College of American Pathologists
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  Q & A





cap today

October 2002

Q.  Does the CAP have guidelines and recommendations regarding patient requests for gallstones?

A.  Patient requests for gallstones are common. However, there are no specific CAP guidelines regarding the release of tissue to patients and other nonmedical personnel.

At the very least, a laboratory should develop a departmental policy for the release of tissues, and it should be developed in cooperation with the hospital’s legal counsel and risk-management department. The policy should take into account the language used in the hospital’s operative or admission permits and the applicable state guidelines regarding patient ownership of specimens. Chemical and biological hazards remain at a low but finite level, even in wet tissues that are fixed and washed, and many institutions have adopted a no-release policy on tissue, with exceptions for religious, cultural, and forensic considerations.

When tissue is released to the patient, the department should have the patient sign a specimen release form that details the potential risks of keeping a specimen and the appropriate methods of disposing of the specimen. The laboratory should keep a permanent record documenting that the specimen was released and that the patient understands and accepts the exposure risks.

Thomas Merrick, MD
Department of Pathology
Presbyterian St. Luke’s Medical Center
Denver Chair, CAP Safety Committee

David Carter, MD
Department of Pathology
St. Mary’s/Duluth Clinic Health System
Duluth, Minn.
Member, CAP Surgical
Pathology Resource Committee

Q.  To perform, report, and bill for HER2 procedures, is a laboratory required to use Dako’s antibody and ChromaVision’s image-analysis system? What validation procedures are required, and how does a laboratory document its activities to satisfy various regulatory agencies? What patients should have HER2 assays performed?

A.  There are two FDA-approved kits for doing HER2 testing by immunohistochemistry: Dako HercepTest and Ventana Pathway. These kits have been approved by the FDA as immunohistochemical tests to qualify patients for trastuzumab therapy if used exactly as provided.1

There is no requirement to use these FDA-approved kits in association with ChromaVision’s image-analysis system or any other image-analysis system. There is no FDA-approved method of interpreting these assays. ChromaVision has obtained FDA approval of its system as a safe medical device, meaning the system can be expected to perform safely and effectively if used according to the manufacturer’s instructions. It is not approved specifically for HER2 testing. Published reports suggest that ChromaVision is a significant aid for pathologists who interpret HER2 assays.2

The antibodies used in FDA-approved kits are also available from the same manufacturers and can be purchased separately for HER2 testing. However, if these antibodies or others that are commercially available are used in a manner determined by the laboratory (a home-brew assay, according to the FDA), it is the laboratory director’s responsibility to show that the test is being done in a standardized way that can reasonably be assumed to provide the same information as the FDA-approved kits.

At the recent CAP-sponsored HER2 conference, Jack Bierig, CAP’s legal counsel, gave a presentation about using antibodies for HER2 outside the FDA-approved methods. He outlined the liability issues of using such alternative home-brew assays. There is potential for malpractice exposure for using non-FDA-approved tests should the patient experience injury from the therapy (in the case of a false-positive test) or disease progression (in the case of a false-negative test) that potentially could have been mitigated with appropriate therapy.

Depending on jurisdiction, use of home-brew HER2/neu tests may require advising the patient and obtaining written informed consent in advance. The pathologist should record the scientific rationale for selecting the home-brew test and document the test validation and quality control. A home-brew test-selection decision based solely on cost savings is not likely to withstand a legal challenge. Pathologists using assays of their own design are advised to check their malpractice insurance coverage about using a non-FDA-approved method when an FDA-approved test is available.3

To validate its methods to satisfy regulatory agencies, the laboratory should follow the same procedures used to validate other clinical laboratory tests. The lab should determine if the staff and pathologists have the expertise to perform the assay. If they do, they should undertake a test of their assay procedure after developing a standardized protocol, controls, and reporting procedures.4-6 For this validation, 30 to 50 cases of breast cancer should be evaluated in parallel by another laboratory that has a validated HER2 procedure. Another way to validate the assay procedure is to evaluate the cases by the other valid method to determine HER2 status—fluorescence in situ hybridization, or FISH, detection of amplified HER2 genes. Cases that are 3+ by IHC should be FISH amplified in at least 90 percent of cases. Cases that are 0-1+ should be nonamplified by FISH in 95 percent of cases. Cases that are 2+ may be FISH amplified in 11 to 35 percent of cases.7

Once the laboratory has established that its results are concordant with FISH or with the results of another validated laboratory, the lab can reasonably offer the test. The laboratory will need to perform and report the test in a standardized way and ensure the competence of the staff through proficiency testing and participation in laboratory accreditation. Such a process will satisfy the regulations for moderately complex testing such as HER2 testing (CLIA ’88).6

The current recommendation is that IHC testing for HER2 is sufficient in cases where the result is 0-1+ or 3+, assuming the levels of concordance with FISH for gene amplification are 90 to 95 percent. If the IHC HER2 result is 2+, it is recommended that the result be confirmed by performing FISH for gene amplification status since cases vary in their amplification status. Similarly, if the FISH concordance rate for IHC HER2 1+ cases is less than 95 percent, these cases should also be confirmed by FISH.

The laboratory can determine which patients should be tested for HER2 status by discussing this with the oncologists they serve. In many institutions, all new breast cancer patients are routinely tested for HER2 status, along with estrogen and progesterone receptor assays. Assays are also done on patients who have recurring breast cancer or for whom trastuzumab therapy is planned.8

1.  Guttman S. Regulatory issues in tumor marker development. Semin Oncol. 2002; 29(3):294-300.
2.  Wang S, Saboorian MH, Frenkel EP, et al. Assessment of HER2/neu status in breast cancer. Automated Cellular Imaging System (ACIS)-assisted quantitation of immunohistochemical assay achieves high accuracy in comparison with fluorescence in situ hybridization assay as the standard. Am J Clin Pathol. 2001;116: 495-503.
3.  Bierig J. Liability and payment issues in the selection of pathology assays. Arch Pathol Lab Med. 2002;126:652-657.
4.  Rhodes A, Jasani B, Couturier J, et al. A formalin-fixed, paraffin-processed cell line standard for quality control of immunohistochemical assay of HER2/neu expression in breast cancer. Am J Clin Pathol. 2000;117:81-89.
5.  Taylor C. The total test approach to standardization of immunohistochemistry. Arch Pathol Lab Med. 2000;124:945-951.
6.  O’Leary TJ, Edmonds F, Floyd AD, et al. Quality assurance for immunohistochemistry. Approved guideline. Wayne, Pa.: NCCLS, 1999.
7.  McCormick SR, Lillemoe TJ, Beneke J, et al. HER2 assessment by immunohistochemical analysis and fluorescence in situ hybridization: comparison of HercepTest and PathVysion commercial assays. Am J Clin Pathol. 2002;117(6): 935-943.
8.  Hayes DF, Thor AD. C-erb-B-2 in breast cancer: development of a clinically useful marker. Semin Oncol. 2002; 29: 231-245.

Elizabeth H. Hammond, MD
Department of Pathology
Urban Central Region Hospitals
Intermountain Health Care
Salt Lake City