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
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
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
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.
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.:
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