CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Anne Paxton
September 2021—Beginning next year, CAP-accredited laboratories that perform HER2 immunohistochemistry in gastroesophageal adenocarcinoma or highly sensitive (hs) ALK in non-small cell lung cancer will be required to enroll in proficiency testing for those analytes. This change comes as the first new IHC predictive biomarker assays are to be added to the monitored list in a decade.
The new requirements are notable not only because the last year an IHC biomarker became monitored was 2011, when ER/PgR for breast cancer joined the list, but also because the requirements culminate many years of consideration and conversation by CAP Immunohistochemistry Committee and CAP Accreditation Program leaders. Reflecting the complexity of the decisions to make these two biomarker tests monitored, the committee has released a list of frequently asked questions to help laboratories comply with the proficiency testing requirement and to improve their testing processes (https://bit.ly/CAP-IHC-FAQ).
Andrew Bellizzi, MD, chair of the CAP Immunohistochemistry Committee, was an advocate for an expansion of the proficiency testing requirements to include non-breast predictive markers. “Probably the most important pillar of quality is the peer laboratory inspection process. But hand in hand with that is proficiency testing,” says Dr. Bellizzi, director of immunohistochemistry and GI pathology at the University of Iowa Hospitals and Clinics.
Dr. Bellizzi
“The main problems in quality in predictive marker IHC reside in suboptimal IHC protocols,” Dr. Bellizzi says, explaining that the decision to proceed with required proficiency testing was motivated in part by the need to address that quality problem. “PT for the highly sensitive ALK assay was where we had the best data. And we consistently had around 15 percent of labs failing that IHC Survey. But it’s not required, so there is no enforcement mechanism.”
Predictive markers are often a tiny fraction of the analytes in a given IHC laboratory but their results carry the greatest weight, with a positive or negative indicating whether a patient may benefit from a specific therapy, Dr. Bellizzi notes. “If the biomarker is negative, that result cannot be predicted based on morphology, so there’s no backup. There’s no crutch. That is unlike typical diagnostic IHC markers, which are used in panels and in combination with morphology and a lot of clinical information to arrive at an overall interpretation of the case.”
The IHC laboratory resides in anatomic pathology, which historically has been an inherently qualitative discipline compared with clinical pathology—the latter with its emphasis on objective metrics, precision, and reference standards, says Dr. Bellizzi. Proficiency testing requirements set by the Centers for Medicare and Medicaid Services appear to reflect this distinction. “There are 81 analytes for which participation in proficiency testing is required by CMS. They are CMS-regulated analytes. They’re all very important tests like Gram stain and CBC and calcium and albumin, but they are all clinical pathology tests.”
“When I joined the IHC Committee nearly a decade ago,” he says, “and I started leafing through the CAP PT catalog, honestly I was shocked that breast HER2 and ER were not CMS-regulated for proficiency testing. Of all the tests in pathology, results of predictive marker IHC have among the greatest clinical consequence.” A decade ago, he adds, the CAP made up for this gap by monitoring the breast biomarkers.
There is the view, Dr. Bellizzi says, that the art and science of medicine could be implicated in proficiency testing monitoring decisions, but he sees it differently. He points out that the IHC readout is part of the analytical phase of the test and whether a HER2 slide is zero or 1+, 2+, or 3+ should be an objective truth. “The result is not being spit out automatically like a chemistry test,” he says, but “when we’re reading predictive marker IHC, to some extent we’re functioning like a chemistry analyzer. There’s no room for personal opinion. What we’re targeting by proficiency testing for these predictive markers is the actual IHC protocol itself.”
Although Dr. Bellizzi describes himself as an “IHC guy,” he considers molecular and IHC techniques to be entirely complementary. “It depends on the specific diagnostic or predictive context. In some instances the molecular is the best. It’s inherently better at multiplexing so you’re able to assess more analytes simultaneously. Most IHC assays are singleplex or dualplex, while for one molecular test you might get 500 answers. But also, with the extraction, the testing, the computational stuff, and the analysis, the turnaround time may be a week or two weeks.”
IHC is fast, says Emily Meserve, MD, MPH, IHC Committee member and technical consultant for immunohistochemistry at NorDx Laboratories, Scarborough, Me., and staff pathologist for Spectrum Healthcare Partners at Maine Medical Center. “In most labs, you can get results within 24 hours,” and they can often be obtained in a few hours or half a day. “And in most cases the test can be interpreted pretty easily by a subspecialty pathologist or a general surgical pathologist.” The typical price for an IHC assay is in the hundreds of dollars while molecular can cost $1,000 or more, she adds, depending on how complex the assay is.
BRAF is a good example of a biomarker for which the decision to use IHC or a molecular assay is context dependent, Dr. Meserve says. “We have a mutation-specific IHC stain that only identifies a very specific mutation in the BRAF gene, but there are other mutations in the gene that are important to identify. So if the immunostain is positive, you’ve confirmed mutation, but if it’s negative, you haven’t fully examined BRAF so you may still need to do molecular. At this point, some labs say, ‘I don’t want to waste my time with the immunostain; I’m going to go straight to molecular.’”
When Dr. Meserve became an IHC Committee member last year, the discussion over requiring PT testing for the HER2 gastric and highly sensitive ALK lung biomarkers had already been underway for several years. She has found PT is important because it provides an opportunity to do an assessment outside one’s own laboratory. “I spend a lot of time counting ER-positive breast cancer cases and determining percent positives in my patient population, and I can compare that to published literature to see if I’m detecting about the right number. But a far superior method is to compare directly to the results of the same tumor tested at hundreds of laboratories across the country.”
In addition, requiring PT for highly sensitive ALK in NSCLC and for gastric HER2 “might help us realize there are more laboratories in a gray zone, that are actually doing pretty well except for certain situations, for which their assays may only need minor adjustment. And that’s better for everybody.”
Often, “you don’t know what you don’t know,” Dr. Meserve says. She cites one case study in which a laboratory performing ER by IHC encountered problems because its assay was not calibrated correctly. “PT is how labs find this out. They thought they were doing everything just fine until they started comparing their results to other labs.” But “the vast majority of labs in this country are doing the right things and the assays are performing very well. Major issues with assay performance are relatively infrequent.”
“What Dr. Bellizzi did in aggregating the data,” she says, “was point out that, yes, it’s a small number but it’s not zero. And patients will benefit if we address this.” CAP leaders agreed.
Just as therapy-related decisions are made for patients with breast cancer based on the results of ER and HER2, she notes, the same weight is put on gastric HER2 in patients with gastroesophageal adenocarcinoma and lung cancer when they have a mutation. “And we should make sure we’re monitoring these carefully, too, and holding laboratories to a high standard.”
This can sometimes be an issue, she says, based on the feeling that anatomic pathology is qualitative, not quantitative, and its values should not be assessed the same way as a quantitative test. “I agree there is an art and science involved in interpretation, but I fall on the side of thinking the standard is helpful and useful.” Her training in public health and epidemiology has tended to convince her that “at some point it is beneficial to regulate at a large level so that the care for everybody is at least at a minimum standard.”