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The diagnosis of bladder cancer is generally made by cystoscopy and biopsy. Moreover, 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 either supplement or supplant these tests have been actively investigated.
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 and dysuria) may also occur.
For patients with hematuria, American Urological Association (AUA) guidelines recommend cystoscopic evaluation of all adults older than 40 years with microscopic hematuria and for those younger than 40 years with risk factors for developing bladder cancer. Confirmatory diagnosis of bladder cancer is made by cystoscopic examination, considered to be the criterion standard, and biopsy. At initial diagnosis, about 70 percent 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 depth of invasion and tumor grade. However, a 50-75 percent incidence of recurrence has been noted in these patients with 10-15 percent progressing to muscle invasion over a five 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, assuming no recurrence.
While urine cytology is a specific test (from 90 percent–100 percent), its sensitivity is lower, ranging from 50 percent–60 percent overall and is considered even lower for low-grade tumors. Therefore, there has been interest in identifying tumor markers in voided urine that would provide a more sensitive and objective test for tumor recurrence.
Tests cleared by the U.S. Food and Drug Administration (FDA):
The BTA (bladder tumor antigen) stat® test, (Polymedco, Cortlandt Manor, NY) is a qualitative, point-of-care test with an immediate result that identifies a human complement factor H-related protein that was shown to be produced by several human bladder cell lines but not by other epithelial cell lines. The BTA stat® test is an in vitro immunoassay intended for the qualitative detection of bladder tumor-associated antigen in the urine of persons diagnosed with bladder cancer.
The BTA TRAK® test (Polymedco, Cortlandt Manor, NY) provides a quantitative determination of the same protein. This test requires trained personnel and a reference laboratory. Both tests have sensitivities comparable to that of cytology for high-grade tumors and better than cytology for low-grade tumors.
Nuclear matrix protein 22 (NMP-22) is a protein associated with the nuclear mitotic apparatus. It is thought that this protein is released from the nuclei of tumor cells during apoptosis. Normally, only very low levels of NMP-22 can be detected in the urine, and elevated levels may be associated with bladder cancer. NMP-22 may be detected in the urine using an immunoassay.
Fluorescence in situ hybridization (FISH) DNA probe technology has also been 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. FISH DNA probe technology is a technique to visualize nucleic acid sequences within cells by creating short sequences of fluorescently labeled, single-strand DNA, called probes, which match target sequences. The probes bind to complementary strands of DNA, allowing for identification of the location of the chromosomes targeted. Vysis UroVysion® (Abbott Molecular) is a commercially available FISH test.
The ImmunoCyt™ test (DiagnoCure Inc., Quebec City, QC) uses fluorescence immunohistochemistry with antibodies to a mucin glycoprotein and a carcinoembryonic antigen. These antigens are found on bladder tumor cells. The test is used for monitoring bladder cancer in conjunction with cytology and cystoscopy.
In addition to the FDA-cleared tests, clinical laboratories that meet Clinical Laboratory Improvement Act standards are marketing urine-based tests. For example, Predictive Laboratories (Lexington, MA) markets a test called CertNDx™, to assess Fibroblast Growth Factor Receptor 3 (FGFR3) mutations. The test is intended to be used in combination with cytology for identifying patients with hematuria at risk of bladder cancer. FGFR3 mutations may be associated with lower-grade bladder tumors that have a good prognosis. In addition, Pacific Edge (New Zealand) is marketing a test in the U.S. called Cxbladder™, which tests for 5 urine-based markers.
Other urinary markers
A number of other urinary tumor markers, not currently commercially available in the United States, are under investigation. These include:
Urinary tumor marker tests cleared by the FDA and in clinical use include:
With the exception of the ImmunoCyt test, which is only cleared for monitoring bladder cancer recurrence, all tests are FDA-cleared as adjunctive tests for use in the initial diagnosis of bladder cancer and surveillance of bladder cancer patients, in conjunction with standard procedures.
The use of urinary tumor markers is considered investigational in the diagnosis of, monitoring, and/or screening for bladder cancer.
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.
For the purpose of this policy, standard diagnostic procedures for bladder cancer consist of urine cytology and cystoscopy, with or without biopsy.
The BTA (bladder tumor antigen) stat® and nuclear matrix protein 22 (NMP22) are immunoassay tests.
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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
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 added.
Blue Cross Blue Shield Association policy # 2.04.07
This may not be a comprehensive list of procedure codes applicable to this policy.