A sizable shift in CNS tumor classification

Karen Titus

November 2021—Much has changed since the last WHO classification of central nervous system tumors was published five years ago.

Case in point: When the group of authors met in Utrecht, the Netherlands, in late 2019, everyone anticipated two more WHO meetings in Europe to work further on the 2021 classification.

Arie Perry, MD, a coauthor on both classifications, says the group photo was cheery. “Everybody was smiling.” The later trips to Europe were canceled because of the pandemic and the group met instead by Zoom. “Now everybody looked grumpy,” he says of a screen shot.

Fortunately, “We got everything done, even if it wasn’t quite as pleasant,” says Dr. Perry, professor of pathology and neurological surgery, Department of Pathology, Division of Neuropathology, University of California, San Francisco. The result is the latest WHO classification, which offers dramatic changes of its own.

“I’m really excited about the new WHO,” he says. “At first it takes a little getting used to”—like, say, a face mask—“but I think it’s another major advance, just like we had last time.”

“Last time” would be the 2016 classification, which itself was a decisive swerve, incorporating molecular methods into definitions in a substantive way. The impact on practices was substantive, too, says Dr. Perry. “It was major,” he says.

That set a high bar for change—one that the 2021 WHO classification managed to leap, a feat that surprised even Dr. Perry. “I didn’t think there would ever be another one that would shift things as much as the 2016 edition. But actually, I think this one, if anything, has shifted it even more.”

The authors have had to be nimble. Dr. Perry credits the role of cIMPACT-NOW, which was formed to keep up with changes in the field. Since new WHO classifications come out only every five to 10 years or so, the cIMPACT-NOW group published updates between more formal WHO updates, “so things wouldn’t be so overwhelming with one document all of a sudden.” Doing an interim review is unusual, he says. “But I hope other people start doing it, too.”

The group produced seven updates between WHO classifications, which enabled the 2021 classification to vault ahead. “I kind of joke that the ‘NOW’ stood for ‘not officially WHO,’” Dr. Perry says, though both groups comprised mostly the same members. “It was kind of a self-fulfilling prophecy that we would accept our own recommendations when the time came. And for the most part, of course, we did.” The interim recommendations have been incorporated into the newest WHO classification.

The evolution in classification, says another coauthor Daniel Brat, MD, PhD, “reflects the use of molecular approaches to establish a diagnosis and establish grading for brain tumors.” In 2007, molecular testing for brain tumors was more rumor than routine—the WHO did not incorporate it into diagnoses or classifications. “Basically all diagnoses were made under the microscope, based on morphology,” says Dr. Brat, the Magerstadt professor of pathology and chair, Department of Pathology, Northwestern University Feinberg School of Medicine.

That was the fourth edition; 2016 represented an updated version of the 2007 WHO, rather than a formal fifth edition. “The daily practice of neuro-oncology had changed so much,” Dr. Brat recalls. “We recognized that we really couldn’t wait until the fifth edition. There was so much data out there about the molecular classes of brain tumors that were critically relevant.”

The authors of the 2016 version added, for the first time, the integrated diagnoses that included both morphology and molecular features. The diffuse gliomas, as is their wont, led the way. Within that category, tumors could be identified by IDH mutation status, which launched the additions of IDH-mutant astrocytomas and the IDH-mutant 1p/19q-codeleted oligodendrogliomas—two major classes of IDH-mutant tumors—as well as the IDH-wildtype astrocytomas grades 2, 3, and 4.

Those changes are more than interesting historical footnotes—they light the way for the latest edition. “In 2021 we have gone further and said these aren’t just subtypes of one another,” Dr. Brat says. “These are really two different diseases.”

Previously, diffuse astrocytomas were called either IDH-mutant or IDH-wildtype, as were anaplastic astrocytoma and glioblastoma. That terminology implied the same disease, one with a mutation and one without.

“Now we’ve separated that out completely,” says Dr. Brat. “We call the IDH-mutant astrocytomas what they are, and we grade them 2 through 4. There’s no longer such a thing as glioblastoma IDH-mutant—there’s a strong desire to get away from that terminology.” Previously, a grade 2 tumor was called diffuse astrocytoma; a grade 3 was an anaplastic astrocytoma; grade 4, a glioblastoma. With the shift in nomenclature, all are now called astrocytoma IDH-mutant, with the grade given within that overall entity.

The authors also made a new reckoning of tumors that used to be graded as 2 and 3 IDH-wildtype gliomas. At the molecular level, these were essentially wildtype glioblastomas, and they all behaved very aggressively as truly grade 4 tumors, says Dr. Brat.

Glioblastoma diagnoses have also taken a big leap forward, he continues. For decades, pathologists have used the presence of necrosis and microvascular hyperplasia, seen under the microscope, to grade a diffuse IDH-wildtype glioma as a glioblastoma. Now they can make that same diagnosis absent those histologic features if the tumor has specific genetic alterations. TERT promoter mutations, EGFR gene amplification, and +7/-10 chromosome copy number changes are all criteria for a glioblastoma IDH-wildtype. “That’s a big change,” Dr. Brat says.

For IDH-mutant astrocytomas, the authors have also included a genetic alteration—CDKN2A/B homozygous deletion—that’s sufficient to call a grade 4.

In short, molecular alterations, used as classifiers in the past, are now starting to be used in grading as well.

The pleasures of naming, of classifying, stretch back to earliest man strolling through the introductory pages of Genesis. Adam didn’t last in Eden long enough to update his nomenclature, but the impulse persists whenever physicians ask: What are we looking at? What does it mean? What should we call this?

As with Adam’s labeling system, the WHO classification by its nature has a global reach. The latest iteration in particular, with its rethinking of diffuse gliomas, should bring change to most labs, says Dr. Perry, given that these are the type of CNS tumors pathologists deal with most regularly. In particular, the pediatric classification has changed quite dramatically.

Pathologists will also notice that some of the embryonal and soft tissue tumors reflect a fair amount of advances since the 2016 classification. Ditto meningiomas, another extremely common entity.

As for pediatric tumors: The big change is in the pediatric diffuse gliomas, where “there’s been a tremendous amount of improvement,” Dr. Brat says. (The most common high-grade brain tumor of childhood is medulloblastoma, and the molecular classes for those, used in the 2016 update, haven’t undergone any major changes in 2021.)

The adult IDH-wildtype diffuse gliomas are recognized as being very aggressive; in children, diffuse gliomas are rarely IDH-mutant. It might seem reasonable to call the pediatric diffuse gliomas IDH-wildtype, but they don’t uniformly behave aggressively so this terminology would be misleading, Dr. Brat says. Advances now allow pathologists to identify specific molecular or methylation signatures in these gliomas and to base a more specific diagnosis on the presence or absence of defining alterations.

Histone H3-mutant gliomas (found in the brain stem, and clinically called diffuse intrinsic pontine gliomas, or DIPGs) are now known to have H3 K27 mutations, almost uniformly, and behave quite aggressively. Likewise, tumors that occur in the cerebral hemispheres and are H3 altered will have a G34 mutation, Dr. Brat explains, and are also high grade.

Both of these are WHO entities. Methylation profiling has further uncovered additional tumor types, called pediatric-type diffuse high-grade glioma, pediatric-type diffuse low-grade glioma, and infant-type hemispheric glioma. Each of these has distinctive clinical, histologic, and molecular features that have led to their recognition and are used to establish their diagnosis.

“We’ve learned a lot,” says Dr. Brat.

Just as adult-type gliomas are now separated, so are the pediatric-type. “It’s another big change,” he says. Diffuse gliomas of adults that used to be recognized by the microscope and classified histologically are now identified as one of three types of entities: astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; and glioblastoma, IDH-wildtype. “In addition to the histone H3-mutant diffuse glioma, we now have pediatric-type diffuse low-grade gliomas, with multiple subtypes depending on the type of associated molecular alterations. Infant-type hemispheric gliomas are uncommon but have defining genetic alterations that separate them from other childhood brain tumors. And then we have pediatric-type diffuse high-grade gliomas, and there are multiple types of those as well,” Dr. Brat explains. “Within each of these broad clinical classes we can identify specific genetic or DNA methylation profiles that seem to correlate with clinical outcome.”

Precision pays off. “For diseases that were lumped together in the past and now are recognized as different, based on molecular testing, we’re doing a disservice to patients unless we do appropriate testing,” he says. “Correct care requires the correct diagnosis.”

And not just for certain patients, he insists. “That’s a reality we’re going to have to deal with in the future in one manner or another,” whether that involves providing equipment and training to developing countries or to smaller community-based hospitals within this country. The response can’t be two-tiered, he says.

“I don’t buy the argument that we don’t have enough resources,” Dr. Brat continues. If there are resources to perform neurosurgery and provide quality in-hospital and outpatient postsurgical care that might include radiation therapy and chemotherapy, then molecular testing or its appropriate surrogates “are a drop in the bucket. In fact, that’s the reason the biopsy is being done in the first place—to get the right diagnosis.” The latest WHO classification should help flip the switch, he hopes, and reinforce that message.

This is not a sleepy field. “No,” says Dr. Brat. “Not at all.”

Nor is this a time to catch one’s breath, he says. “Let me tell you about the next paradigm shift.”

That would be DNA methylation profiling. Dr. Brat calls it a kind of bioinformatics separation of tumors based on their methylation fingerprint. The method, advanced by the Heidelberg group in Germany, is now considered a gold standard in brain tumor classification.

When faced with a challenging case that eludes even molecular profiling, Dr. Brat and colleagues will send it out for methylation profiling, which identifies tumor type based on its methylation pattern. “It gives you a degree of certainty on that call.” In a field already bursting with advances, he says, “It’s a huge breakthrough.”

The technique looks at thousands of genes throughout the genome for a level of methylation. As Dr. Perry explains, “The patterns you get overall seem to be related to a level of histogenesis.” Whatever the cell of origin—and in most cases it’s unknown—it tends to have a unique methylation profile, which is likely maintained in the tumors that arise from that cell, including some of the very high-grade or poorly differentiated tumors, he continues. Algorithms have learned to separate these tumors from one another.

It’s a powerful technique, Dr. Perry says, in neuropathology as well as in bone and soft tissue pathology. He predicts it will establish a role for itself in all other subspecialties eventually.

More breakthroughs should follow. Methylation profiling is specific for a given type of brain tumor. Once a methylation profile is identified, that tumor group will almost always have a defining genetic alteration and a fairly standard clinical course. This diagnostic path has given rise to many of the new entities recognized in the WHO 2021 classification. It represents a new wave in diagnostics. “And it’s going to be with us in the future,” says Dr. Brat. In some cases, it’s already here: The WHO classification has incorporated methylation profiling into some diagnoses, including it as a “desirable criteria.” (The other category is “essential criteria.”) In the next WHO classification, he predicts, methylation profiling will be one of the methods for establishing a primary diagnosis.

Dr. Brat estimates that only three or four centers in the country do methylation profiling. “So you can imagine that if there were serious considerations about inequality of technology for the 2016 edition, if we incorporate methylation profiling into classification, it’s going to be even more problematic.” Even many academic medical centers will find it out of reach, at least in the short term. At Dr. Perry’s lab, “We have it available for research, but we haven’t quite gotten to the point where we can do it for clinical testing.” When they need it clinically, they turn to the NIH. “They’re doing it right now free of charge. Free is always good news,” he says with a laugh.

Access is only one concern. “Once you add a new platform, it opens up all new types of applications, investigations, and practices,” Dr. Brat says.