A sizable shift in CNS tumor classification

He calls DNA methylation profiling a disrupter. Perhaps mindful that medicine has already had plenty of those recently, he hastens to add, “But I mean that in a positive way. Because if you think about patient care coming first, methylation profiling is probably the most accurate predictor of a specific tumor type. And that goes along with prognosis in general.”

Having said that, however, Dr. Brat notes that methylation profiling is not always adept at grading. The future, he says, will combine many steps: microscopy, NGS, other molecular profiling, and the gradual incorporation of methylation profiling into pathology practice. His own lab does perform the latter, and was about to go live with it diagnostically when he spoke to CAP TODAY in late September. And some tumor types are still primarily diagnosed purely on morphology, including the most common one, meningiomas, especially for grade 1.

The open-ended role for morphology will be a relief to some, given that practices change at different rates. In his own consult service, Dr. Perry sees the gamut—highly experienced neuropathologists, large private practice groups, and smaller private practice groups “that maybe take a little longer to implement changes.”

For the most part, he says, adopting the molecular definitions set out in the 2016 document went smoothly. “People learn along the way,” he says, adding that he tries to educate colleagues while explaining how he arrives at his diagnoses. “It takes time for everybody. We don’t automatically, the next day, implement everything that’s in the WHO.”

Even with basic nomenclature changes that seem minor at first, says Dr. Perry, “It takes everyone a little time to get used to it. Whenever you change the name of something it causes confusion,” as anyone who works for an oft-rebranded medical system knows.

The challenges can also be financial. As he works on consults, Dr. Perry says part of the education he does includes recommending adding, for example, NGS to a case, explaining why, and asking for permission.

That leads to the practical matter of billing. “I try not to assume anything,” Dr. Perry says. Some practices want his lab to bill insurers (including Medicare); others prefer to have him bill the practice. It’s not a scientific matter, “but it’s a practical issue nonetheless. Certainly with the more expensive tests, I try to make sure they’re OK with the billing before I go ahead and run them.”

Worth noting is that third-party payers don’t change overnight, either. They, too, need time to catch up to new classifications, and to understand the cost-benefits of even NGS, not to mention DNA methylation. It’s a long game, although the new classification should bump things forward a bit. “I hope so,” Dr. Perry says.

He takes up the perpetual choric: Payers too often eye the costs of specific tests for specific patients. “But you really have to factor in the global cost of giving the wrong therapy due to the wrong diagnosis or a less accurate diagnosis.” While $3,000 to $4,000 for an NGS assay sounds like a lot of money upfront, it’s not, he says, when compared with the costs of multiple neuroimaging studies, surgery, anesthesia, radiotherapy, and chemotherapies.

How will these freshly sharpened classifications shape the conversations between patients, their physicians, and those in the laboratory?

The new classification of pediatric diffuse gliomas aids clinical colleagues greatly, says Dr. Perry, even absent targeted therapies. “Pediatric oncologists really appreciate that, because they’ve known for many years even though we were calling many of these by criteria for adults, they’re quite different for children.”

Moreover, Dr. Brat says, additional mutations, deletions, or amplifications may provide additional prognostic information. The aforementioned CDKN2A/B homozygous deletion indicates that an IDH-mutant astrocytoma that was thought to be grade 2 is actually going to behave in grade 4 fashion. Similarly, if it’s IDH-wildtype and looks histologically grade 2 or 3 but has an EGFR amplification, it too will behave in a more aggressive fashion.

Dr. Perry calls his laboratory colleagues “lucky, because in our field, we’re making discoveries fairly quickly. We’re learning how a tumor forms and how it progresses.” For oncologists, it’s true that the conversation sputters a bit as researchers try to translate that knowledge into targeted therapies. Nevertheless, knowing about a unique genetic fusion that can be targeted or that drives a tumor is helpful. “Absolutely,” he says, given that it can help determine prognosis as well as help physicians sort through available therapies.

Are therapeutics keeping pace with diagnostics? “I wish they were,” says Dr. Brat. “It is a conundrum in this field that we probably have the most potential targets for therapy, but the actual targeting of them has been more challenging in the brain than in other organs.” For example, EGFR amplifications are present in over half of IDH-wildtype glioblastomas, but targeted therapeutics have failed in clinical trials. Likewise, the finding of angiogenesis in glioblastoma raised the possibility of targeting the VEGF pathway, but those efforts came to an unsatisfying ending as well. And immunotherapy, a success in other organ systems, hasn’t provided clear outcomes in brain tumors.

“So,” says Dr. Brat, “we’ve got a lot of work to do. But if I can tell you one thing about the brain tumor community, it’s that we work very well together as a team collaboratively across the world to uncover new targets and potential therapies, and do the clinical trials together.” Since these tumors aren’t as common as breast, lung, or prostate cancer, “We really need multi-institutional, sometimes multinational approaches to clinical trials.“

People are still getting used to categories that were a prominent feature of the previous classification, Dr. Perry says, including NOS. “Some people use it a lot, and others don’t.” He suspects oncologists find it useful; it usually indicates that molecular testing was not done, and therefore the diagnosis was rendered purely on morphology.

Some, however, are reluctant to use the NOS designation. “I’ve noticed some groups—those that maybe don’t have a lot of resources—feel a little resentful of having to put NOS on there,” Dr. Perry says.

That ties into a common question Dr. Perry gets: “Can they get away with doing immunohistochemistry?” To give an example, several tumors are now defined as being a higher grade if there’s homozygous CDKN2A deletion. Given that the protein product for that is p16, will IHC for p16 suffice? In most cases, Dr. Perry says, the answer is likely no—IHC alone provides some information, but it’s not good enough to replace the more sophisticated molecular techniques. “There are still many, many diagnoses that are diagnosed by morphology alone. Fortunately, we do have a lot of good surrogate markers,” Dr. Perry says. But p16 isn’t one of them.

Dr. Brat suggests the NOS category will eventually fade as molecular testing lands in more hands.

While the 2016 classification discussed the problem of interobserver variations, that problem, too, is becoming diminished, for the same reason. “The molecular classes are actually very tight,” Dr. Brat says, adding, “What I tell our neuro-oncologists and neurosurgeons is, ‘Our diagnostic accuracy and our consistency among neuropathologists has gone up dramatically.’”

That’s the good news. “The bad news: ‘It’s going to take two weeks to get your diagnosis.’”

For now, at least, that time frame is likely acceptable, Dr. Brat says, given that labs provide results in a stepwise fashion. IHC, with its next-day TATs, will generally allow pathologists to put tumors in the correct category of neoplasm, giving clinicians a diagnosis they can work with until the molecular profile is available.

Ultimately, he says, the goal is to identify tumors based on methylation profiling or NGS. “But then to identify more user-friendly and cost-efficient ways to establish the diagnosis, potentially by FISH or by immunohistochemistry, so that it, number one, isn’t as costly, and, number two, doesn’t take as much time to achieve a final diagnosis.”

Dr. Perry is often asked which testing modalities are best. Not surprisingly, the answer is complicated.

Some guidance will come from a new CAP guideline that “dovetails nicely” with the WHO classification, says Dr. Brat. While the WHO classification makes a major change in what to call diffuse gliomas, the guideline shows how to test for them. It was done in collaboration with the American Association of Neuropathologists, Association for Molecular Pathology, and Society for Neuro-Oncology.

The focus is narrow but nevertheless “is a significant subset—diffuse gliomas are potentially the most important subset within the WHO,” says Dr. Brat, who is the guideline’s lead author. “The WHO provides classes and grades of neoplasm. It is agnostic on how you get there in terms of testing. So the guideline provides guidance to practitioners on how to do the biomarker testing, and what the test results imply, and the strength of evidence for that testing.” The guideline has been accepted for publication in Archives of Pathology & Laboratory Medicine.

Seeing how much the brain tumor classification systems have changed, says Dr. Brat, “The CAP recognized there would be a need for guidance around the diagnostic testing of diffuse gliomas as a family.” He and others on the expert panel (Dr. Perry is a coauthor) put together 10 guidelines and three practice statements as the basis for a diagnostic testing algorithm for community practice pathologists. When testing is as complex as it is for diffuse gliomas, it may seem straightforward only to those at academic medical centers who closely follow the evolution of classifications. “But for those who don’t have that historical grasp, it may seem like just a tremendous amount of unorganized diagnoses,” Dr. Brat concedes.

That would be where the flow chart comes in, he says. “It starts off with IDH testing, and then it branches into IDH-mutant gliomas and IDH-wildtype gliomas, and then within the IDH-wildtype gliomas it branches into age groups, locations, and it works through the diagnostic test results that end up in the WHO classification at the end.”

A certain coziness comes into play as experts develop guidance for their colleagues. With the added cIMPACT-NOW interludes, the latest WHO iteration brought few genuine shockers, apart, perhaps, from having to transfer the process to Zoom meetings.

Nevertheless, Dr. Perry says, “I’m always surprised that there’s always some controversial issue, or some questions for which there’s not quite enough data. And therefore people argue about which way they think we should go.” In most cases, he says, the answer is likely: Don’t go too far until we know more.

This isn’t unique to neuropathologists, he suspects. “Whenever you have experts around the world, all of us have strong opinions. And,” he laughs, “they’re not always the same opinions.”

A reasonable consensus does emerge eventually, he says. “And then, hopefully we get smarter again by the next WHO.”

Dr. Brat agrees. Putting together a brain tumor classification with a group of 12 internationally recognized neuropathologists is, he says, “often a discussion. It’s acknowledging we are on a journey and this isn’t the last classification that will be used. It’s really meant to be put in place as kind of a guidepost during our evolution to guide clinical care, to the best extent we can, at this point in time. I can guarantee you that the next classification of brain tumors will have evolved from the 2021.”

It always remains to be seen, for instance, how well a new classification of tumors will stand the test of time, especially if it’s based on morphology. Perhaps researchers will find a genetic subtype, or a methylation profile that provides additional information. “Until the 2016 classification, we didn’t incorporate genetic alterations at all into our classification,” says Dr. Brat, noting that just five years later, half of the brain tumor entities have essentially a requirement of molecular profiling to make the diagnosis.

Dr. Brat calls it an evolution, while noting, “We’ve come a long way in a short period of time.” They have a long way to go as well.

In the meantime, the only thing standing still might be the experts themselves. Dr. Perry says he used to travel 100,000-plus miles a year. “Now I’m a homebody. I don’t go anywhere.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.

The 2021 fifth edition classification is due tentatively to be published online in November, with print to follow.