Transcription:
Evolution in Meningioma Classification and Management

Andrew Wilner, MD (Host): This is Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner, Associate Professor of Neurology at the University of Tennessee Health Science Center and Division Director of Neurology at Regional One Health in Memphis, Tennessee.

Today we are discussing brain tumor research and treatment with Dr. Stephen Magill, Assistant Professor of Neurological Surgery at Northwestern Medicine. Dr. Magill specializes in Surgical Neuro-Oncology and his research focuses on meningioma biology and patient outcomes. Welcome Dr. Magill.

Stephen Magill, MD, PhD (Guest): Thank you for having me.

Host: Dr. Magill, I'm a Clinical Neurologist and the first sign of a meningioma in my patients is often an epileptic seizure. I have to figure out how to treat the seizures and the meningioma. I've learned that meningiomas can be classified into three grades. Can you talk us through this diagnostic process, the three different grades and the implications for the patient?

Dr. Magill: Yeah, absolutely. Meningiomas are the most common primary intracranial tumor. So, when someone like you is in practice and you encounter a patient with one, oftentimes if it's a seizure, they come through neurology or the emergency room if it's a first time seizure. Other times, family doctors, and internists may see it when they have a patient who just has a progressive headache that won't go away or other neurological deficit from compression of adjacent structures by the meningioma as it grows. And the growth of meningiomas in general, is slow relative to cancers that we're familiar with, like lung or breast that are very common, grow quickly and you have symptoms come on over a period of you know, maybe a couple of weeks. For meningiomas, they're classically thought of as benign tumors, although not all meningiomas are benign and they're thought that way, because they don't typically metastasize outside of the central nervous system and because of their slow growth, you may have insidious onset of symptoms over many years. Because of that, they can grow quite large in size. Oftentimes I'll see patients who have a six or seven centimeter meningioma, which is taking up a significant portion of their intracranial space and they had no idea until they have a seizure or start to lose vision if it's near the optic nerve or have hearing or balance problems. Just depending on where it is, the symptoms can be anything. So once we get pathology from the tissue, we take it out surgically; we classify meningiomas into three grades; grade I, grade II, and grade III.

Grade I are your classical meningioma, they account for about 80% of all meningiomas that we'll encounter in practice and are generally very slow growing. When we follow them with observation, you may see growth of if you're growing a couple millimeters a year, that's considered radiographic growth. So, millimeters over a course of years, grows a centimeter or two over the course of a decade. So a much slower process than an aggressive cancer. And a grade II, which is the other 20 to 25%, depending on the study, they tend to grow a little faster. So they may grow a centimeter over six months or a centimeter over a year. And when we see that, we're worried about a faster growing tumor and, what that all means is that when we take them out, when you treat them with surgery or with radiation, a grade II is more likely to recur or to progress despite treatment.

So you take it all out. A grade I meningioma at 25 years, about 75% will not recur or more. A grade II meningioma may have a 25 to 30% recurrence rate at five years. So these are things that considering, the typical age of onset is about 65, 66 years old, if you make it 25 years most patients aren't going to have a problem. So, surgery can often be essentially curative for those patients. But if it's a grade II meningioma and it comes back in four or five years, in three years, all of a sudden now you have this tumor, that's a little more difficult to deal with.

The grade II tumors also tend to happen more commonly in young folks. So people in their thirties, forties, things like that. And meningiomas are much more common in women, but, that's predominantly the low grade, the grade I's. Grade II meningiomas are actually about a 50-50 split between men and women.

So when you see a young man with a meningioma, they have almost a 30% chance that it's grade II. Grade III meningiomas I will just mention for a second here. They are the most aggressive. They are actually much more like a cancer. Closer to a sarcoma than they would be to a meningioma in their behavior. They grow aggressively. They invade through structures. You take them out, they come back within a year or two. They're a really difficult tumor to treat, but thankfully they're only about 1%, maybe one to 3%, depending on the study, of all meningiomas. So they're relatively rare.

Host: Oh, well, thanks for that. That reminded me of some of the facts I'd learned in medical school, plus some new ones. So very, very helpful. Now we call meningiomas brain tumors, but I guess the name meninges they're really not brain tumors in that sense, I guess. And then the biology sounds different. These grade II and III sound like a whole different animal. you talk a little bit about that?

Dr. Magill: Yeah. I think that's a wonderful thought because as all of us clinicians know when you see tumors behaving differently, even though they may all have the same name, you realize that there's probably biological differences that are driving these behaviors that we see. Whether it's more rapid growth, shorter time to recurrence, refractory growth despite radiation and surgery. So, the biology of these tumors, is quite interesting and classically we knew there was an NF2 mutation loss of chromosome 22. You get a lot of meningiomas in neurofibromatosis type 2. We know that, but in the last 10 to 15 years, there has been an explosion in papers really last eight or nine years of exploring the biology. In particular, this has been driven, by sequencing based approaches and we've identified different subsets of meningiomas that are characterized by certain gene mutations outside, of NF2. More recently, we are beginning to incorporate some of the molecular findings, both from DNA methylation profiling, looking at the whole epigenetic state of each different grade, as well as specific gene mutations or gene losses that really affect behavior. In fact, in the World Health Organization's New Central Nervous System grading scale, that came out in late 2021; they have now incorporated certain mutations. One is a TERT promoter mutation, and another is a homozygous loss of a cell cycle gene called, CDKN2A or B. And that are actually, if you have those genetic changes it now warrants a grade III diagnosis, which we didn't know before.

Getting back to your question about these tumors also are they a brain tumor or not. You mentioned that you are correct, that they arise from the meninges, from the coverings of the brain. And that's why, when we say they're the most common tumor, it's actually most common central nervous system tumor. So they grow typically from inside the skull and then grow from the lining of the skull, the dura matter that covers the brain and compress the brain.

The higher grades, like, grades II and grade III can actually invade into the brain tissue. They're not as infiltrative as something like a glioma, but they do invade into the brain. And there are also certain flavors of meningiomas that drive bone growth. So even though they start in the meninges on the surface of the brain, they actually grow out into the bone, most commonly around the orbit, but they can do it any of the bones of the skull they can infiltrate through. I took one out week ago that had a big component that was just under the scalp and on top of the skull, then it was growing through the skull and then had a large component pushing the brain. So they grow from outside of the brain and specific gene mutations are reflecting different biological behaviors and actually being incorporated into our World Health Organization grading for them.

Host: Clarify something for me. We talk about grade I, II and III. Now in the old days, all of the pathological classifications were based on histology and staining and what you saw under the microscope. Now, the grade I, II and III that we're talking about here, is that classification through the microscope or are we actually using the genes and the gene deletions that you to make the classification?

Dr. Magill: Yeah, that's a great question. You're cutting right to the very edge of the forefront of medicine right now, and meningioma is right there, along with many other cancers. But when we look at meningioma under the microscope, it's actually a very beautiful tumor on H and E stain in classic histopathology, what you see under the microscope. And if you just look at the histopathological variation, there's an incredible array of patterns. There's a couple histopathology criteria that can lead you to a grade II or grade III, but that's a relatively small portion. There's actually, I think it's like 14 different subtypes of histopathological appearance of meningioma and only two or three are related to being higher grade.

And one of the dilemmas within meningioma care is exactly this, that we would see something that under the microscope looks like a grade I meningioma. The other thing you look for to say hey, is it higher grade, is the number of cells that are dividing. So the number of mitotic figures that the pathologist can count. But what we knew as clinicians, is there would be some of these patients that would have a grade I meningioma, but it was an aggressive tumor, invading through the bone and compressing the brain, recurring after surgery, growing through radiation, and you're just like, this is labeled a grade I. And when you look at the pictures, it's a grade I, but it's not behaving like one.

And that's really where some of the latest research is being translated into the clinic. And what we're finding is that if you look at the methylation profile of these tumors, you can actually see there's three subsets of methylation profiles, reflecting kind of the global state of the nucleus of the cell, there is some correlation with WHO grade, but not complete. And we find tumors that look benign on a histopathological analysis like a WHO grade I tumor; and when you look at their genetic, profile or their DNA methylation profile, they actually have a very aggressive pattern. These are cells with there's more cell division within it. There's upregulation of the cell cycle. And these tumors are ones that when we look at how they've behave, in retrospective studies, we can look back at the pathology and say, you know, if you look at that methylation profile, that patient had a much more aggressive course, than you would have expected from having a grade I tumor. So this is things that this methylation profiling is something that we do at Northwestern. Our Neuro Pathology colleagues led by Craig Horbinski can accept outside consultations and do the methylation profiling.

And I have a paper, actually, along with my colleagues at UCSF that is coming out. It's in press at Nature Genetics, where we have defined three methylation based classes of meningioma that much more accurately predict recurrence, which is a surrogate of the aggressiveness of the tumor, how fast it's going to come back. And we validated that in an external international cohort and are working to validate it here in our samples at Northwestern, and really trying to bring this into prime time.

And I think in the next three to five years, the things that we're doing right now routinely on all of our samples here at Northwestern, will be starting to be incorporated in things like the NCCN Guidelines and Cancer Treatment Guidelines for meningioma, because they capture a much better picture of the biological state of the tumor compared to standard histopathology imaging.

Host: That sounds a like terrific example of real bench to bedside research that's helping patients. Just to sort of put all that together, at Northwestern, say a patient comes in, they're referred, they have a meningioma; how do the neurologists, the neurosurgeons, the neuropathologist, how do they all work together to make sure that the patient really gets the optimal care that's possible?

Dr. Magill: It's one of the most fun things as part of my job because it's the multidisciplinary collaborations that really allow us to provide cutting edge care for our patients. And I have two examples, that come to mind. I had two patients about three or four months ago, six months ago, they came in very similar timeframe and both had a very large convexity meningioma. One was five centimeters, one was six centimeters. It was compressing the brain. Both presented with a seizure, previously healthy, normal, functioning people, no idea they had these big tumors in their heads. Imaging, both looked like grade II meningioma. So when a patient presents clearly when you have symptoms, seizures, neurological deficits from these tumors, the first step is to remove the tumor. So on the convexity, we can get a total resection which I was able to do for both patients. Both had a good, smooth post-operative course. And then that's really at the point that the multidisciplinary team kicks in. So, we have epilepsy specialists, and both these patients had seizures. So of course, we start them on antiepileptic medication. But then the epileptologists, follow them and will work to taper off the medications and see if we can help them come off anti-epileptics and have no more seizures, which happens around 65% of the time in patients with meningioma once you remove it. Once the patient is recovering from surgery, the tissue goes to pathology and there I work with Dr. Horbinski very closely, who's the Head of our Neuro Pathology Department. And we are doing DNA methylation profiling, next-generation sequencing panels, looking at a host of 500 some different cancer genes.

Out of this, we get a copy number profile for the tumor, and then I can take that methylation profile, and put it into our algorithms that we've discovered that are just coming out now. And it tells us what is the biological state of these tumors? And it was very interesting because one patient was a man. One was a woman and the gentlemen, his tumor was very aggresive. It had activation of the cell cycle, it had chromosome gains and losses that we know are associated with a high risk of recurrence. The lady who had almost the same tumor, same presentation, both on H and E staining were WHO grade II meningiomas. Her methylation profile and copy number profile showed that the tumor actually is a much more benign tumor. It had grown like this, but it was, not biologically as aggressive. So when these patients come here, we then present them at our tumor board. Now we have this molecular information. We know, even though the histology says it's the same tumor, WHO grade II meningioma, the question is, do you radiate or not? And if you have a big cavity from a six centimeter tumor, that amount of radiation even with conformal radiotherapy is not something that you jump into trivially for a patient. And, when I looked at both tumors, we said, you know, hey, this one, there's clinical equipoise.

We actually have a clinical trial here where one of the sites for a randomized trial for radiation, for grade II meningiomas cause it's not known whether radiation is helpful or not, or who should it be used in. These patients weren't interested in participating in that. And so for the gentleman, we chose to go forward with radiation because he had such an aggressive looking copy number profile and methylation profile, and the lady, with a much more benign profile, we're electing to observe. And I think this is a great example of how what we're learning about the biology of the tumor, what we at Northwestern are able to apply to the tumor is actually impacting the clinical recommendations and patient choices that they choose to do in an area where we don't know the answer. I think that the future of this will be biomarker guided clinical trials, but we have very few of them in meningioma right now. So I think this is a great way that that team comes together, we present them at tumor board, discuss it and then make those decisions or recommendations.

And the patients ultimately decide how they'd like to proceed. But that's one of the ways and I think a nice example of how we're seeing this new information transform what we do for patients.

Host: for that Dr. Magill, that really thorough and I can see the process. That sounds fantastic. Running time. Is there anything else you'd like to add?

Dr. Magill: One other exciting things, in addition to having a multidisciplinary team and everything is some of the developments that we're using in imaging to help guide surgery and to give a short example here, we had gentleman, a young man, in his fifties who had had two prior surgeries for a meningioma, fully fractionated radiation.

He'd had a recurrence and they'd done a radiosurgery boost to it. And the tumor started to come back. And it had actually occluded his sagittal sinus at this point, which gave us the opportunity to get a more complete resection, than they had ever done before. Take the bone out. Take a wide, margin of the dura and everything like that.

But when you see a situation with a lot of scar tissue, it's often hard to know on a scan, is this just scar tissue and post-surgical changes or is this tumor. And one of the unique things about meningiomas is they express somatostatin receptors and we can use a specific PET tracer called dotatate which is a PET tracer that binds to the somatostatin receptor. And that actually showed us which parts of the tumor were active and had active meningioma in it. So when we planned our surgery, we could take out the bone. We designed a custom cranioplasty where the bone was. So he had a great cosmetic outcome, but we could actually design the surgery based off these novel PET tracers to totally resect the tumor in a patient whose tumor really was getting to that end, where there's really no medical therapy options. There are some clinical trials. We have about four different clinical trials open for meningioma at Northwestern, but this was kind of his last shot, surgically. And so I think by incorporating these novel PET based imaging biomarkers, we actually are able to tailor our surgery more to the active biological part of the tumor, and maybe take a wider margin or in some areas, a narrower margin, because we know there's not active tumor there.So that's an area where not only are we pushing in the medical treatments, with clinical trials in the diagnostic treatments with our neuropathology, but actually trying to bring in adjuvants to help plan and prepare. So when we do go through surgery with the patient, we take them there. We do the absolute best job that we can and get as complete resection of all the biologically active tissue. And I think that's actually helping us. I think, in the long-term we will see that that will be associated with reduced rates of recurrence as we've shown for complete resections when we didn't have that information. But in these situations, it's very difficult to know what is tumor and what is not. So it's an exciting area that's an adjunct and, as a neurosurgeon, I'm always excited about the ways we can make surgery better. So I'm excited about that.

Host: Well, it sounds like you really have a great combination of neuro specialists there that work together at Northwestern to help the patients, just do as good as is humanly possible with their brain tumors. That's terrific.

Dr. Magill: We have Neuro-Oncologists, the Neurologists doing epilepsy, we have the Neuropathologists, radiation oncologists, and myself who all work just hand in hand, really trying to provide the best possible care for these patients. And I think it makes a difference and I see that in our patient's lives. I see it in our scans, you know, when we have excellent outcomes and also in the patients who have kind of failed all the normal there's a standard of care. So it's an exciting time.

Host: Dr. Magill, I want to thank you for this very informative discussion and for joining me on Better Edge.

Dr. Magill: Thank you.

Host: To refer your patient or for more information, head on over to our website at breakthroughsforphysicians.nm.org/neuro to get connected with one of our providers. And that wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Thank you for listening.