My name is Nienke Biermans, I'm an endocrinologist from Leiden University in the Netherlands and I'm a pituitary expert. I run a pituitary clinic in our center from the endocrinology part of the game and together with neurosurgeons we have a close interaction to perform multidisciplinary collaboration. I have no financial disclosures within this talk but on the other hand I have some other disclosures because I've never been publishing about aggressive corticotrophic tumors or aggressive pituitary tumors. And it feels a little bit uncomfortable to be an expert here and on the other hand I see many, many, many pituitary cases every year, like hundreds. And there's always you have to have a sense of awareness that it could be an aggressive one or it could turn out to be an aggressive one. And I think that's mainly the reason that I accepted this talk because I think that that's the part of the care for aggressive tumors that is needed to know by everybody who's caring for pituitary patients. And so the learning objectives of this meet the professor session is that it would be good to think about distinguishing aggressive tumors from the behind behaving ones and tumors that are at risk for aggressive behavior or have aggressive behavior. And important to realize it will not be black and white and that we can use the predictive factors that are around to predict. And of course there's basic research going on but what can we already use in the clinic? How we can proceed with multidisciplinary management and what is the patient perspective? And I said we run a clinic and we've been trying to develop as a center of excellence recent years and that means that we adopted quite structured care paths, multidisciplinary care paths with a start and a date of surgery and a six weeks and a six months and a yearly evaluation. And this is Dutch so you don't need to read it. But just as a concept we try to define the condition, the intervention and if you have structured that then it's the next thing is that you want to evaluate your outcome. So we also try to make a simple more but comprehensive but simple but an achievable way of evaluating outcomes and we try to do that according to the three tier model that was proposed by the value based healthcare experts. And that's of course already difficult for pituitary disease because there are always so many things that are of interest for the patient but not of interest for all patients. And that's true for all standard pituitary adenomas and I want to mention it here because I think it's also applicable to patients with aggressive courses. And so this is what we try to do and then we are evaluating these kind of multidimensional outcome measures and then you have the problem that despite the fact that you try to organize the group as a whole and I think that's better than make all specific conditions like acromegaly and cushing etc. So see it as a pituitary adenoma but then in the next thing there are so many more factors that can be leading to determining outcome. And for example we came to mind that at the preoperative stage it's very important that you try to define as a group what you want to do, what you expect to achieve. So that is a basic concept and this is a kind of a flowchart that we adapted as a team and it's more or less applicable to every case that can go to surgery but also if you consider other treatments. And the idea is that we think it's very important that when you want to do an intervention that you try to define and prospectically register what you think that you are going to achieve. And then you can evaluate whether the course went as you expected or that it is unexpected and those unexpected cases can of course be due to something that the team could have done different. It can have been an unforeseen complication but those unexpected cases, well they can be the ones that turn out to be different from the standard course. And I think one of the important things of specialised pituitary experts is that they try to find a sense to understand, to have awareness that a case can be different and that there is need for awareness for aggressive course. And I think our challenge is that we need to find simple ways to record those, well the parameters that are of interest but as a first and I don't think there are any publication, I think that is also important is that we need to record what we expected. And of course there are many factors as a KNOSP criteria etc. but sometimes there is more than that. And it's also true of course for what happens during surgery. Well, if we are talking about aggressive tumours, I think it's very, very important that we realise that it's a spectre and it's a developmental situation. And so patients can have normal pituitary tumours but they can have subclinical signs of aggressiveness and that can turn out to be clinical relevance and aggressive and even result in carcinomas that may metastasise. And well, the more aggressive ones are more and more ultra rare and that's, I think when you are working in a regional centre, not too specialised, you will probably have this proportion of patients and you have to watch out for this one. And if you have a more specialised centre, probably you are more here and if you are the top expert that runs national tumour boards, then you will encounter more and more of these cases. So it really depends where your area of expertise is and you need to, well, I think your clinic is, well the way you are involved in those referrals will determine whether you need to be more or less aggressive with decision making. I think there's still work to do, but on the other hand, it's clinically quite, well, good, this definition that the aggressive pituitary tumour is defined as a combination of aggressive behaviour, invasiveness in surrounding tissues, multiple recurrence, the rapid growth, rapid unexpected growth, resistance to conventional treatments as surgery and radiotherapy and the standard endocrine drugs and the pituitary carcinomas may metastasise. And of course, metastasis is, well, then we're sure that it's a carcinoma and it can be metastasised to the leptomeningeal spaces and in the distant metastasis and that's ultra, ultra rare. But the difficult part of the above is that there's always the comparison with more indolence, pituitary adenomas, since they can also invade and they can also recur. But you have to try to find the way to sense those suspected and proven to be aggressive. And, well, it's often so that, well, that you only retrospectively can say, well, this was one. But as you become more aware, then probably in a more prospective way, you are, well, try to be able to identify cases. But still, because some of the patients identified as potentially aggressive, well, have still a quite benign course and should not be subjected to too aggressive treatments. Well, there's a lot of research going on to find predictive factors. And for now, the clinical predictive factors, as you can measure on clinical parameters and radiology, is invasion and growth. And the pathology predictive factors is the Ki67 and the mitotic counts. And the definition is that it could be above 3% in the Ki67. And the p53 is also a marker that is used. But to be honest, for example, in our units, we usually have to get back to the pathology to actively ask. Because sometimes they, well, they mention it as a regular tumor and a typical adenoma. And then, well, they have to be asked again to do these kinds of labelings. And, of course, every center has its own policy. And, well, in the current literature, I think it's advocated that at least these factors are recorded in the pathology reports. So let's go to your own experience who have seen pituitary carcinomas. More than five pituitary carcinomas? Yeah, so it happens. And if we are thinking about suspicion of aggressive disease in your regular clinic, is it more than 20% or less? More than 20? Yeah. Well, I think the idea is the pituitary carcinoma. When it's a pituitary carcinoma, I think in the end everybody will agree. But the suspicion of aggressive disease is still difficult to define. And especially the difference between suspicion of aggressive disease and a recurrence that just needs, for example, repetitive and finally radiotherapy and is silent afterwards. So if I speak from my clinical practice context, then I acknowledge that they are ultra rare, but that it's important to have the awareness. And that's in the main cases that turn out to need additive treatment as dimazolamide. Still there is, well, there are slow growing, long trajectories. But sometimes there are really aggressive, quickly progressive tumors that just not react on anything. And it's also true that those tumors can change in the time, for example, from non-functioning to functioning or from functioning to non-functioning. And that could indicate a change in the aggressiveness. That you have to find the right balance between being very aware and have intensive surveillance and let people live their lives. Find a way to act on the clinical relevant symptoms instead of on the measurements only. Well, there is guidelines, happily there are guidelines. But as soon as there is a step up towards additional therapy, therapy refractory from dimazolamide, I think it's expert based opinion. But it's also very dependent on what is possible in a country. And maybe we can discuss later. I think the availability of immunotherapy, experimental immunotherapy is not everywhere the same. And it's always good to have the step of the first regular multimodality treatment and the dimazolamide and then the last resort. And I think there is a discussion. What is the place of dimazolamide? Whether you can do it a little bit more in advance or first try to work out all options of radiotherapy and surgery. Well, this is a case report from Lynn et al. And I like this timeline because it helps you with understanding the course of some cases and the very, very individualized course. And I think this is one of the reasons that make good studies beyond case reports so difficult. Because, well, there are so many challenges in recording. And on the other hand, I really believe that that should be the way to go to better be able to tell your patient in the waiting of your clinic what they can expect from their tumor. And so there are many interventions. There are different time to progression. And in case of the rarity, it's so difficult. So I think we are doing initiatives to find a way to better record data, but still I think those case reports also help to get data available to better understand prognosis. Because there are very limited data on mean prognosis and the big question is whether you really need mean prognosis because it's so individualised. This is one of my cases. In 2012 she presented as a Cushing patient with a history of five year fatigue and then a more recent change in body composition with edema, hypertension, fat deposits, etc. So you can speculate that this disease was already there for five years and that there was a change two years later. And then she presented, well the biochemistry was clearly a Cushing, and then she presented with this macroadenoma and it was not, well it was a little bit, it's a macroadenoma and there was discussion whether there was invasion or compression or, well the prediction was that there was a good chance of total resection. And then she had surgery in 2013 and then it was an ACTH producing adenoma and there were no signs of atypical changes and we asked again later and there were, in this specimen there were no signs of atypical changes. And then on the left we can see the postoperative MRI scan and then there was no tumour remnants and she had a clinical remission with a nice low cortisol value. So this was a typical, well total resection, nice remission of Cushing and she became cortisol independent after nine months. So everything as you like it and except for that it's remarkable that she had a macroadenoma at presentation, which is not too typical in Cushing's disease. And then three years later she had this recurrence as shown on the left. So then there was a big regrowth and we did not make MRI scans in the meantime because she was in remission, we had no clinical suspicion of recurrence of Cushing's disease and so there's a lack of radiology follow-up, which I can understand because there were no, well there was too little awareness that this could be an aggressive one. And then she did not have, she did have biochemical values compatible with recurrence of disease, but it was not as aggressive as the diagnostic test. So it was only mild hypercortisolism. And then we did surgery on this one and we were quite satisfied with the cortisol values that were a little bit less low as the first time, but still, well she fulfilled the cut-offs of remission. And then there was, I think, a patient-related reason, but also not enough awareness by the team. So there was not a post-operative MRI scan. So I can't tell you, and it's annoying when you want to understand this clinical course, whether this was a total tumour resection or not. And two years later, she did not have complaints of remission, but then we realised that there was no post-operative MRI scan and we also had suspicion of aggressive behaviour. And then we did a surveillance scan and then there was a large tumour regrowth. And now, because this was unexpected and it was large and there was some subtle compression of the optic nerves, we attempted a third surgery. And during that surgery, the surgeon had more difficulty with removing the tumour. So it was more firm, it was more difficult to dissect, etc. And then, so this is prior to the third surgery and this is after the third surgery. And you can see that there is some mass removed here, but this part was just inaccessible for the surgeons as they evaluated during surgery. And that was also the reason to do an upfront MRI scan also, of course, because we wanted to irradiate her afterwards. And then, well, there was a more aggressive, proliferative pathology staining with a positive GI67 value. And then we asked the pathology who did not record a GI67 in 2016. And so then, in retrospect, this was the same. And I think we should have known that then. And I think that's always the difficulty. The awareness is key in understanding what you need to do. And then we did radiotherapy and we were really satisfied with what happened here. She had an extreme good response, but it was a very short response. And after one year, there was a total regrowth again. And her clinical cushioning is not, well, too much of interest. So it's mainly about treating her for the tumour volume. And, well, we had this and then we were at a stage that we say, are we switching to Temozolomide or are we trying Pazireotide? And it was also the moment that Corona kicked in. So we decided to give her the benefit of the doubt. And we did three months of Pazireotide. So that's a little bit short to be sure. But on the other hand, we tried and she was not feeling well with the drug and we did not see good shrinkage. So, well, based on more or less this picture, we proceeded with Temozolomide directly after the first lockdown in our country. And so then the Temozolomide did really well and she had up to 13 cycles and then she had a pause of six months. And it was because we don't know how long we should continue. And there was a wish for the patient to have a moment of drug-free periods. And recently we restarted again because there was regrowth. So this is a 10-year story about the life of one of my patients. And, of course, 10 years is a long time, but on the other hand, she's still young. So we want to try to continue the best we can. And for now, Temozolomide is fine. And if there will be progression, we will discuss a different option of immunotherapy. But maybe there's also consideration of, well, asking the neuroradiologist for doing additional radiotherapy, but probably it's too much spread for that. And I think she's doing fine. So her hypercortisolism is more biochemical than clinical. And she has subtle diplopia that is not invalidating. And that's, of course, a main reason to treat. And for now, the clinical situation is stable. And, well, get back to the idea on management. I think it's always key to review all information that has been provided that is available. And it helps when you have a lot of MRI scans. So then we have the endocrine course, which in this case was a switch from very productive to less productive corticotroph tumor. Well, we felt insecure for a while because of the missing of the postoperative MRI scan. So I think the timing of MRIs is really helpful in aggressive tumors. Well, we learned from this case that really the pathology staining is important and that if you don't get a result from the pathology, you have to go back to the pathologist for additional stainings. And of course, this was a case with a strong own opinion about therapy. And that dictates, of course, the choices that you make and that's shared decision making. And the ophthalmology is, of course, if you have those invalidating nerve policies, then the ophthalmological collaboration to optimize that, also to help to cope with that, is very important. In this total review of information, the effect of interventions is to understand the effect of interventions, the effect of the growth velocity with and without the intervention is very important. And we need to find ways to make that standardized, so you can exchange patient's information in an effective way. Because usually, if a patient is referred, you have to redo everything again. And that's good on the one hand and it takes a lot of time on the other hand. The patient deserves the time, of course. And I think also these are cases that are in repeated MDT discussions. Well, there are guidelines and I think this is a great guideline, really helping with a lot of basics in aggressive pituitary tumors. But you always need to combine the basics with the expert opinion. And well, of course, you know the guideline probably yourself, but the things that are difficult when you're reading the guideline, it is the evaluation of invasiveness. And my others have been publishing about that. But I think that's always from when do we check the box of invasiveness? And GNOSP is a neurosurgical evaluation, preoperative or during surgery, of invasiveness in the cavernous sinus. But of course, during surgery, there's also the evaluation of a tumor is invasive or not. And sometimes it's only compressing, but sometimes it's really invasive, gross and difficult to dissect tumor tissue. And well, I think in the end, the team needs to conclude whether it's invasive or not. So it's not only, well, sometimes it's clear, of course, but if it's not clear, it's not only the radiologist that can call it invasiveness. It's the combination of what the pictures show, what the surgeons evaluate during surgery. And it's not only GNOSP because the growth is also in the skull base or more in the supracellar range through the diaphragm. And of course, for those invasiveness, they're so familiar in many prolactinomas without aggressive course that it's still difficult when you really conclude that it's an invasive feature predictive of aggressiveness. And so that's one thing. And the other thing that's important is that it's quite difficult and we can discuss for ages about how to measure tumor growth. And well, then the nicest way to measure is a nice 3D volume calculation, et cetera, et cetera. But the difficult thing is that that's not practical and that's not feasible. And you also want to stick to the other special oncology ideas in the world. And then, of course, they have the concept of resist criteria that are clearly defined that work for most tumors and have really a place in evaluation of trials. And then progression is defined as a new lesion of a 20% or greater increase in longest or combined diameters. And it should be at least five millimeters. So we have some challenges in pituitary because it's usually one lesion. It's usually not a nice circle or it's not, it is difficult to measure lesion. And well, there is research that it's usually okay to just measure the longest diameter. And maybe for research purposes, for registry purposes, that would be really the way to go. And on the other hand, you also need to think as a team and to interpret all the pictures. And sometimes there is a clear progression and everybody see it, but it's not completely compatible with the criteria that are made for progression. So that's sometimes a difficult thing. And the other difficult thing is that sometimes there is, well, only minimal, minimal growth, but it turns out to be clinical relevance growth because new compression, deterioration compression, and that's also important to realize. And again, the importance of the repeated MRI, you really need to think careful and be careful with what is happening and also, and that's not on the previous slides, sometimes there is a kind of a tumor necrosis that makes really changes in the tumor and then there, so something is happening, but it's not really measurable in millimetres. And I think that's also an important pitfall. Now, but I like the flow diagram, the proposal that Giraud, he's here in the audience, made with the group thinking about to try to to make it practically and clinically easy to, as easy as possible, to to define what we do and especially because these are the steps that make the decision that dictate the decision to do something else, to wait and scan or to proceed to another treatment. And then, so there is a clinically non-relevant tumor remnant, so that's there, it's not critical and it's not not yet growing. And there is a clinical relevant invasive tumor remnant that cannot be removed by surgery, but it's critically because it's close to a critical structure like the optomic nerve. And then, of course, things can grow and if there's measurable growth in a short time, then you probably call it an aggressive tumor and you need to proceed to other treatments. And sometimes it's not because of measurable things, but because of clinical relevance, more compressing tumor mass, you need to continue. And I think these initiatives are really important if we want to make registrations to do multi-center outcome evaluation. We can do a lot of work to try to find the right way to measure, but in the end it's about what the team concludes and why the team concludes and what is the next step. I think these factors help. So histopathology, it used to be typical and atypical and that was not well correlated with outcome. And now there are new evaluations with the atypical characteristics and the subtypes more prone to aggressiveness and of course, well, you can read them here, the silent ACGH is among them. Well, I've not worked with this in the clinical practice, so maybe the audience have and can highlight about it, but this is a another clinical practical proposal to identify patients with risk and it combines the pathology, the immunohistochemistry with radiological and the surgical idea of invasiveness. Then there is a fair good correlation between aggressive behavior and prone to be aggressive behavior or not and especially to be patients are of interest and they're only the small subset of the total group, but it's I think it's quite an interesting way of looking at things and I'm not using it in practice, but I can imagine that we are especially if you are trying to find a way who of the patients you can discharge to regional hospitals, etc, that you want to be in your own hospital to have the good the same MRI scans every time, etc, etc, but maybe there can be a discussion about this later on. And then there is a well, there has been a discussion in in the field about what to do, PITNET, pituitary adenoma, pituitary tumor. How are we going to call it? Well, we we can choose either route, but in the end it is about what it is about patient care and this discussion does not solve the problem of the difficult identification of the aggressive ones among the big group of less aggressive of non-aggressive ones. The follow-up interval is of course fair. I think that's a challenge because on the one hand you want to have data to understand the clinical course. On the other hand you don't want to make the patients, to put too much burden on the patients. And also you want to have to be critical about MRI scanning. We have to be very critical because of the capacity and so I think it's a challenge to find out which patients need an MRI scan every three months, which patient can have one every six months and well beyond that it's either one year or once every three years. And I see this as an important responsibility for us to to make good choices in this and not miss too many patients that can be operated and have radiotherapy before they are untreatable aggressive tumors. And having said that I think there's a lot of questions about the the stage of radiotherapy. If earlier radiotherapy can really prevent a tumor from becoming aggressive or is it just a well it's it's going to be an aggressive tumor and radiotherapy at some stage will help with delaying the process. I think these are also data that's that really needs to be addressed in in multicenter outcome studies. Well, I think we have been talking about the standard therapies. If there is a case with aggressive tumor, I always go back to the basics and I always discuss in a team, but I also discuss if there is a chance with the surgeon just alone or ask the surgeon to have an extra look not not at the MDT room, but really himself thinking about options, stressing the needs, the indication that we want to achieve and the same is true for radiotherapy. Of course, we have a lot of different ways to to irradiate. Choices are made by the experience of the center. They're made by the idea that if you have options to choose that sometimes gamma knife or proton beam is better than the fractionated ones. But in these exceptional pituitary tumors, sometimes there is a reason to do an redo of gamma knife or as a last resort radiotherapy, and you have to balance these options against start of demazolamide in a certain stage of treatment. Well, drug treatment sometimes pessarytides, it can delay but if it's an aggressive tumor, you usually need more. Then demazolamide is the off-label drug that has not been studied very well, but on the other hand is is the one that has has been used most and there are quite okay results of 30 to 50 percent response for for a period. Well, for example in the guideline, the idea is if you have a response in three months, then it's usually a patient sensitive too. And then you can continue and how long we can continue? Well, there are a lot of questions marks again. You can continue quite long for years. You can try to stop and restart and the unsolved question is whether it's deleterious to do the stop or that you need to proceed or that you can safely stop and restart if it's needed. If you stop and it's stable, then you don't need drug and if it stops and progressed again, then you need to start again. I think my timer did not start. Well, how much time do I have? It's a Okay Well, I was already I think I've been telling this. Then I think I need to go to my concluding slides and I think I've more or less told you this. And so total review, discuss about the needs, always the team discussion and the other thing that I want to stress is that well, if you are in a late stage, well, why not discuss with others? And I think there are four their national tumor boards and I think that's really important that we try to link to each other to find the best way. So, thank you, I think I need to go to questions. Thank you, just a question not on my paper, but for your case. At this stage, it's not so normal to have a optic nerve palsy. It's not common for an adenoma and I think it's important to propose to do some extra imaging looking for metastasis at this stage, because you will identify a carcinoma only if you look for metastasis and even if the tumor is not growing so quick in this part and you will identify them only if you do maybe an MRI, a pan-MRI, a spine MRI, maybe at least a PET scan and for your patient for the future treatment, maybe a dotted gallium to see if you can maybe treat this patient with PRRT. So in this case, at least I will do this. I think that's a good addition because you only find metastasis if you are looking for it. And the question is whether you need to do it in every case or that you need to do it based on symptoms and You already treat this patient with the mother's mind. This is chemotherapy. For other cancer, you do a staging before starting your chemotherapy. Yeah, no, that's a very good addition. Thank you very much. Hi, Parnipal, Oxford. Thanks for a lovely talk and for sharing that typical heart sync patient. Can you comment on, you mentioned she didn't have any clinical symptoms of recurrence. Do you do any biochemical monitoring? So her HPA axis recovered. Would you comment on that? Yeah, I think the idea is, of course, that's just as radiological evaluation, they need endocrine follow-up. And yeah, I think you can individualize that. So this patient has some mild hypercortisolism and is well aware of symptoms of adrenal insufficiency. So sometimes she takes a little bit of hygrocortisone and I follow because I know that that's the parameters that is best to do in her case. Just the serum and sometimes a midnight salivary cortisol to look and see whether she's deteriorating. And I check her metabolic parameters. And sorry, a second quick question. In terms of a corticotroph recurrence, would you have considered, with these cases, would you have considered earlier radiation? With these cases, would you have considered earlier radiotherapy? So at the timing of the first recurrence, do you ever? Yeah, I think we could have considered radiotherapy after the second surgery. And it was a little bit delayed because of loss to follow up by the patient and an insufficient pressure from us that it was needed. Also because you were, well, satisfied with the biochemical values and reassured by not a warning from the pathology. But I think there, and I don't think that it's because she had a great response on radiotherapy, but then she recurred very quickly. So I don't think that it would really matter in this case. But of course, we don't know. Thanks. Thanks, Nico, Tony, and UCLA. Actually, the last questioner kind of asked my question. We all have these cases, and we only really figure them out when we get further down the line, as in your case. But if you're looking back and thinking, as we do, what could you have done differently? I think the comment earlier about earlier radiation, do you think would that have changed the outcome? I'm curious as to whether it's possible to look back at some of the centers around the world, particularly in the UK, where radiation was pretty much standard for every residual. And if you compare that data to current, do we get any insights as to ways to impact the outcome for these patients? And then one other question, you mentioned cortisol in your patients, was there any trend in ACDH across this whole evolution? No. So ACDH was not a tumor marker anymore in her situation. So they're normal-ish and do not really change in relation to tumor mass. Do you think if you had irradiated her back in 2016, would you have impacted the outcome? Well, of course, I'm not sure. But because she also had a total resection, and she was really in remission, and there is something in her tumor that is probably going to recur. But of course it is possible, but I don't think so. I think this was an aggressive tumor. Thanks. Philip Semry, interpreting de-differentiation is a problem. Is there any role for a liquid biopsy to try to detect pro-hormones in blood in addition to the mature hormone? I think that's a fascinating question, and not only for aggressive tumors, but also for endocrine excess syndromes. Understanding why some patients with tumors have so many symptoms and others have not. There is also, of course, the ultra-sensitive assays that sometimes do not detect changed growth hormone or something like that. I think it would be very interesting to have another panel of over-secretion, and probably that will explain some understood bad quality of life of our patients. Thank you. I think we conclude this session. Thank you so much for your attention.

Nienke Biermans

endocrinologist

Leiden University

aggressive pituitary tumors

challenges

management

multidisciplinary care

recurrences

conventional treatments