Dr. Sarah O. Vargas - Pathologic Underpinnings of Cystic Lung Disease (What is CCAM/CPAM?)

you Yougent for comparison Okay, good morning, everyone. Thanks for joining and thank you to everyone on Zoom for joining as well. I have the pleasure of introducing Dr. Sarah Vargas today, who's been gracious enough to come and speak to us. Dr. Vargas is an associate professor of pathology at Harvard Medical School, practices as an attending pathologist here at Boston Children's Hospital, where she's the director of pulmonary pathology. She earned her undergraduate degree from Harvard College before completing medical school at the University of Vermont, residency at Brigham and Women's Hospital, and fellowship in pediatric pathology at Boston Children's Hospital. She has mentored 40 Harvard graduate students and medical trainees. She's the director of quality and patient safety in the Department of Pathology here, Boston Children's Hospital. And the contributions over her extensive and successful career are innumerable, and I had the pleasure of reading through those and learning more about her work. Highlights that I noticed included those in pediatric tumor pathology, such as her discovery of a new cancer syndrome called T1519 Personoma. That was subsequently recognized by the WHO at classification of tumors. And she additionally helped identify a new inactivating mutation and novel gene WTX that's present in one third of Wilms tumors. And she has additionally moved the field of pediatric lung disease pathology forward in impressive ways. And today we're fortunate enough to have Dr. Vargas share her work as she describes the pathologic underpinnings of cystic lung disease and tells us what is C-CAM and C-PAM. So with that, thank you very much. Well, thank you very much for having me. And thank you for giving me all these specimens over the years. Every case that I'm going to show today came from one of you. Well, there's a textbook definition of congenital cystic adenomatoid malformation. Otherwise known as congenital pulmonary airway malformation. Maybe I could just show this slide and be done. It's a common benign localized cystic congenital lung lesion. It occurs in one for every 8,000 to 35,000 live-verse. Frequently identified an anti-natal ultrasound. And it can cause a range of symptoms from severe respiratory death or distress, even death death in utero or afterbirth or no symptoms at all. And it has no systemic blood supply. So there has been a classification scheme applied to C-CAM. Well, there's been a few, but the main one has been the stocker classification scheme. And this slide here, Dr. Lilah has put on his glasses. This is very tiny. And it's tiny because you don't need to read it, really. Nobody can fit any one single C-P-M into this schema. This is always going to have overlap and fit in more category than one or cannot fit neatly into any one category, basically. So this scheme that I'm showing here is circa 1997 when stocker was still calling these congenital cystic adenomatoid malformation. He typed to them. So this was after he'd changed the scheme from Roman numerals to Arabic so that he could encompass a type 0. And then later in 2002, he gave a symposium where he said that congenital pulmonary airway malformation was a better name. So this is the publication in 2002 where he probably neither is a great name, but he decided that C-P-M was a better name. And this was published in Dr. Stocker for years gave the pathology sessions in the AFIP sessions that were given to radiologists. So a generation of radiology trainees went and heard that you're supposed to use the word C-P-M. So it did catch on first in the radiology literature and then eventually more widespread. So but you still see it both ways in literature. Now when I've tried to describe this darker classification to the pulmonologist, I've used, I've pulled up their classification for cough. So there is a classification for cough that has four types. And you see from how it's built that you could find a patient that can't fit cleanly into any one category. But then even if you've managed to cram your patient into one category here, really all you've got is, oh, that he just has a high respiratory rate and he's aged two to six and it's got right right right. You don't really have the cut. So you've got a classification system great, but wouldn't it be nicer if you had a more specific diagnosis like maybe the cough is from cystic fibrosis and maybe you even know the genetic mutation. Maybe the cough is from foreign body aspiration. Might even know that it's a nut versus milk. Maybe the cough is from inflammatory myofyroblastic tumor or mercinemonia. So you can see how a specific diagnosis that encompasses the ideology is much more satisfying. And there's another classification scheme for C-CAM that is large cyst versus small cyst, which is just as unsatisfying. So should we be moving to an improved classification that is more ideology based, that is the question. So instead of the stocker type 0 through 4, should we be talking about things like acin or dysplasia, which got described and then stocker just took it and said, let's call that type 0. That one never really, people don't really use stocker for that and it's so different from other C-PAM. Anyway, should we have a category that's called Dicer-associated lung cyst or something along those lines for the cystic Dicer lesions? Should we have one called Ronkyl atreasia associated C-PAM? Or the very interesting category, other? So I'm going to go through these categories. So congenital acin or dysplasia is when a baby just hasn't developed alveoli. There's no alveoli. It's a profound hypoplasia. And it's a diffuse lesion. It's not cystic. So why give it the C-CAM name? These babies, this is an infant that died two days of age. These patients die at or around birth and it just seems like a different disease. This particular baby was a two day old girl and she was never tested but others in her family with varying degrees of severity of it ended up having a TBX for mutations. So she virtually certainly had TBX for mutation affecting development of the lungs. And this is a spectrum. So you can have this mutation and also have a few alveoli developed. Like in this case, this was an infant with severe pulmonary hypertension in the NICU in an Iowa hospital. Sorry, this is one case that's not from here. And there was a chromosomal deletion that involved the TBX gene. So there's a spectrum here and doesn't fit well in as something called C-PAM. Okay, another category that the stock or classification would try to encompass is DASER associated lung cyst. And the cystic disease caused by DASER has been called PPB types I, which means entirely cystic. One are the R stands for regressed meaning it doesn't have any cellular components in it. And this case is classic. This is a seven month old who had a mass that encompassed the right middle and right lower lobes, metastinal shift and respiratory distress. So his C-PAM had to come out clinically it was C-PAM. And here the microscopic features are classic for a DASER associated lung cyst. So you see these cysts with fibresceptive. And there is this increase in cellularity that we call a cambium layer, right underline the epithelial lining. And then there's a few little nodules of primitive cartilage in the wall. And the septar line by mainly cuboidal type epithelium. And the cellularity here is bland. It's not malignant appearing. The solid types can get much more frankly malignant. So this would be considered a benign cyst type one chloropulmonary blastoma. An interesting thing about this case, many of you might remember this case. I think at least Dr. Weldon was involved. So this patient's older brother was being followed for a C-PAM. And once you find a chloropulmonary blastoma in one brother and the other brothers being followed for a C-PAM, it's probably a DASER lesion. So it's going to come out. So it did come out. And then so the older brother was 23 months old. So we put through the whole of the cyst in like 30 cassettes. So we're getting 30 glass slides. And only in one area in one slide was there any little bit of cellularity. The rest of the lung cyst was just had very bland, fiber-septa without any hypercellularity in it. So it would have been hard to tell that it was a chloropulmonary blastoma. And if it had been, we would have called it a type one R. But here there was this tiny little bit of cellularity. So like it's the world's smallest type one chloropulmonary blastoma. And this was a 23 month old. And it does bring to mind the question that you might have about the nomenclature. Why do we call this regress to if it's a baby? Could it be incipient? We don't know. The name regress is just made up and we don't know that much about where it really is in its biological continuum. So names that we could apply to Dicer 1 associated cystic lung disease could be chloropulmonary blastoma type 1, chloropulmonary blastoma type 1R, or perhaps regressed, chloropulmonary blastoma, or maybe a subtle PPB precursor type lesion. But to cut, to put it, you could put some of these either into a type 4 C, CPM or type 1 CPM. That does not tell us much about the biology. And the management points here are that chloropulmonary blastoma can be associated with germline dicer variants in patients and their family members. So testing can inform surveillance plans. You can also have somatic mutations, but those somatic mutations may be mosaic and involve other parts of the body and still explain other disease. So the germline testing can be done in advance or after surgical excision. And it's important to note that additional chloropulmonary blastoma, of course, can subsequently rise in other lobes and the patient or their family members may be prone to other dicer related tumors and conditions, which are many. The next category would be bronchial atreja associated lung maldevelopment, which corresponds most closely with what talker, stocker called type 2 CPM. If you don't pay attention to his size requirements of this, and this would be known as bronchial atreja sequence as well. So just I'll back up and give a clinical and gross diagnostic scheme for the atreja associated lesions. So I'll put them all out. CPM or CPM is a segment of lung that does not have a systemic arterial supply. An intra-lobe arse equestration is an area of lung that does have a systemic arterial supply. Extra-lobe arse equestration is, of course, an extra pulmonary mass that's invested by its own plurra. It's got a systemic arterial supply, and of course, it's not connected to the lung. It doesn't have any bronchial connection. And then low baremphysema is a lobe with moderate or marked enlargement without a systemic arterial supply. And this is an example of an atreja associated CPM. This is a one-month-old boy with an antinatal ed detected cystic lung mass. The CT scan was interpreted as CLE, Continental Lover and Physema of the left lower lobe. See the area here. And then this is the classic pathology. This section in the right plane, you see this big glob of mucus because the affected area was supplied by an atretic bronchus. So when it tried to drain its mucus, it accumulated. And you see a dilated bronchial like structure, which is seen here. Well, it is a bronchus, dilated bronchus, where the mucus had accumulated. And this still to that, you see the lung is a bit paler. And the alveolar spaces are so large that you can resolve them. Normally you can't with your naked eye really resolve the alveoli. And then histologically, this is the classic appearance of atreja associated CPM. You see these too many of these thin walled airway like structures. They're kind of baggy and convoluted in their contours. And then the alveolar spaces are too big, just like they are in congenital lovar and physema. So there's kind of an overlap and continuum between this and congenital lovar and physema. And a clinical overlap as well. That's why the radiologists went for a CLE on that case. If you're very lucky, as a pathologist, you might get the exact plane of section to show where your airway got into trouble and became a tretic. And that brings up the fact that although we know the etiology for the maldevelopmental changes that arise distally to this, we really still don't know why there was the atreja in the first place in most of these cases. Occasionally, there'll be tons of amniotic debris that seems to be clogging things. And sometimes that the cause of atreja is apparent, but most often not. So Boston Children's Hospital has a role in this evolving concept of bronchial atreja sequence, which has advanced over the years. The first evidence that bronchial atreja was associated with the C-CAM came just from a few case reports describing the two occurring together. And then Dr. Mark at Mass General Hospital did this elaborate sectioning that involved hundreds of sections through individual blocks of tissue. So quite cumbersome, but was able to demonstrate the atreja in a number of cases. And then came Harry, Harry, cause a cabbage in this department. So around this time, he started doing these meticulous design sections of our C-CAM here. And he had a brilliant method. It was very easy. And not necessarily always time consuming, but Harry took a last time with it. And so he puts the specimen under the dissecting microscope and then just from the highland snip, snip, snip until he hit the atreja. And he was able to just demonstrate atreja in virtually all, you know, almost all these specimens and the ones that he didn't, you would postulate that the that the atreja maybe was still in the patient, the point of atreja. Because sometimes you just see lots of mucus, but not the not the atreja. And in this case, here the the surgeons in 2000 early in 2006 published a study of pathology reports and got 33 cases. And then Harry published this article that is so beautiful. I refer you all to it. The pictures are stunning and the sections are really beautiful to show an example. And then most recently, at Lee from our radiology department published the CT findings in this these lesions. So this is a paper that shows Harry's at the sections. This is a CPM that was detected in utero. You can see a mucus ill here at the highler aspect when specimen comes out. The mucus ill is here here. Harry's done barium injections. It shows some small connections to the distal lung representing those malformed airway like structures. And then you hear he's cleared the mucus ill of mucus showing the openings. And then if you back up, you see that distal to this is this cyst like change. And here this is a good example of why the large cyst some institutions are using large cyst type small cyst type. I mean, here's a very large cyst and here's a very small cyst. It shows why also that classification system is not great. And then under the microscope, this is the classic appearance with two large air spaces and dilated airways than walled airways. This is a, this is at Lee's work with the radiology and he found so we gave him cases where the pathology had had definitely shown something that looked at treat you like mucus ill like. And he went back and looked at the CT findings in 18 patients. And in 17 out of 18, he was able to demonstrate that on the one windows, the mucus eels are very hard to identify because they blend in. And they look just like all the vessels. So here's the mucus ill and it's blending right in you would never know. But when you switch over to the soft tissue windows, you see the difference in enhancement and all the vessels are enhancing, but the mucus ill does not enhance. And I just they look the same one to the next here the mucus ill is blending in with all the vessels and then here it's showing non enhancement and these mucus eels are located on the in general on the higher aspect of the lesion. So the management points here are that bronchial atreasia associated C.M. is not associated with recurrence or malignancy. High resolution CT can identify features supporting B.A. associated C.M. in advance of surgical management decisions. But there's a caveat that this is still early days and might be important to consider what caused the atreasia and I'll get to that later. The next category I'll cover is K.R.S. associated C.M. and now that we're doing molecular testing more readily, some of you have hardly received this diagnosis recently. So K.R.S. associated C.P.M. harbors mutations in the K.R.S. gene and it's generally characterized by more exuberant epithelial proliferation. So here would be a classic appearance of a C.C.M. that has see this saw tooth epithelium looks very proliferative here at seeing on the other side and here's airway or alveolar like structures that are aligned by exuberant cuboidal cells that look like type two pneumocytes. And then of course, the these K.R.S. associated C.C.M. can have these mucus cell clusters. So this is a classic example of that. They're usually small clusters. They see the nuclei are basically located and they are secreting mucus at their apical aspect. And these we ignore these and babies we don't call them cancer. We just call them part of the epithelial proliferation in a C.P.M. but they look exactly like what in adults get called mucus and it's adenocarcinoma. The old term for that is bronco alveolar carcinoma. So the literature is right with case reports of we reasons that look like this that are called bronco alveolar carcinoma in a occurring in a C.C.M. So you have to read that literature discerningly. And recently that was looked at systematically. So mucus and cell clusters in infantile C.P.M. mimic adult mucus and is adenocarcinoma but are not associated with poor outcomes when appropriately resected. The our old fellow from here Jenny Pogorriller looked at the experience at chop and found that no one came back with a adenocarcinoma. And then they she also has a nice chart that reviews the literature and only ever are there just a handful of patients that have even weak evidence that the proliferation behaved aggressively enough that you might consider calling it cancer. And so it's fairly recently that Kate Rass was identified like maybe 2003 in these mucus and its proliferation and the literature was kind of saying, oh this means they could become cancer but that's not really proving to be true. And even so and then even more recently it's been found that it's not just the mucus and its proliferation is every cell in the area of the C.C.M.s that is harbors the K.R.S. mutation. And even when that was first discovered, the thought of as an indicator of potential malignant behavior, but you do have to remember that we see mutation in a lot of things that we consider malformations K.R.S. mutations are found in lots of things including endometriosis that we don't consider cancer. So again, read these things with a grain of salt and then our Jennifer Pogarilla again showed this that the K.R.S. mutations occur in other elements in the lung very nicely by in situ probes that show both the K.R.S. mutant. And the wild type K.R.S. because you've got two alleles in occurring in other elements in the C.C.M.s besides the mucus and its proliferation including the type two pneumocytes epithelium that's not mucus and its stromal cells, you know, the whole gamut. And then she, I think probably because reviewers are still hung up on using the stoker type, she explains that if she ignores the size criteria and a few other things she puts them into, she still tries to put these things into stoker classification. And she describes the rate of different K.R.S. mutations in them and in the type that corresponds with the atreasia associated C.P.M. type two, she's not finding them. And then she is, we'll skip over this. Management points here are K.R.S. associated C.C.M. may have an exceptionally low rate of behavior construed as malignant or life threatening. But still, you may want to consider complete resection considering the very few cases where the mucus and its proliferation has gone on to fill up the lung. And a diagnosis also, a diagnosis of K.R.S. associated C.C.M. you think about it as a mosaic recipe, it could potentially help to inform other syndromic findings in an effective patient. So I'm going to show a case from here, a recent case to illustrate this. So this was a 15 year old male who had recurrent left pneumothorax. He presented with his first pneumothorax at age 11 at an outside hospital. And there he underwent two tube thoracostomy procedures prior to that fluoridesis. And then he presented to the VCHED eventually with a left tension pneumothorax. And CT scan was obtained due to suspicious, suspicious cystic lesions that were seen on chest X-ray. And the CT showed a very large left pulmonary airway malformation comprising about half the left lower low. And then it was, old records were retrieved and the CT from the outside hospital did in fact confirm that the cystic lesion had been present three years previously. So it was thought to be C.C.M. So here's the outside hospital studies at one time when you had quite a large pneumothorax. The collapse lung shows a cystic area with internal septations. That's the C.C.M. that wasn't recognized. And then here at Boston Children's Hospital with the lung reinflated, you very clearly see the large cyst. So this was a chest that had fluoridesis and lots of chest tubes and instrumentation in the past. So our partial left lower lebectomy specimen was wedged out. And you can see it was a very ratty looking flora and lung. And then under the microscope, you see these areas of large cyst with epithelium that's getting a little exuberant, a little thought to. So you might be thinking K-RAS right here as a pathologist. And then also there's more epithelial proliferation here of a different type. This is the small cyst type or quote, add a nomatoid type that's stock or described in this type three C.C.M. So again, here's a large cyst type and a small cyst type together illustrating example of why that pneumonclature is not that great. So you're looking at this and thinking that it's probably K-RAS. And then oh, here's the adenomatoid proliferation at higher magnification. And then there were also not just little newsonous proliferations, but very sizable ones. So I don't have a scale bar in here, but here's a here's a sizable airway in a broncovascular bundle. So this is a good couple millimeters. This musonous proliferation is it's not just filling an alveolus or two. And here's the musonous proliferation at higher magnification. So this was a K-RAS associated C.C.M. and completion low-bep to me as advocated by looks to the literature was considered. But this patient was not an operative candidate and he'll probably do fine. And then I have the category of other C.P.M. And this is a I mean all these are emerging categories, but this is the most emerging and it's just not well defined. But I'll show an example to explain what I mean. So here's a 14 year old boy with a right lower low C.P.M. And here we're looking at low power and at higher power. You can see it's it's a blend. This was sceptre that have just blend fibers tissue and an epithelial lining that is it's not entirely flat to keep boil like a Dyser is, but Dyser would still be in your differential. And then so that would be a type of one PPP would be in your differential and maybe you put K-RAS in your differential. Well now we have a panel so we can take our paraffin tissue from our blocks, send it the DNA gets made. We do targeted next generation sequencing using a panel. It's called an uncle panel. It's the same thing that we use for our cancer tissue now all the time. And turns out this patient had autism, spine, abysida and congenital itypapic and stagmus. And the lesion showed pick three R1 loss of function variant and that result in a regulation of PI 3K signaling and thinking about it, it really seems like something that could account for assist. So and potentially if his he has other tissue involved some of his other symptoms. So it's not really a diagnosis yet. I mean you wouldn't find it in textbook, but pick three R1 associated benign lung system. This is an example of what we're dealing with and we have other cases like this where you know it's not really a defined entity, but we're probably finding the underlying cause. So for the last little bit of this talk, I'm going to take you into the world of pathology and you will become a thologist so that you can understand and empathize what we're going through when we ask the question, are we ready to apply a new classification scheme? So this is a one day old premature 33 week female infant with a large left lower lobe cystic lesion and respiratory distress. And so we're looking at the slides and we see an area like this where there's just too many thin walls, airway like structures, you know practically right next to each other. And then here is normal size LVLI up here and then down here you see there are two large. So this is classic. It could go in a textbook for an atreasia associated CKM, which most closely aligns with the stalker type two. So that's what the first area of this lesion looks like. Well, the next area that we come to in the same lesion looks like this. So here you see this large cyst area really with proliferative looking at pathelium. I can see even at this magnification the sawtooth epithelium and then there's this smaller proliferation that reminds you of the adenomatoid change. So this kind of reminds you of caeras caeras across between stalker type one and stalker type three vaguely classification. So could it be caeras well, let's go to the next field. All of a sudden in the next field we see this proliferation of striated muscle skeletal muscle and skeletal muscle can be seen in atreasia. It can be seen in extra low bar sequestrations most commonly, but can also be seen in CKM that are caused by atreasia. Usually just it is really just little slips like one or two. So this is kind of a nodule of a skeletal muscle. So maybe you now you want to start thinking of dyser because dyser can have benign and malignant skeletal muscle in the tumor. This would be benign. This is benign muscle striated muscle. And then oddly there's this vessel with angiodesplasia, which is something that we see in metanefrixtromal tumor and I don't know what it's doing here. Okay, then so now we might be bringing dyser into the differential is very confusing. And then you see a assist that seems to have primitive cartilage in the wall. So now maybe dyser is really getting more to the top of your differential. If you were pathology trainees, I would have been calling on you, but I I spared you. So we turn to the molecular to confirm the this this hunch because you know it's confusing. But there's no K-Rest mutation is all dyser here. There's the classic germline mutation and then the second hotspot mutation that is what we usually see in pleural pulmonary blastoma. And so this patient did have a germline dyser mutation and this finding prompted testing in her one year old brother who's also affected. So it's significant not just to the patient but for the family. Okay, I've got another case. So this is an 18 year old female recent case presented with acute shortness of breath and a left upper low of cystic lesion. So looking at this. Maybe the first thought is a dyser of maybe a regress to dyser because there's no cellularity. There's just bland fibers tissue in the wall. There's a little calcification and sometimes regress to dyser in the adult will show that but other things can show calcification. So that's what you might be thinking. And then in another area you see epithelium that's no longer just cuboidal. It's really columnar and there's a bit of saw to think so you're going to bring K-Rest into your differential diagnosis. Also, there's areas right next to the lining where there's exuberant take to new mucites in a it looks like alveolar adenoma in adults. But it's just another sign of epithelial proliferation that really might make you think about a K-Rest mutation. So does anyone want to guess? We don't know. We did the testing dyser. So this is best regarded as a ppp type 1R. And the patient had a germline dyser mutation and so she must have gotten it from the mother because the mother was already status post thyroidectomy for nodules. And at last I checked the two brothers were not yet tested but they were going to be. So last case I have is 11 year old boy with a large right upper lobe or plural and or plural cyst. And this cyst showed all kinds of epithelium from cuboidal to squamous. And here you see some more cuboidal. And then here's mucinous. It's not exactly the same kind of mucinous that we saw in the type in the K-Rest associated C-KIM. And then there's more squamous epithelial lining. So it's a cyst with all kinds of lining. And it's hard to know what might be underlying it genetically. This patient had actually undergone testing before the surgery and had a germline dyser variant. And then there's a lot of other things that are going to be happening in the case of the ppb type one. So we're still really defining the spectrum as the molecular becomes more and more integrated into our practice defining the hisologic spectrum of these dyser lesions and other lesions. And then there's a lot of other things that are going to be happening in the system in progress, like so many other diseases in this molecular era that we are living in. This is just like the vascular malformations. And it's happening in all our our fields. So we're moving toward this classification, but we're not 100% there yet. But you'll probably see us trying in our pathology reports to make these advancements. So to summarize C-KIM and C-PAM are a heterogeneous group of disorders that have some time been pigeonholed into classification schemes and terms that do not reflect the anatomy and biology of the disease. And it's an exciting time to be in pediatric pathology and pediatric surgery to since so many genetic discoveries are being made providing the chance for phenotypic genotypic correlation and improved understanding of the biological impact of genetic disease. And then speaking of the tracheobronkyl tree and nomenclature, my my middle name is Oaks. It was my grandfather's mother's maiden name family name. It happens to mean someone living near an oak tree or an oak forest. And the name stocker also refers to a tree. And any symbolism here is just fear coincidence. And that's it. Are there any questions? Thank you so much for joining us and educating us and letting us into your world where things aren't so clear. And it's not just memorizing patterns and reading out and telling the surgeon and the family what somebody has. Your contributions you give predatory cancer, which but it's clear that you are in large part and have been a drug force along with him in understanding these pulmonary lesions and a whole host of other fields in which you have contributed to which I have had honor of partaking in as an observer in the many participants giving specimens. I want to remind the people online to put in the Q&A on zoom and I will try and read off your questions. It's interesting you say it's an exciting time because like when we went to medical school, maybe not some of you, but some of us went to medical school. We read the books, open Rob's and Kotran and this is what this is what the way things are. And nobody could ever imagine all of these genetic explanations or confusions. And so we're living a whole new world. As you've sort of alluded to, I've had the opportunity to sort of live in a field that wasn't paid attention to for decades, centuries. And we're still sort of when I started in a master, an almost we're in the beer cup, we're like describing things by the way they looked and then you and so your colleagues have. And I've been down in the pathology office and literally the way things in medicine happen is by smart people like you looking at things talking to people. Who will look at the patient from a different perspective and say what makes sense and literally apply names. And last week's cell lecture, I talked a little about a history of how some of the things were were named and talked about the contribution pathologists. And literally we have things that we describe now for decades, pronounced because of the accent of one of the pathologists and sounded better. Right? You know, reach. It's not rich. It's rich. Because the pathologist was French and he was here in the basement on the Sunday and John Malik and like the way it's out. And what you're showing us is that something that we learned about, there's sequestration and there's sea camp. And then we sort of got confused. And I don't know how many people are less confused now. But it's clear that you're pushing this more towards the truth. So you said we're still in early days. Where do you see the evolution of pulmonary malformations? When will we not call it early days and when will this make sense? Oh gosh. Well, I remember when I was in medical school and one of my professors said that 50% of what we're teaching you is going to be proved to be wrong. And I can see that's absolutely true. So I just want to be humble and say that 50% of what I said today, I'm sure will be proved to be to be wrong. But where are we going? I think we are going toward a classification that is like this. And I think that will employ more and more genetic testing and maybe get to a point where we can know the phenotypic correlation well enough that will have some cases where we won't have to in the future always do that testing. But they'll probably in the future be a lot more testing of these cases. And I think well, I already know that there's more genes involved than just the ones just K-RAS. So of course, we see the patients sometimes before they're born after they're born and we have to counsel families do we don't we operate? And that has evolved over time and some people in this room have contributed to change in practice. Do you think you're going to tell us with certainty when we should or shouldn't operate? Well, I think that at least project is helpful and I don't want to give any way any secrets, but he might we might see a paper from him looking at what the K-RAS associated lesions look like. I think the problem is that even if we see the atreasia, we don't always know what's causing it and maybe a tumor could be causing it or like I had showed that first Dicer case in my mystery cases. So yeah, I think I think that that is evolving. Well, thank you for your meticulous reports because the area is just evolving so quickly. You know, we really struggle in the fetal center and then postnatally what to do because we did not find these lesions 20 years ago with the fidelity of the prenatal imaging. And I would say the international community is pretty split. If you're born in Europe, you're going to get observed for your asymptomatic low bar process. And if you're born here, you're probably going to get a take it out. So we're actually combining and doing an international registry to look at and follow it's not being prescriptive and how you take care of the kids. It's just you do whatever your normal practice would be, but a lot of our decisions are based obviously on the radiologic interpretation of the imaging, which is muddy when you start to really look at the reports. And then we're going to evaluate the lesions that were resected based on the pathologic criteria. So my question is you're doing an incredibly elegant job trying to define this, but is this widespread and how do we like what factors should we take into consideration? We're looking at our pathologic outcome to try to answer these questions. So that's kind of like how widespread is this classification among the colleges and major children centers that are going to be contributing to this database. And then the second question is I'm completely intrigued by what people used to call carcinoma because we're taking these out because once the parents hear there could be a chance of cancer, everybody's panicked. So do we over call it? Are we mistating this? I'm just really fascinated by that. Yeah, my hunch is that we're over calling it, but most that's not what you're reading in literature. I don't think there's going to be very much uniformity at all in how these are called at other institutions. I think that there are there are apologists who are just still struggling with trying to apply a stalker classification. And you'll see these things named all kinds of things. So you're not going to have uniformity. Unless you have a some kind of central review. I don't know how practical it would be for someone to it's easy to do germline germline testing in advance in a developed country. That would help pick up a substantial proportion of the dyes are tumors, but I wonder if the cave rats associated ones which are not having a tree is usually and they're the ones that become super infected more commonly. If they are amenable to BAL and then genetic test because it's there it's not going to be the whole patient that carries the mutation there. That could be something to try that would be novel and could be helpful. Sarah, thank you so much. I'm looking forward to this talk and in some of those cases look very familiar. We share and we've had interesting, you know, so back and forth the email over what do we do with this genetic finding on this patient. I think one of the things that really set out to me was which I didn't realize was that the finding you pointed out about the muousinous changes actually sort of a normal variant is what I understand for a baby versus for an adult. I might be assigned a bronchialiobuolar carcinoma and I think that really might explain why there's such a variation in the rate of malignancy identified in certain case series where it's like people report really high rates of cancer in low beck to me where we're not seeing that and that probably explains a lot of that. My question is for a practical standpoint I think we talked a little bit about the difficult decision of parents in your clinic with the baby who is asymptomatic and there's this thing that we found the decision to operate. But then let's say okay we're going to operate but then there's this other aspect of okay do we do a low beck to me do we do a lobe sparing non anatomic resection and then do we do it minimally basically less morbidity or do we make a big deal. Or do we make a bigger incision to get the whole specimen out in one big chunk because when we do a minimum based on I'm sure you know you struggle with my specimens I'm sure whether sort of piecemeal a bit to get out through tiny incision any tips on on that as far as you know when the situation we should say you know what we should give give you the whole thing versus little piecemeal. What. Well here at this hospital we haven't given too much concern to going for the completion low beck to me over time and we haven't had children come back I mean we don't get long term follow long long term follow up into adulthood on these patients but it's the very rare patient that has their lung fill up with this musonous epithelium so it's I think that the risk is fairly negligible but this chop this chop study that looked at their cases really advocates low beck to me and that is kind of empiric because you don't know exactly where the mosaic rass off of the starts and stops and why is that you know that bronchus of like the perfect resection point it seems it seems kind of empiric so I don't know I don't think it's to even a literature saying low beck to me I think it's kind of empiric. Sarah have you seen or called ppb that was dyser negative and what are the characteristics of that if you've seen it. No you do see that in the literature that at x percent of ppb's are dyser negative for me at ppb it has to be it has to have dyser I'll give it a different name I haven't that's not my my framework really. One of the challenges and opportunities we have in the pediatric world is the question is really what is the long term and it's none of us practice long enough to see our patients 75 years later no whether you have lung cancer from something we're taught we can it's logistically challenging but the point that that for Oak brings up. You know if our database or path life database and our surgical database is extensive enough we have hundreds of lesions that intersected and have had love sparing procedures we could find those kids right and we could have them get next right you could get an IV to do that that would probably be big contribution just like what Terry's describing in terms of comparing the European experience and the American experience. You know you can look at the pathology of those we take out here but really you want to know is what's the long term follow up of the ones in Europe that didn't get the right and hopefully that's in plans. Your demonstration to us not only for this disease but for the entire sort of understanding of how ppb's and pathology works is really eliminating and thanks so much for joining us in surgical hours and for the incredible work that you have done. With us and for us over I won't need trouble we grew up together here and thanks for your continued partnership spectacular thank you.