancer