Urinary Biomarkers for Cancer Screening, Diagnosis, and Surveillance

POLICY NUMBER

A.2.04.07

DESCRIPTION

The diagnosis of bladder cancer is generally made by cystoscopy and biopsy. Bladder cancer has a very high frequency of recurrence and therefore follow-up cystoscopy, along with urine cytology,is done periodically to identify recurrence early. Urine biomarkers that might be used to supplement or supplant these tests have been actively investigated. Urinary biomarkers have also been suggested to have utility in identifying colonic polyps.

Urinary Bladder Cancer

Urinary bladder cancer, a relatively common form of cancer in the United States, results in significant morbidity and mortality. Bladder cancer 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, and dysuria) may also occur.

Diagnosis

The criterion standard for a confirmatory diagnosis of bladder cancer is cystoscopic examination with biopsy. At initial diagnosis, approximately 70% of patients have cancers confined to the epithelium or subepithelial connective tissue. The 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 three months for one to three years, every six months for an additional two to three 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. Intravesical bladder cancer treatment can also confound interpretation of urine cytology. 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 (eg, immunohistochemistry) methods.

Commercially available tests approved or cleared by the U.S. Food and Drug Administration as well as laboratory-developed tests are summarized below.

The table below lists urinary tumor marker tests approved or cleared for marketing by the FDA. The FDA approved or cleared tests are indicated as adjuncts to standard procedures for use in the initial diagnosis of bladder cancer, surveillance of bladder cancer patients, or identification of colonic polyps.

FDA-Approved or Cleared Urinary Tumor Marker Tests

FDA: U.S. Food and Drug Administration; FISH: fluorescence in situ hybridization; NMIBC: non-muscle invasive bladder cancer; NMP: nuclear matrix protein; RT-PCR: real-time polymerase chain reaction.ªFISH is a molecular cytogenetic technology that can be used with either DNA or RNA probes to detect chromosomal abnormalities. DNA FISH probe technology involves the creation of short sequences of fluorescently labeled, single-strand DNA probes that match target sequences. The probes bind to complementary strands of DNA, allowing for identification of the location of the chromosomes targeted.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Urine-based tests are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of these tests. Laboratory-developed tests include:

• Cxbladder Monitor (Pacific Edge) measures the expression of 5 genes (MDK, HOXA13, CDC2, IGFBP5, CXCR2). Pacific Edge also has Cxbladder Detect and Cxbladder Triage tests.

• Xpert® Bladder Cancer Monitor (Cepheid) measures mRNA (ABL1, CRH, IGF2, UPK1B, ANXA10) in voided urine by reverse transcription-polymerase chain reaction (RT-PCR).

• PolypDx™ (Metabolomic Technologies) is a urine metabolite assay that uses liquid chromatography–mass spectrometry. An algorithm compares urine metabolite concentrations to determine the likelihood of colonic adenomatous polyps.

POLICY

The use of urinary tumor markers is considered investigational in the screening, diagnosis of, and monitoring for bladder cancer, or screening for precancerous colonic polyps.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

8/1999: Approved by Medical Policy Advisory Committee (MPAC).

6/28/2001: Coding Reference section updated, tables added, CPT codes 81000, 81001, 81002, 81003, 81005, 81007, 81015, 81020, 81099 added.

11/2001: Reviewed by MPAC; Bladder Tumor Antigen or NMP-22 (Nuclear Matrix Protein 22) medically necessary.

4/18/2002: Type of Service and Place of Service deleted.

8/29/2003: Policy title "Bladder Tumor Antigen" renamed "Urinary Tumor Markers for Bladder Cancer, "Description" section updated to be consistent with BCBSA, NMP-22 added to the "Policy" and "Policy History" sections, Sources and Code Reference sections updated, ICD-9 diagnosis code range 188.0-188.9, 198.1 listed separately, CPT code range 81000-81020, 81099 listed separately, hyperlink moved to the "Description" section.

4/7/2004: Code Reference section updated, CPT code 86316 deleted from covered code table, non-covered table and CPT codes 81000, 81001, 81002, 81003, 81005, 81007, 81015, 81020, 81099 deleted.

3/15/2006: Coding updated. HCPCS 2006 revisions added to policy.

12/04/2006: Description and policy section updated. Code Reference section updated. Added CPT code 83365, and ICD-9 code 599.7.

4/29/2008: Policy reviewed, no changes.

9/19/2008: Annual ICD-9 updates effective 10-1-2008 applied.

7/24/2009: Policy Description section updated for clarification of the commercially available tumor biomarkers, Policy Statement section updated for clarification of the commercially available tumor biomarkers; and modified for FDA-approved uses, Policy Guidelines section updated, CPT Codes 86316, 88271, 88299, 88367, 88368 added to covered table, ICD-9 Diagnosis code V10.51 added to covered table, note added to CPT code 88299.

06/07/2010: Policy description updated regarding available tests. Policy statement unchanged. FEP verbiage added to the Policy Exceptions section. The definition of investigative service added to the policy guidelines. Deleted outdated references from the Sources section.

03/07/2011: Added new CPT codes 88120 and 88121 to the Code Reference section.

08/11/2011: Policy reviewed; no changes.

09/25/2012: Policy description updated regarding available tests. The medically necessary policy statements were deleted. Policy statement changed to state that the use of urinary tumor markers is considered investigational in the diagnosis of, monitoring, and/or screening for bladder cancer. The Code Reference section was changed to Non-Covered.

08/07/2013: Policy reviewed; no changes.

04/25/2014: Policy reviewed; description updated regarding available tests. Policy statement unchanged.

12/31/2014: Code Reference section updated to revised the description of the following CPT codes: 88365, 88367, and 88368. Added the following new 2015 CPT codes: 88374 and 88377.

04/01/2015: Policy reviewed; description updated. Policy statement unchanged. Policy guidelines updated to add the following statement: The BTA (bladder tumor antigen) stat® and nuclear matrix protein 22 (NMP22) are immunoassay tests. Revised investigative definition in policy guidelines section.

08/14/2015: Code Reference section updated for ICD-10. Removed the following ICD-9 diagnosis codes: 188.0, 188.1, 188.2, 188.3, 188.4, 188.5, 188.6, 188.7, 188.8, 188.9, 198.1, 233.7, 236.7, 239.4, 599.70, 599.71, 599.72, and V10.51.

01/12/2016: Policy reviewed; no changes.

06/06/2016: Policy number A.2.04.07 added.

07/11/2017: Policy description updated regarding tests. Policy statement unchanged.

03/27/2018: Code Reference section updated to add new CPT codes 0012M and 0013M, effective 04/01/2018.

11/01/2018: Policy title changed from "Urinary Tumor Markers for Bladder Cancer" to "Urinary Biomarkers for Cancer Screening, Diagnosis, and Surveillance." Policy description updated regarding urinary tumor marker tests. Policy statement updated to add screening for precancerous colonic polyps as investigational. Code Reference section updated to add CPT code 0002U.

01/11/2019: Policy description updated regarding FDA-approved urinary tumor marker tests and laboratory-developed tests. Policy statement unchanged.

01/15/2020: Policy reviewed; no changes.

02/01/2021: Policy reviewed; no changes.

02/03/2022: Policy reviewed; no changes.

12/20/2022: Code Reference section updated to add new CPT code 0363U, effective 01/01/2023.

03/30/2023: Code Reference section updated to add new CPT codes 0365U, 0366U, and 0367U, effective 04/01/2023.

05/01/2023: Policy description updated. Policy statement unchanged. Policy Guidelines updated to remove statements regarding standard diagnostic procedures and immunoassay tests. Code Reference section updated to add CPT code 86386.

12/21/2023: Code Reference section updated to add new 2024 CPT code 0420U, effective 01/01/2024.

01/11/2024: Policy description updated regarding urinary tumor marker tests. Policy statement unchanged.

07/01/2024: Code Reference section updated to add new CPT code 0467U.

12/20/2024: Code Reference section updated to revise description for HCPCS code 0365U effective 01/01/2025.

02/06/2025: Policy reviewed; no changes.

04/01/2025: Code Reference section updated to add new CPT code 0549U, effective 04/01/2025.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.07

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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