Currentmedical mutual - ohioPolicy AHS - G2125 - Urinary Tumor Markers for Bladder Cancer, 1

Urinary Tumor Markers for Bladder Cancer

Defines coverage and non-coverage criteria for urinary tumor marker tests (BTA, NMP22, UroVysion FISH, ImmunoCyt/uCyt and other urinary tumor markers) for diagnosis and surveillance of bladder cancer, with clinical background and guideline references. This part covers policy description, indications/limitations, terminology, scientific background, proprietary tests, analytic/clinical validity, and guideline positions.

Policy Summary

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PolicyUrinary Tumor Markers for Bladder Cancer

Policy CodePolicy AHS - G2125 - Urinary Tumor Markers for Bladder Cancer, 1

Change TypeCoding and background/references update (no material coverage change)

Effective DateSep 18, 2015

Next Review Date

Key ActionDocument that the test is being used as an adjunct for either diagnostic exclusion with atypical/equivocal cytology or monitoring of high-risk non‑muscle invasive bladder cancer; other indications risk denial.

POLICY UPDATE CHANGES

Added CPT code 0549U (effective date 4/1/2025).

Updated code description for CPT code 0365U (effective date 01/01/2025).

Added CPT codes 0452U and 0465U (effective date 07/01/2024).

Reviewed and updated background, guidelines/recommendations, and references; literature review did not necessitate changes to coverage criteria.

2Tests meeting coverage criteria (categories)

MultipleProprietary tests discussed

SeveralGuideline organizations referenced

Coverage Summary

This policy addresses coverage for urinary tumor markers for bladder cancer. It defines specific situations when urinary biomarkers meet coverage criteria and when they do not, and includes definitions, scientific background, and listed procedure codes. The coverage stance is mixed: some urinary biomarkers and uses are covered as adjuncts, while many tests and indications are not covered.

Effective date: 2015-09-18; Last review: 2025-03-05. The policy highlights that urinary biomarkers have limited indications per the policy (see covered adjunct uses vs. not-covered uses) and references specific CPT/HCPCS codes for reporting when billed.

Policy statistics

Tests meeting coverage criteria (categories)2

Proprietary tests discussedMultiple (e.g., CxBladder, Bladder EpiCheck, Oncuria, URO17, Xpert BC, UBC Rapid, Bladder CARE)

Listed procedure codes>15 (see policy CPT/HCPCS code list)

New CPT code added in this revision (0549U)1 (Added CPT code 0549U; effective 04/01/2025)

Guideline organizations referencedSeveral (NCCN, AUA, USPSTF, EAU, NCI, ICUD-SIU)

Medical-Necessity Criteria

Medically Necessary / Meets Coverage Criteria

Urinary biomarkers MEET COVERAGE CRITERIA in any of the following situations:

ANY of the following

As an adjunct in the diagnostic exclusion of bladder cancer for individuals who have an atypical or equivocal cytology.
As an adjunct in the monitoring of high-risk, non-muscle invasive bladder cancer.

Medically Necessary / ImmunoCyt/uCyt

Fluorescence immunocytology coverage

As an adjunct to cystoscopy or cytology in the monitoring of individuals with bladder cancer, the use of fluorescence immunocytology (ImmunoCyt/uCyt) MEETS COVERAGE CRITERIA.

Coding

Procedure codes listed in policymixed

86294	Immunoassay for tumor antigen, qualitative or semiquantitative (eg, bladder tumor antigen).
86316	Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each.
86386	Nuclear Matrix Protein 22 (NMP22), qualitative.
88120	Cytopathology, in situ hybridization (eg, FISH), urinary tract specimen with morphometric analysis, 3-5 molecular probes, each specimen; manual.
88121	Cytopathology, in situ hybridization (eg, 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; 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; Pacific Edge Diagnostics USA, Ltd).
0363U	Oncology (urothelial), mRNA, gene-expression profiling by real-time quantitative PCR of 5 genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm incorporates age, sex, smoking history, and macrohematuria frequency, reported as a risk score for having urothelial carcinoma (Proprietary test: Cxbladder Triage; Pacific Edge Diagnostics USA, Ltd).

1–10 of 17

1/2

Other applicable codesmixed

No codes listed

Provider Actions

Documentation Required

Indication documentation

Document that the test is being used as an adjunct for either (a) diagnostic exclusion in individuals with atypical/equivocal cytology or (b) monitoring high-risk, non‑muscle‑invasive bladder cancer; other indications risk denial.

Adjunct in diagnostic exclusion for atypical/equivocal cytology
Adjunct in monitoring of high‑risk non‑muscle invasive bladder cancer

Denial Risk

Claims for screening or hematuria evaluation

Claims for urinary biomarkers for evaluation of hematuria, asymptomatic screening, diagnosis in symptomatic individuals, or any unspecified indication not meeting the policy criteria are not covered and may be denied.

Background & Evidence

Bladder cancer arises from the urothelium and is a common malignancy of the urinary system; typical presentation includes painless hematuria and other urinary symptoms, with most patients presenting with superficial (non–muscle-invasive) tumors but a substantial minority presenting with invasive disease. Cystoscopy (white-light) with urine cytology is the established gold standard for diagnosis and surveillance, though it is invasive, uncomfortable for patients, and costly.

A wide range of urinary biomarkers has been developed — including protein assays (BTA, NMP22, Oncuria), DNA- and epigenetic-based tests (methylation assays, utDNA, Bladder EpiCheck, Bladder CARE), mRNA panels (CxBladder, Xpert BC), immunocytology (ImmunoCyt/uCyt+), and others (miRNA, cytokeratin fragments/UBC Rapid, URO17). While some multi-target panels show promising sensitivity and negative predictive value, many biomarkers have lower or variable specificity and sensitivity than cystoscopy, perform less well for low-grade/low-stage tumors, and can be costly — limiting their routine replacement of cystoscopic evaluation.

Evidence / Source	Key metric
Meta-analysis sensitivities range	0.57 to 0.82 across biomarkers; CxBladder highest in one study at 0.82
Cystoscopy sensitivity/specificity (reference)	Flexible cystoscopy sensitivity 0.98; specificity 0.938
Oncuria performance (Hirasawa et al. 2021)	AUC 0.95; sensitivity 93%; specificity 93%; NPV 99%; PPV 65%
URO17 reported performance	Sensitivity 100%; specificity 92.6% (small study)
EAU 2024 statement	CxBladder, ADX-Bladder, Xpert Bladder and EpiCheck may approach cystoscopy sensitivity for high-grade disease but not accepted as routine replacements.
FDA approvals	BTA stat, BTA TRAK, NMP22 Test Kit, NMP22 BladderChek, UroVysion, ImmunoCyt approved for specific uses

Assay thresholds

BTA manufacturer-recommended cut-off14 U/mL — manufacturer-recommended assay cut-off (assay-specific)

NMP22 FDA-approved cut-off10 U/mL — FDA-approved assay cut-off (assay-specific)

Definitions

BTA — Bladder tumor antigen: a protein test detecting complement factor H–related protein; manufacturer-recommended cut-off 14 U/mL.

NMP22 — Nuclear matrix protein 22: a urinary protein marker available in quantitative and qualitative formats; FDA‑approved cut-off 10 U/mL.

FISH / UroVysion — Fluorescence in situ hybridization assay (UroVysion Bladder Cancer test): detects chromosomal alterations (aneuploidy for chromosomes 3, 7, 17 and loss of 9p21) in urine specimens.

Revision History

06/19/2024coding update

Added CPT codes 0452U and 0465U (effective 07/01/2024).

12/04/2024coding update

Updated code description for CPT code 0365U (effective 01/01/2025).

03/05/2025policy review

Reviewed and updated background, guidelines/recommendations, and references; literature review did not necessitate changes to coverage criteria.