Dr. Link's a man of many talents. Thank you very much. Well, it's a real honor to be asked to be here. And I'm going to follow up several, both Dr. Gentile and Manish both alluded to, and Mike just now, Dr. Link, that the actual nuances of our pathology are changing rapidly. And I'm going to expand upon that when we, in the meningioma realm. We're really in the midst of a real reappraisal of how we think about meningioma. And I'm excited to share some of that work with you. Okay, so we'll review evolving concepts and understanding meningioma. My interest in meningioma, really, I trained at the Brigham and then I went on to work with Professor Al-Mefti, and I have always been fascinated by it as a tumor, but we're really in the midst, as I mentioned, of this incredible revolution of how we conceptualize this tumor. And because it's the most common primary brain tumor, everybody in this room is going to be struck by this work in the next few years as likely the World Health Organization begins to adopt some of this and how we think about these tumors. And if you haven't read this and you have a lot of free time on your hands, go back and look at Cushing's work from 1938 where he canonized that term. It's as relevant today as it was in 1938. I don't know if anyone recognizes what this is, this is an introduction for tonight's episode, but the meningioma really has many faces, and we know anyone who's operated on many meningiomas understands that really no grade one tumor is alike, no grade two tumors are alike. And we know that this is a real heterogeneous group of tumors. And once again, I would acknowledge the work that Dr. DeMonte and Dr. Gentile's group and others have done in changing our understanding of these tumors. I want to touch on some nuance of the WHO criteria and incorporation of novel biologic information and how we can both think about tumor behavior, but also think about treatment implications. So those two concepts. This information helps us understand how they behave, and it helps provide additional armamentarium for therapeutic targeting. So historically, you know, for many years our main thoughts on meningioma really revolved around surgery, which they still do, but we know there's more to it. So it was the science really revolved around extended resection, and the more you removed the better the patient did. And along came, as you know, the WHO meningioma classification, and it's been very helpful in helping us understand how tumors behave. I would cite a very recent publication, which is fascinating, in which they use, the authors use radiocarbon dating, the same thing you'd use in fossils. And so it's showing that the average grade two meningioma has been present in a patient for less than a few years and your average grade one for over 15 years. But it really is an imperfect system to classify these tumors, and I think you would all agree with that. So for instance, if you just look at the criteria that create a grade two or a grade one, you'll see to be grade two you can have as few as 14 mitoses and as many as 19. So can those tumors really be the same? Can a tumor with four really behave similarly to one that has 15 or greater than that? And does having three typical features, is that the same thing as having five atypical features? You'll look back to grade one even, and so does having zero mitotic figures present in a high-priority field, does that equate to having three and having zero or two atypical features? And you have to just assume or infer, and I'll show a little bit of data supporting this, that these are likely multi-factorial groups of tumors embedded within groups. There's no accounting for proliferative index in the World Health Organization classification scheme, and there's a developing sort of subgroup of tumors, a grade 1.5 or grade one with atypical features that's emerging, that really acknowledges just this concept, that is that you're not abnormal enough to be a grade 2, but you're not a standard grade 1. And Helen Shee from Mass General has really written quite a bit about this, showing the increased likelihood of recurrence if you have atypical features within being a grade 1, and that it's predictive in a multivariate analysis, as is elevated MIV-1, and a subtotal resection in predicting recurrence. So how much you incorporate that information as a neurosurgeon, your patients will ask, I just moved to Oklahoma City, they do it there too, so if they're doing it in Oklahoma City, they're doing it where you are, they're asking for the pathology reports, they're asking you what that means, and, you know, you really have to understand that. So it is a predictive factor that governs, that can portend an increased risk of recurrence. We just talked about mitotic index, if you just look at that alone, this is work from Toronto a few years ago, across all grades, mitotic index alone is predictive of recurrence, and so this group where you have 4 to 19 mitoses, obviously you can understand that that is really a blunt instrument in grouping them in that way. Other biologic considerations that have been, that have dominated the field of meningioma biology really has, have been governed by the female predominance of the grade 1 tumor, which is the most common variant, and so, and I'm sure some of the audience have read or been part of some of this literature, thus emerged a really robust literature about steroid receptors. Estrogen, progesterone, androgen, there must be something to the female predominance or the increase in growth, growth where you see during, during periods of hormonal alteration in female patients, and that culminated in hormone antagonist therapy, which is largely unsuccessful, but we'll come back to this. As is many things in our field, what is old sometimes is new again, and we'll revisit that in a minute. So really layered on top of thinking about grade and these other features we just discussed, MIB1, atypical features, mitoses, are some newer ways to interrogate meningioma that, again, really have two main reasons to be interested in them as neurosurgeons here in the audience. Number one, to predict how they might recur and what their behavior may be, to learn more about the tumor, and two, could they provide targets for therapy. The other thing I would say is that, you know, as neurosurgeons, if we don't, if we don't sort of understand these and grasp and embrace these concepts, I think you'll see that other fields will begin to move into this, as it's already happening, move into the meningioma space and occupy that and fill that void. So really what we're seeing now is a World Health Organization classification scheme which is being complemented by the annotation of those grades with specific molecular features, and I want to go through some of these in turn. So the idea that meningiomas have a chromosomal complement that's different from a normal cell has been studied for some time. It's just much easier to get that information and obtain that information now. So your standard grade 1 meningioma, block that red figure out for a minute, has just a loss of chromosome 22. That's your standard grade 1 molecular profile and a chromosomal complement. Interestingly though, it has, again, predictive behavior. So we and others have looked at grade 1 meningiomas. We have access to a robust tumor bank that had gone on to recur, and I know maybe in your practice, no grade 1s ever recur, but it does happen in some situations, and if you go back and look at the initially resected specimen and look at chromosomal alterations, it does predict the ones that had gone on to recur are quite different than the ones that did not recur in terms of the chromosomal alteration profile. If you look at grade 2 and grade 3 meningiomas, not unexpectedly, the more aggressive the tumor, the more irregular or disturbed the chromosomal profile. So red means gain and blue means loss. You can see with grade 2 and 3 increasing spectrum and incidence of regions of chromosomal alteration. A radiation oncologist that I formerly worked with, I think, performed a powerful study looking at number of chromosomal alterations just across all grades of meningioma, and interestingly, independent of extent of resection, which we counsel patients as a really powerful predictor of recurrence, and grade, which we also counsel as a really important predictor of recurrence, just the number of chromosomal alterations alone is a powerful predictor of your risk of recurrence. So there's something about that underlying chromosomal complement that says something about tumor behavior, and what the relationship is between your standard, what we standardly receive from our pathologists and a deeper level of information, it's an imperfect correlation. We and others have looked at this across a number of tumors. So if you look at just histology, again, what we would get standardly in our practices, grade 1, grade 2, grade 3, and so forth, and then look at the corresponding molecular or chromosomal profile, the way it aligns, it correlates with a degree of correlation, but there's really strong but imperfect correlation between what a pathologist provides to us standardly and what you might find if you look a little farther beneath. And again, Dr. Link mentioned this, we all have these tumors that behave inappropriately, and you wonder if markers like these are predictors of why tumors sometimes don't behave the way that we expect them to. This is a pathology report I got before I left my old institution, but we're beginning to get these integrated pathology reports. So you get some grade information, then you may get layered on top of that if the pathologist has access to the information and additional chromosomal profile. So this is actually grade 1 tumor, and then looking a little deeper, this patient had additional chromosomal alterations, so they integrated that and called it a grade 2. So that's really important information that we could have access to. Again, it likely will suggest and lead to grade 1s that have more aggressive-looking profiles and perhaps grade 2s that will have more benign-looking profiles. So how could you use that information? We're in the midst, as well as others have mentioned at this meeting, of trying to understand the role of radiation specifically in the completely resected grade 2 tumor, and I'll highlight the RTOG and this randomized trial that's ongoing now, BN003. So even though most practices are radiating completely resected atypical meningiomas, and I say that because I've moved to a new location, and it is just standard practice in many parts of the country to do that, we know that that's perhaps not always the right thing to do, and you could perhaps use additional biologic pieces of information like chromosomal profile to help think about who to radiate or not. So I'm going to show a couple examples really dominated by patients that just refused radiation, but this is a 40-year-old man who had a tuberculin meningioma and completely resected, and it was an atypical meningioma, a little bit of a strange location for an atypical meningioma. MIB1 is 2%. Patient refused meningioma. We happened to profile him, and he had monosomy of 22. That's the same profile you'd have with a grade 1 meningioma. So he wasn't going to have radiation anyway. He'd gone on to be recurrence-free for as long as I followed him, which was two years before I left. On the other hand, this is a younger gentleman with an atypical meningioma, complete resection, 7%, MIB1, and you would be more concerned about this tumor based on some of the information we just discussed. So 1P deletion, 14Q, 22, and that's a patient that was agnostic about the choice of radiation, followed a recommendation, which is a little more common in Oklahoma City than it is in Boston, that you would just submit to what the surgeon recommends, but that's somebody who I think would be a high-risk tumor for recurrence, and this is another example of that. But overall, increased chromosomal changes seen in your first resection suggest more aggressive tumors, specifically the complement of 1, 14, and 22 lost together in atypical meningiomas and an additional spectrum of these changes in grade 3 tumors. There's also been, so that's really natural history information, and information you can incorporate if it's available to you, and it likely will be available going forward as it becomes easier and easier to obtain this information. But all this information is helpful to think about the behavior of the tumor, not so much for, and maybe choosing additional adjuvant treatments, but not specifically therapeutic. I think the alteration and understanding of mutations in meningioma is more therapeutically relevant. So the grade 1 meningioma landscape now looks much different than it did five years ago, and we have an understanding that about half tumors are driven by NF2, just under half, and the remainder driven by an overlapping series of mutations, and a few extras here at the bottom. And so really, here's some broad themes about that information. So if you look at several hundred tumors in the literature, each column's a tumor, each row is just, I've highlighted some of the more common mutations. There are some themes that emerge. So these are not NF2 patients. These are sporadic meningioma. So there's an NF2 driven or NF2 altered set of tumors, either through loss of chromosome 22, on which that gene resides, and then separate mutation. And there's an NF2 wild type group of tumors that are driven by a separate group of mutations altogether. And what's been exciting for the field has been that about 15% of the overall mutation count is governed by AKT1 and smoothened. These are the same genes that are mutated in other cancers that are already being targeted. So these are activating mutations for which you could then translate easily to therapeutic targeting. And Priscilla Bracianos from Mass General has led this effort. Dr. Ogdee mentioned an alliance trial for craniopharyngioma. This is one in meningioma. And if the tumor harbors those mutations, smoothened in AKT, and it progresses or recurs, they'd be eligible for trial. So that's a great example and really one of the first examples. And a cranial-based tumor of this information being therapeutically relevant. Like copy number alterations, there's also natural history information you can obtain from this. So it turns out that if you have, if the tumor has one of these two mutations, there's a very high likelihood it's going to be present in the skull base. And again, could be eligible for that trial in a very difficult recurrent case going forward. But the French group last year also has gone on to show that if you have a grade one olfactory grouping, and most of those are grade one tumors. If you have the smoothened mutation, you're much more likely to recur than if you don't. So there's also natural history and biologic behavior information that we can learn from mutational profiling as well. It would be ideal if the really difficult tumors that recur, atypical or anaplastic meningiomas, if they had a similar spectrum of meningiomas, but they don't, unfortunately. So if we look at high grade, high grade really means, obviously just by numbers, there are more grade twos to study than grade three. But if you amalgamate the literature from our and many others' work together, you see a real predominance, increasing predominance of the role of NF2 in these tumors. And really very few of these sort of semi-exciting targetable mutations. So overall, unfortunately, they're dominated by NF2 alterations, but that's a non-targetable pathway really right now, and the pure absence of a targetable mutation. I want to highlight a few other mutations that, again, your pathology reports might show down the line, which really are negative prognostic factors for survival and recurrence, rather, and survival. So the World Health Organization does denote a few histologic subtypes that have rhabdoid features. There's grade one with rhabdoid features, and there's just a straight grade three rhabdoid meningioma. It turns out that these have a real reasonable chance of having a mutation in a germline patient, rather in a gene called BAP1, which is a tumor suppressor. And not so much for therapeutic targeting, but again, for natural history information, if the tumor has absent BAP1, there's a significant decrease in your recurrence-free progression in that tumor that features a BAP1 mutation. Another mutation that is present in many of the tumor types that we see in other parts of our practice that portends a poor prognosis and a significantly more aggressive behavior is if you have a mutation in the terpene promoter. That is not a common mutation, but you could either have that mutation de novo, or it can emerge if a tumor recurs. So its emergence during recurrence progression or its presence de novo in an initial resection really predicts a shorter overall survival than if you have that tumor does not feature that promoter. And again, it's a mutation that may be featured in a pathology report going forward. Probably one of the more exciting developments in the last two years, and some of this work has been done in the Toronto group with Professor Gentile's partners, has been this idea that what we talked about before had been changes in either DNA complement or the DNA architecture itself in the actual coding of the gene. You, going back to, reaching back to earlier stages in our education, you remember there are also other ways of influencing how genes are expressed, and that's through alterations in the way genes are packaged and chromosomes are packaged, so-called epigenetic modifications. And so multiple tumor types, pituitary adenomas and others have undergone large-scale methylation classification. So just unbiased, I'm going to look at hundreds of tumors and see if they stratify into different groups based on their methylation schemes. And this original work was done in Germany, but there is just a fascinating story that's emerging in meningioma right now that, just look at the top cluster and the bottom cluster here. So unbiased methylation classification, there are now six groups that really emerge. And they do have some associated mutational and copy number alteration information associated with them, but look at the correlation with progression-free survival. It's really striking. So these first three groups that cluster out from their work really have excellent progression-free survival, and you can see these other three groups really have significant differences in the way that those patients do over time. And look at this third group here. It's the sixth methylation group is associated with some of the other alterations we've talked about. They tend to have term mutations. They tend to have greater degrees of copy number alteration. More male, more male, more genital equivalents than your more benign variants. But this is entirely independent of World Health Organization grading. It's just dependent on the methylation classification. And I know specifically, again, this is a really work being led in Toronto, I think. It's being incorporated into some decision-making in a really novel and I think very exciting way that most of us will see over time. One of the punchlines here is that they had a large data set, reference set, with recurrence information. And it was actually the methylation was classes were more predictive of, far more predictive of predicting tumor behavior than were the actual World Health Organization initial grading schemes themselves. And again, I don't mean to say anything negative about the World Health Organization grading. It's the best that we have right now. But one of the points in the discussion here is to let you know that there's likely a significant amount of biological information which might replace that over time. You can't work in neurosurgery today and not have at least one patient receiving immunotherapy for something. If you've worked on any patients with metastases or perhaps not even in glioma or glioblastoma. And it turns out that, again, borrowing another lesson from our oncology colleagues, meningiomas feature an increasing expression of a very hot checkpoint protein right now, PD-L1. And the idea with PD-L1, as you increase from grade one to grade three, the idea is that that checkpoint protein inactivates local immune regulatory cells. And so a therapeutic strategy in cancers has been inactivating that, thereby restoring our immune response. But it also can be leveraged in meningioma. And we've been part of a trial. This is, most of the patients haven't responded well, to be honest with you. But this is an exceptional responder. And you can see, I'm sure all of us have some of these patients where they've just been, just treated significantly with multiple rounds of surgery, gamma knife. And I think when you have a meningioma and a vasodilator, you know, really the cat's out of the bag. But this patient in particular responded really in a phenomenal way radiographically. And it turns out, through a lot of genomic annotation, had greater numbers of overall mutations than had a few other genetic predictors of a response. But again, this is really borrowing from the oncology field and leveraging that in the study of patients with desperate meningiomas. And I want to come back to something we sort of glossed over in the very beginning. This is, I think, a very compelling report from, again, a very innovative group in Paris, the Calambrides Group. And they looked at a large number of female patients, grade one meningiomas, who had been exposed to progesterone agonists. And I don't know if anybody here in the audience is asked by their female patients, can I take hormone replacement? Can I be on birth control? Is that safe? And I think generally we have, the field has moved generally towards, well, you know, if you really need it, that's fine. Although we know that there's a slightly increased risk with both birth control and hormone replacement. But this is an interesting study where they then sequenced the match controls, the female patients who had not been on progesterone agonists, compared that to the sequence of results from the tumors from patients who had been on, exposed to progesterone for at least a year. And the mutational spectrums were totally different. So here's your wild types. It's a different way of representing the information we looked at before. NF2 alterations, you see some of the other mutations we talked about here, and a very small PI3 kinase mutation complement overall. But if you'd been exposed, if patients had been exposed to hormone replacement, you see a complete shift in the mutational spectrum. So you now have a dominance of this other mutation, PI3 kinase, and a real regression in the incidence of NF2 mutations overall. And it's one of the few examples, you know, when patients ask us what are the risk factors for getting meningioma, we say, well, if you have NF2, and if you've been exposed to radiation in your life. This is sort of a third, possibly, a third example of an exogenous agent that has molecular influence in these patients. So steroids have really, I think, gone out of favor in meningiomas to the point where most pathologists were not even recommending looking at hormone receptors altogether. But this is, I think, a really compelling report that's recent. So I just want to wrap up some of the concepts that we've gone over. First of all, our understanding of meningioma is evolving rapidly. Your pathology reports over time will look increasingly complicated. I think comorosomal alterations tell us something about tumor behavior. In addition to grade, and it may predict recurrence, it possibly could be incorporated to clinical decision making. There are some mutations that we talked about, which are targets for treatment and offer the chance for trial inclusion in difficult-to-manage tumors. Specifically, they're present in a higher frequency of the skull base, although overall, they're rare in meningioma and really absent in higher-grade tumors. Higher-grade tumors have different mutation spectrums. There are some mutations that predict bad actors, BAP1 and TERT in particular. We talked a little bit at the end about methylation systems and how they may be more accurate than grade in predicting behavior. There are some other biomarkers, like PD-L1, which may offer therapeutic possibilities for recurrent tumors. And there's this what's old is new again, which is a role for steroids. I think we'll be revisiting that in a major way. But I think overall, grade is important. But meningioma really is this disease of the derm meninges with a continuum of assessable features, which can be used to predict behavior and offer therapeutic targets. And I would really highlight Geller-Izade from Toronto had really gotten together an interesting group to, in a consortium fashion, and really highlighted many of these recent discoveries in a recent compendium issue of neuro-oncology. Thank you very much. So it seems like, at least in our practice, that the leptin cells are the way to the tumor. How we do radiate, observe. It seems now you have more evidence as to how you base those decisions. Do you have an algorithm in your practice now to become consistent with you? I'd also like to ask, you know, for the rest of us, how far are we away from being able to get these answers when you're getting an archeologist to do actual, you know, next chance? Well, I think the second question, I think it's a cost issue still. Although, as costs are coming out precipitously, I think this information is going to be more easily attainable. As to the first question, obviously there's patient preference, and some patients have very strong opinions about what they want. If it was just up to me, I do think if the MIB1 is low and we have some additional information we've obtained that really suggests something that looks more like a grade 1, and especially if it's a large field and a younger patient, I'll try and hold off.

meningioma

evolving understanding

pathology

grading system

molecular features

treatment