Pathology/Lab Coding Alert

HER-2/neu testing for breast cancer patients may involve procedures from surgical pathology to clinical lab tests to cytogenetic studies. Although the purpose is the same the analysis of breast cancer for changes in the HER-2/neu gene or its protein product the source, method and indications for the tests vary widely.
 
With recent code changes and no clear consensus regarding which test methods are most predictive, coding and reimbursement for these procedures can be tricky. "Local Medicare carriers and third-party payers have a wide range of coverage criteria for these tests," says Richard Zarbo, MD, DMD, chairman of pathology at Henry Ford Hospital and Medical Group in Detroit. In addition to knowing these local rules, coders must be familiar with the procedure methods to accurately report the services.

HER-2/neu Testing Methods and Indications

Elevated levels of the HER-2/neu gene or its protein product generally indicate a poor prognosis for breast cancer patients. With the breast cancer tissue as the specimen, some tests identify amplification of the gene, while others identify overexpression of the protein product of the gene. Yet another test identifies elevated levels of the protein in the serum, rather than in the tumor tissue.
 
The tests may be used for risk assessment, treatment indication, and monitoring. Specifically, assessment of HER-2 status plays a major clinical role in determining a patient's suitability for Herceptin (trastuzumab) treatment. Herceptin is a monoclonal antibody targeted at the HER-2/neu protein.
 
Although selection for Herceptin therapy was originally determined through tissue immunohistochemical (IHC) testing, some studies indicate selection based on the results of fluorescence in situ hybridization (FISH) gene detection assay. "However, there is not a clear consensus regarding how the tests should be performed and the results reported and interpreted for diagnostic and therapeutic purposes," Zarbo says. A description of the procedures, codes and clinical applications for the various forms of HER-2/neu assessment follows.

HER-2/neu Protein Overexpression Testing

"The immunohistochemical HER-2/neu test is a special stain of the breast tumor tissue that indicates overexpression of a specific protein associated with aggressive tumor growth," says Peggy Slagle, CPC, billing compliance coordinator, University of Nebraska Medical Center in Omaha. "The test is typically carried out with an estrogen receptor assay (ERA) and progesterone receptor assay (PRA) on the breast tumor tissue." Each of the three stains is reportable as a separate unit of 88342 (Immunocytochemistry [including tissue immunoperoxidase], each antibody) and is reported in addition to the surgical pathology code for evaluation of the breast tumor (e.g., 88307, Level V Surgical pathology, gross and microscopic examination, breast, mastectomy partial/simple).
 
Assessment of HER-2/neu protein overexpression through tissue IHC staining has been considered the standard method for indicating Herceptin therapy. HercepTest by DAKO was the first commercially available IHC test to be FDA-approved for that purpose, and now Pathway by Ventana Medical Systems has also been approved. Also, laboratories may perform this assay using their own in-house analyte-specific reagent test. IHC, HercepTest, Pathway or in-house assays are reported with 88342.
 
However, insurers may not reimburse for all of these tests. Coverage varies, according to Zarbo. For example, some states specifically require the DAKO HercepTest and will not pay for an IHC HER-2/neu test (88342) carried out using in-house reagents. "Quality assurance is an issue with in-house testing due to variability in HER-2/neu antibodies and the inability to compare in-house assays with the original clinical trial assays," Zarbo says.  
 
Many local Medicare carriers and third-party payers consider any of the female breast cancer codes (174.0-174.9, Malignant neoplasm of female breast) a payable diagnosis for the IHC HER-2/neu test. Because this has  been the only assay that is FDA-approved as an aid in the assessment of patients for whom Herceptin treatment is being considered, this test has been more universally covered for that purpose than the FISH assay.
 
A strongly positive IHC result (3+ in the HercepTest scoring system) is generally accepted to identify women who may benefit from Herceptin therapy, but indications are less clear for IHC tests that show only weak or moderate membrane staining (2+). Also, there can be variability in IHC test results due to varying sensitivity of anti-HER-2 antibodies used, variations in tissue fixation, and lack of a standard scoring system and threshold for positivity. For this reason, some laboratories first conduct the IHC test, and perform FISH only for borderline cases. "Our standard of practice is to conduct the less expensive tissue IHC test first, and follow up with FISH testing for patients with non-determinate results of '2+'," Slagle says. "Even with that approach, reimbursement for FISH testing varies, because it is a less-established methodology."

HER-2/neu Gene Amplification Testing

The FISH assay determines the amplification, or increase of HER-2 genes in the breast cancer tissue. Although Herceptin treatment targets the HER-2/neu protein (measured by IHC), not the gene that produces the protein (measured by FISH), studies show that the two measurements correlate strongly.
 
"In January, the FDA approved labeling the PathVysion test for use in identifying women with metastatic breast cancer who could benefit from Herceptin therapy," says Abbott spokesman Don Braakman. PathVysion is a commercially available FISH HER-2 assay manufactured by Vysis, a subsidiary of Abbott Laboratories. "FDA approval of the test for this purpose should lead to increased coverage for the FISH HER-2/neu (specifically, PathVysion)," Braakman says. However, because the approval is recent, many carriers and third-party payers may still list only IHC testing, not FISH testing, as a reimbursable procedure to indicate Herceptin therapy. 
 
The FISH assay is a cytogenetic study that involves a series of steps to allow visualization and measurement of the HER-2 gene using a fluorescent dye and specialized microscope. The source for the test is breast tumor tissue, generally formalin-fixed and paraffin-embedded. Each step is separately reported as described below.
 
The procedure uses DNA probes, which are small segments of fluorescent DNA material. One probe with a certain color attaches specifically to chromosome 17 (where the HER-2 gene resides), and another of a different color attaches specifically to the HER-2 gene itself. This process is called hybridization and is reported with 88271 (Molecular cytogenetics; DNA probe, each [e.g., FISH]).
 
Because there are two probes and the code definition indicates "DNA probe, each," many laboratories report 88271 x 2. This is the correct coding according to Vysis. However, other laboratories interpret the second probe as quality control, and only report one unit of 88271.
 
Using the fluorescence microscope, clinicians examine cells to determine if the ratio of chromosome 17 fluore-scence and HER-2 gene fluorescence is 1:1 (normal), or if there is an increase in HER-2 gene fluorescence, indicating gene amplification. This process is reported as 88274 (Molecular cytogenetics; interphase in situ hybridization, analyze 25-99 cells).
 
In addition to the hybridization and fluorescence microscope analysis, it is appropriate to report a separate code for the pathologist's interpretation and report of the FISH study. This service is reported as 88365 (Tissue in situ hybridization, interpretation and report).
 
As with IHC testing, reimbursement for HER-2 FISH testing requires a diagnosis of female breast cancer (174.0-174.9). However, many local Medicare carriers and some third-party payers do not routinely reimburse for the test. As previously mentioned, PathVysion is the only commercially available FISH HER-2 test that is FDA-approved to identify women who could benefit from Herceptin therapy. The other commercially available FISH HER-2 test, Inform by Ventana Medical Systems, is FDA-approved for prognosis of women with lymph node-negative invasive breast cancer. 

HER-2/neu Serum Oncoprotein Testing

A new code was added to CPT 2002 to report a procedure for measuring HER-2/neu protein in the serum of breast cancer patients 83950 (Oncoprotein, HER-2/neu). The test commonly uses immunoassay technique and was previously reported with the nonspecific code 86316 (Immunoassay for tumor antigen; other antigen). Code 86316 should no longer be reported for the HER-2/neu serum test, because the more specific code is now available.
 
"The serum HER-2/neu test is FDA-approved for follow-up and monitoring of Herceptin and other chemo-therapy treatments for breast cancer," Zarbo says. It is not approved for diagnostic purposes or to identify patients to be treated with Herceptin therapy, he says.
 
For example, a patient with a positive IHC HER-2/neu tissue test may be identified for Herceptin therapy. A baseline serum HER-2/neu level may be measured, and once the patient is on drug protocol, serial determinations of serum levels may be taken. Changes in HER-2/neu levels in the patient's blood allow the physician to monitor the effectiveness of therapy. Because this is a new code, most carriers and third-party payers have not yet determined coverage guidelines such as diagnosis coding and frequency limits. As with FISH HER-2 testing, check with individual insurers and carriers for specific coding and coverage guidelines.