We're going to review the classification of diffused cystic lung diseases and the common mimics and just outline a basic diagnostic approach for patients with a presumed diagnosis of diffused cystic lung disease. So first, when we talk about anything, so what is a lung cyst? And this actually comes up because sometimes we get referrals to the clinic for patients that are emphysema, while sometimes we have patients that have been called emphysema for years when what they have is actually diffused cystic lung disease. So pathology is any round circumscribed space that is surrounded by an epithelial or fibrous wall of variable thickness. Radiology is a rounded parenchymal lucency with a well-defined interface with normal lungs. So basically, round structure surrounded by normal lung and it has the wall supposed to be thin, usually less than two millimeters. So the diffused cystic lung diseases, what they share is the presence of parenchymal lung cyst. Aside from that, they're actually an heterogeneous group of disorders. All of the causes are rare. Actually they affect less than 200 individuals in the U.S., which is the FDA definition for rare diseases. The incidence and prevalence, you'll see in a bunch of review papers how they quote the incidence and prevalence of these diseases. It's all estimated. And in reality, it's probably underestimations because of lack of recognition. There's different mechanisms of cyst formation. So there's ball effect, ischemic dilation, connective tissue degradation, and the history of the diseases also varies a lot. We lump them together because of the radiology aspect of the cyst, but how they behave is very heterogeneous. So how I think about it is first. So are these true cysts or not? How many of them are present? Does the radiologic pattern actually tell me a specific diagnosis? Does the patient have any systemic manifestations outside of the lungs that can guide me about what the actual diagnosis is? And are there any symptoms or evidence of decline? So I'm going to try not to talk too much about radiology, but just some basics of mimics of cysts. So emphysema, they don't have a very defined, they don't have a clearly defined wall. There's also something called the central dot sign, which is when in the center of the area of emphysema, you can see the bronchovascular bundle in the middle. So you're going to see like a little dot in the middle. Fibromyalgia, well, it's a gas-filled collection, but usually has a thick wall greater than two millimeters. Honeycombing, which we see in fibrotic ILDs, and our cluster cystic spaces, they usually tend to have a similar diameter, and they can be either stacked up on each other or be just contiguous in a single row. And then blevs, which are air spaces that we see that are sharply demarcated, have a very thin wall, and usually occur peripherally and with concomitant emphysema. So when we see cysts, and this happens a lot more now that people are getting scanned for multiple reasons, is, are these truly an incidental finding, or are they truly diffuse cystic lung disease? So we know from prior studies that cysts actually increase with age, and it's now believed that some cyst development is actually part of the normal lung aging process. So in this study that was really interesting, where they look at the Framingham Heart Study participants that had a CT chest, they were able to find that about 8% of those patients, a little bit under 8%, had at least one cyst. And looking at all the demographic associations, what they found was older age and then low BMI had a significant association whether you had cysts or not. Their hypothesis was that the low BMI might be associated with poor nutritional status, which has also been known to predispose to emphysema. Now multiple cysts have only been seen in about, were only seen in less than 1% of patients. And you can see here how the cyst, the presence of cysts increase with age. How many cysts are significant, depending on where you read. More than 5 has been quoted, others quote more than 10. For example, in the LAM guidelines, they make a distinction about the patients that have less than 3, 3 to 10, and then 10 as being like their cutoff for significant. But 5 is a good number. So if you see one or two cysts, that really doesn't mean much. So how do we classify the cystic lung diseases? So different mechanisms, so pathophysiological classification, so neoplastic, genetic, associated with lymphoproliferative disorders, infection. You can also see it associated with ILD. We see it all the time when we are discussing cases in an ILD conference, and a case that looks like AHP or we know is AHP will have some cysts, smoking-related ILDs, and then other some rare causes that are just for pimping the fellows. Fire-eater lung, hyper IgE syndrome, is another good way of visual description of the classification of diffused cystic lung diseases. So which of the diffused cystic lung diseases are most common? So I told you that the prevalence and incidence of these diseases is estimated, and they're probably underestimating. So it's hard if you try to go by that. So I thought this article was really interesting. I haven't seen any other article with these scopes out there. But basically, they look at a LAM referral center and all their patients with cystic lung disease for 13 years, and they look at the diagnosis that they got. So 70% of the patients were LAM, and then Bird, Hog, Duvet, LIP, and PLCH were the most common ones. And again, it was within the LAM clinic, so there's going to be some selection bias. But it still goes along the lines of based on my experience, what we see in LAM clinics. And also, I thought what's very interesting, and I'll talk a little bit more about this, is that undiagnosed was actually about 18% to 19% of patients that they could not get a diagnosis despite the work. I'm not going to go in detail, because you'll hear more about this later. So LAM, so it's a rare, slowly progressive neoplasm in which there's smooth muscle cells that are infiltrating the lung. It's almost seen exclusively in women, and has lymphatic and renal manifestations. Bird, Hog, Duvet is a genetic disorder, it's autosomal dominant. It has to do with mutations in the protein that encodes folliculin, and it's associated with renal and skin findings. It's associated with interstitial pneumonia, it's a benign proliferative lung disorder. We don't understand the pathogenesis, but there's a huge list of things that it has been associated with, and we'll talk more about that later, but it can also be idiopathic. Then PLCH, which is a disease in which we have destruction of the lung by infiltration of CD1A Langerhans cells, and it's an inflammatory neoplasm. The interesting about PLCH is the near universal association with smoking. So almost all patients are smokers, and I will say it's smoking, vaping, tobacco, but also marijuana. There's some reports of association with that, so I always, when I talk to patients about it, I always ask about marijuana also. And the pathogenesis, now it's understood that it's actually due, almost all cases have asthmatic mutation in the mitogen-associated protein kinase pathway, which is interesting because aside from smoking cessation, there wasn't any good treatments for PLCH, but now this has opened other avenues to explore. So things I look at in the history. So age, like I told you, the older the patient, the higher the frequency of cysts, also the older the patient on presentation, then the less concerned I'm going to be about working them up. I recently had a referral for an 88-year-old that had incidental lung cyst, and after talking to her, we both agreed that we were not going to do anything about it. Gender, LAM, like I said, in women, smoking and vaping, tobacco, marijuana, PLCH. Then the family history, you can see it in births of duvet, tuberous sclerosis. Also manifestations, right? So pneumothorax, chylothorax, and then extra-pulmonary manifestations, which there's a broad group of things and questions to ask to the patients, and the more knowledgeable you are, the easier it's going to get to try to narrow down the differential. So renal tumors, skin lesions, always ask about dry eyes and dry mouth, seizures, diabetes infipidus, bone lesions, and then the history of recurrent infections and immunodeficiency in general. So radiology, I'm not going to talk much about radiology except to say that the HRCT is crucial to the evaluation of diffuse cystic lung disease. When we sit down with radiology, the things that we think about are, okay, so what is the distribution, what is the size, what is the shape, and are there other parenchymal abnormalities aside from the cyst? So if you think, this paper was interesting, in which they looked at just the accuracy of HRCT to diagnose diffuse cystic lung disease, and they looked at expert radiologists, pulmonologists, general pulmonologists. In general, most people did well for LAM, and they also asked them to rate when they thought they were confident about their diagnosis. Of course, they did better. And for non-LAM cases, that's when it really goes down. What I did extract from this paper, which I think is important to point out, so just looking at the expert radiologists, so the expert radiologists overall had an accuracy of 80% and an accuracy, even when they said they were confident, of about 90%. So that's why it's such an important part of this approach to review the case with a radiologist that has experience preferably. And then, not going to talk much about the radiologic differences, but they don't look the same, right? So laboratory evaluation, so initially, there's no standard about what is the right testing to do for these patients. So the things I initially consider is BGFD for LAM, for liquid gene mutation analysis, for Birkhoff-Duvet, and then for LIP, so ANA, SSA, SSB, and an HIV. And then if that doesn't give me an answer, then other things I think about are RFCCP, immunoglobulin levels, testing for paraproteinemias with SPEP, UPEP, serum-free light chains, and then EBV and HTLB. Bronchoscopy and biopsy, there is a role if the non-invasive workup doesn't show us, doesn't give us a diagnosis. There's always, we need to discuss the risk and benefits with the patient, particularly because there's this concern about the increased risk of diatrogenic pneumothorax. Undiagnosed diffused cystic lung disease, so when I started doing this, one of my main concerns was how many patients I would work up that I would end up without an answer. So I started asking my colleagues with more experience at other centers, hey, what am I doing wrong here? And the reality is everybody sees this, patients that we work up and we don't find a cause. So at this point, some patients, if we think they're progressing or there's signs that there's something worrisome, like underlying malignancy, things that we suspect need more workup like a biopsy, but for patients that are asymptomatic, normal PFTs, post-menopausal women, low cyst burden, that actually just reassuring the patient and monitoring them, normally I tell them, okay, I'll see you once a year, as long as you don't have any symptoms, and I'll just check your PFTs, and at some point you will develop more symptoms or manifestations or nothing's going to happen. Things that I tell them also, avoid smoking, stay up to date with vaccines. We talked about flying. They always ask about flying, and I tell them that there's no great data, but that in general it's safe. Now, after pneumothorax, again, there's no consensus, but normally I say at least two weeks. The British Thoracic Society statement actually says one week after you've proven that it resulted in chest X-ray. And I just tell them, if you ever have sudden chest pain, shortness of breath, go to the AED, and if you ever get a pneumothorax, we have to talk about pleurodesis. And then, in summary, heterogeneous group of disorders that vary a lot, despite being grouped together, when is it meaningful, more than five, make sure it's not a mimic, expert radiology review, knowing which are the extra pulmonary manifestations, and if you don't find a diagnosis, sometimes reassurance and monitoring is what you need to offer the patient. And just a shout out to the people I work with, our collaborators at the Yale ILD Center, and that's it. Thank you. And now, I'll leave you with Dr. Chung. So what a pleasure it is to be here. I am a radiologist. I used to work at University of Chicago, recently moved to UCSD, and so if I look tan, that's why. Usually I'm not this tan. So, real pleasure here. I'm going to be talking about the radiology of cystic lung disease in a real practical approach. So there are lots of cystic lung disease we could talk about, and so if we want to cover all of them in good enough detail, probably take at least a half hour, maybe even more than that. But in the allotted 15 minutes, I think we can hit the four biggies, and I'll go into what the four biggies are in just one second. These are my disclosures, none of which are directly pertinent to this talk. So after this talk, you are able to list the common causes of cystic lung disease on imaging, identify the presence of cystic lung disease using a general diagnostic approach, and you could discuss specific findings more suggestive of bird hog duvet as opposed to lymphocytic interstitial pneumonia. I feel like I would have been successful. So these are the first four underlying diagnoses are, in my mind, the big four cystic lung disease. This is what the data suggests, that in most clinical practices, if you gave this differential diagnosis, these first four things, you'd be right the vast majority of the time. So long-hand cell histocytosis, lymphangial myelomatosis, LIP, and bird hog duvet syndrome. So we're going to go through all these in just one second, but I wanted to talk about approach first, because very few patients walk in, well, sometimes they do, but very few patients will walk in with a diagnosis already stamped on them. They're going to come in with some sort of nonspecific cystic lung disease on imaging. Very often, this is how they're detected. We use so much more imaging now, CT, both in the chest and in the abdomen. And so it's instantly detected, and now it's the radiologist's job, and sometimes your job, to figure out what the patterns suggest on imaging. So what's a practical approach? This is what I teach my residents and fellows. First things first. So there are mimics, as aforementioned, to cystic lung disease. So the thing that's most common is probably centralibular emphysema. We see this all the time. And then also, in addition to that, you can also have paraceptal emphysema as well. So these two things, they look like cysts, and you wonder to yourself, is it cystic lung disease or is it just smoking-related emphysema or emphysema from some other cause? Also, a lot of patients will have post-infectious, post-inflammatory, or post-traumatic pneumatoceles. These can occur as well. And so I was taught, this is based on very, very not great data, that if someone walks in off the side of the road and they have more than five to seven cysts, you start thinking about diffuse cystic lung disease, like real cysts. We're not talking emphysema. We're not talking honeycombing, things like that. Real cysts, they have walls, they meet the definition per the flexion criteria, you start thinking about that. Obviously, if someone has a strong family history of cystic lung disease, or someone has a history of tuberous sclerosis, or if there's some other clinical finding that makes them higher risk for cystic lung disease, then probably even a couple or a few is enough to make you worried about an early cystic lung disease. OK, so once you've excluded mimics of a diffuse cystic lung disease, now what are you left with? So you want to figure out, well, is it LCH, long-hand cell histiocytosis, or lymphangel-lyme hematosis? At least in my clinic, some of the data is mixed, I think it depends on what clinic you work in. But in the clinics that I've worked in, lymphangel-lyme hematosis is by far the most common diffuse cystic lung disease. Then long-hand cell histiocytosis, I wonder if that's actually under-diagnosed at many places. And the fault of that would be the radiologist, right, so the radiologist is the one who's going to be diagnosing these vast majority of cases of long-hand cell histiocytosis. And then to consider lymphocytic interstitial pneumonitis and bird-hug-to-bay syndrome. Long-hand cell histiocytosis is usually very, very different-looking than these other diffuse cystic lung disease, and I'll show you that in just one second. OK, so here's some classic examples of paraceptal and central lobular emphysema. I think that these are pretty characteristics. In most situations, you need to figure it out, especially the paraceptal emphysema and the central lobular emphysema also, in most situations, unless there's some sort of superimposed infiltrative process, you can note that there are these areas of hyperlucency, but they have the central dot. They have this vascular structure within the middle of them, and if you look really, really carefully, they don't really have walls. These aren't cysts. These are just areas of lung destruction. So it's important to really first rule these things out. Obviously, you get more destructive emphysema. This is advanced destructive emphysema. This doesn't really even look like a diffuse cystic lung disease to me, but I think I'd be remiss if I didn't at least mention it. Okay, so I mentioned my practical approach to diffuse cystic lung disease, and I think it's—someone told me it's rudimentary. They said, it's too simple, right? It's like you're—it's not sophisticated enough, and you're not going to make enough diagnosis, and I said, okay, that's fine, right? And so one of my mentors, Dr. Lynch at National Jewish, he actually wrote this great paper with Eskalon here, when Eskalon was a fellow there. I forget where she is now, somewhere on the East Coast, maybe Connecticut, but anyhow, they had this algorithm, they created this algorithm, which was very accurate for the diagnosis of diffuse cystic lung disease, specifically these three subtypes of LAM, lymphocytic interstitial pneumonitis, and Birdhug-Dubé syndrome. Why did they exclude lung cancer, histiocytosis? Because it looks really, really different from these other types of diffuse cystic lung disease. In a few slides, I'll show you how phenotypically it's very, very distinct. And so first step, you want to see, is the distribution diffuse or lower lung preponderant, right? And if it's diffuse, so it involves all portions of the lungs, you start thinking about lymphangial lymepitosis. And already, that's sort of like the diagnosis you're thinking of in the back of your head, even before you even look at the imaging. If you know the patient's diffuse cystic lung disease, based on the data, you're thinking LAM, LAM, LAM, LAM. So you need findings that sort of push you away from LAM. So if it's diffuse, you kind of make a presumptive diagnosis of LAM, and you kind of work down here. Obviously, if it's a male, you pause, because a male with lymphangial lymepitosis, that'd be highly unusual. You probably have to go back to the drawing board and reconsider. But as a female, diffuse cysts, beautiful cysts throughout the lungs, again, I'll show you an example of this in just a bit, we're going to go down that LAM route. And again, based on even the pretest probability of diagnosis, even before you have that CT scan, you'd be thinking about LAM. So we're done with LAM. If it's lower lung preponderant, now you're thinking about lymphocytic interstitial pneumonitis or birdhug-de-bay syndrome. So how do you differentiate LIP from VHT? And so what you do is you look for a preponderance of paramedia stenosis. So are there greater than two elliptical paramedia stenosis, or a disproportionate collection of paramedia stenosis? If so, then more likely than not, the diagnosis will be birdhug-de-bay syndrome. I don't know why birdhug-de-bay likes the paramedia stenosis portion of the lungs, but it sure does. I had multiple examples of it clustering along the paramedia stenosis portion of the lungs. In this algorithm, they didn't look at the upper abdomen, because that would be cheating. Obviously, some upper abdominal findings will kind of make you lean one way or the other. And so they excluded that from their evaluation. But again, I'll show you some examples of how upper abdominal findings can help you make the diagnosis as well. So if it doesn't have this paramedia stenosis thing, then you make a presumptive diagnosis of lymphocytic interstitial pneumonitis. Obviously, you need a good clinical workup. Certain patients with immune deficiency are going to be more likely to develop lymphocytic interstitial pneumonitis than Sjogren's syndrome. But based on this algorithm, that's what you would make the diagnosis of, okay? So relatively simple, just a couple steps here. The data suggests that this is about 85%, maybe 90% accurate. Some people were more successful than others in using this algorithm, but it's pretty darn good. And my approach, I actually have no data. I don't know exactly how good it is. I think it's pretty good, but again, I'm biased, because it's mine. But if you want, actually, an algorithm that has data associated with it, this is the one to go after. All right. Now, let's talk about pulmonary lung cancer, histiocytosis, and why it's not part of that diagnostic algorithm, because this really just looks different. So PLCH, and I'll probably just call me LCH from now on, it has a distinctive look. It's ugly. It's just ugly. So very often, you have these bizarre-shaped cysts, often asymmetric thickening of the walls, as you see here. They start to coalesce into each other, which gives you these sort of bizarre-shaped, ugly cysts, as you can see here. You can see rounded cysts as well, but very often, the rounded cysts have a little bit of wall thickening. They're not quite cavities. Cavities. They're not that thick of walls, but they're thicker than the cysts that you're going to see in the other diffuse cystic lung diseases. Very commonly, you also see associated central lobular nodules, and this is where the cysts emanated from. They start out with these little central lobular nodules, which then cysted out. And so because these nodules are cysting out to create these larger cysts, very often, you'll see these small cavitary nodules, right? So we call them cereals. I'm sure you guys heard that Cheerio sign. This is kind of what the Cheerio sign is referring to. These small little nodules, little holes reminiscent of the cereal Cheerios. Almost always, LCH is upper lung preponderant. I think I've seen lots of cases of LCH now. I'd say I'm sure well over 100 at this point, and I think there's only one case I've seen where it was in upper lung preponderant and didn't spare the costopreneus. One case. And that one, I'm wondering if maybe the diagnosis is wrong. So this is one of these cases where, as a radiologist, I'm not going to hedge. Radiologists often hedge. That's our favorite plant, right, the hedge? In this setting of LCH, I think I can confidently say that more or less you will never get a case of LCH where the lung bases are not at least relatively spared. Another example of LCH here, again, beautiful example of these bizarre-shaped cysts with these associated central library nodules. Some of these with these cheery-like configuration, cosphrenic angle is spared. Another example here, bizarre-shaped cysts, not many nodules in here, just a couple here and there. Some of these are sort of thick-walled, these ugly cysts. But again, note the beautiful sparing of the lung bases and the cosphrenic angles. Another example here, again, I think I'd be remiss if I didn't mention this, again, here's the cosphrenic angle which is spared. Sometimes these LCH cases, we call them like burning out, like the inflammation goes away and you're left with this appearance that kind of looks like emphysema plus scarring or fibrosis. That's kind of the feel of it, it's with this extra articulation, and that's exactly what it is. So this is probably a combination of emphysema plus some cysts plus a little bit of scarring slash fibrosis. And so that's sort of the burned-out manifestation of LCH. So you will see this from time to time. All right, so now let's switch gears here. So that looks completely different. That's completely on left field. I have four minutes left and I have three diagnoses to go through, so I better talk more quickly. So lymphangial amyotosis, thin-walled cysts. These are beautiful cysts, round, oval in shape, and involves a lung diffusely, as you can see here. It's just beautiful. So if you imagine what diffused cystic lung disease will look like, this is the archetype. It's just like cysts in there, intervening lung completely normal, cosphrenic psilocyte are involved. In the upper abdomen, look for renal and hepatic angiomyopomas, and so what are the manifestations here? You're looking for fatty tumors, things with fat in them within the kidneys and within the liver. Sometimes you get these cystic lesions as well, lymphangiomas. Here's another example of lymphangial amyotosis. This is using a MINP, minimum intensity projection image. The patient has a small right-sided pneumothorax as well, so one of these cysts probably popped. So there's a little bit of a fistula connection there. But again, beautiful example. Okay, so lymphangial lymph, LAM, that's a case, those are examples of LAM. Beautiful cyst. So now we're talking about lymphocytic interstitial pneumonitis, or pneumonia. These are a little different. In the inflammatory phase, a lot of these LIP cases, you're going to see ground glass opacity, as you see here, ground glass opacity and reticulation. But when the inflammation starts to calm down, very often you're left with this chronic diffuselistic lung disease. Variable in number, but very often they're going to be parabronchovascular, as you see here. But you can also see some subpleural cysts as well, in my experience, but they're almost always basal predominant, in my experience. I mentioned that you can get some reticulation there. Amount of reticulation, in my experience, is pretty mild. So here's an example, a little bit of ground glass opacity with a little bit of variable reticulation there. And sometimes you'll see associated central lobular nodules, though this doesn't seem to be a major pattern that we see in most cases of chronic lymphocytic interstitial pneumonitis. Another example here of some ground glass opacity with reticulation. Here's another case where it's really a pure diffuselistic lung disease at the lung bases. We see it's parabronchovascular and subpleural in its distribution, and clearly basal predominant, as you see here. And just another example, just more of the same. This patient does have some concomitant nodules and patchy ground glass opacity within lungs, implying some degree of associated inflammatory changes. Sometimes because it is parabronchovascular, we see this pericystic dot. And so very often people like to look for this if they're worried about lymphocytic interstitial pneumonitis. And so now we'll talk about Birdhug-Dubay syndrome. Birdhug-Dubay syndrome and lymphocytic interstitial pneumonitis sometimes can be very hard to differentiate from each other. And so you're really, really lucky if you see all those paramediastinal cysts, because then you can feel much more confident that it's going to be Birdhug-Dubay. But there are cases of Birdhug-Dubay, I've seen actually a few of them, where you don't get that paramediastinal concentration. But it's clearly Birdhug-Dubay syndrome. So as I alluded to before, and I'm making a big deal about now, you're looking for these paramediastinal cysts. If you just look at the morphology of the cysts themselves, they look very similar to LIP, very similar to LAM. Some of these cysts at the lung base with Birdhug-Dubay syndrome, they can be multisubstituted, and they can show the air cuff signs. What is the air cuff sign? Essentially the cyst is, it almost looks like an area of emphysema. You're almost seeing the vessel within the central portion, the vessel with the central portion of the cyst itself. But it's clearly a cystic lung disease. It's not a case of emphysema. So another example here of the central, the air cuff sign. We see this vessel here, and around it we see the cyst completely encompassing that vessel. And so here are some other examples. This is another Birdhug-Dubay syndrome. On the left we have the axial, regular axial image. On the right we have the coronal minute, minimum intensity projection image. And again, look at the beautiful paramediastinal cysts. This is, you can't miss that. It's just beautiful. And another example here of paramediastinal cysts in Birdhug-Dubay. This is an example of Birdhug-Dubay where it kind of just feels like LIP. I looked at this and said, oh, it feels like LIP, just basal predominant system, paravonculvascular. Here's the minute, minimum intensity projection image. But here we saw bilateral renal cell carcinomas. So remember, with Birdhug-Dubay, you can develop renal tumors, and they're not angiomyopoma. They don't have the fatty lesions in them. These are going to be solid tumors, renal cell carcinomas or oncosectomas, renal cell carcinomas being much more prevalent. So here's my summary slide here. So remember, LAM, diffuse, beautiful cysts, PLCH, long-hand cell histiocytosis, ugly cysts, upper lung preponderance, and smoke-related lung disease. It looks completely different. LIP and Birdhug-Dubay, they're both basal predominant cysts. Remember, Birdhug-Dubay loves the paramediastinal portion of lungs. Not quite sure why. And that's my alarm telling me that I've gone over a little bit. Anyhow, I apologize for going over by a few seconds. Thank you guys very much for your attention, and these people I'd like to acknowledge. Good afternoon, everybody. I don't know why I put my picture here. I realized later that that was not supposed to be a place for photo, but maybe I was worried that I won't be visible behind the podium. So anyway, I will talk about diagnosis and management of three conditions, which is Birdhug-Dubay syndrome, LIP, and LAM. And I do not have any disclosures. Starting with Birdhug-Dubay syndrome, it's a rare autosomal dominant inherited conditions with prevalence of about two cases per million. It is caused by germline mutation in the FLCN gene, which encodes for a protein called folliculin. And folliculin protein is responsible for cell growth, proliferation, and survival through mTOR signaling pathway. To date, FLCN gene is the only gene responsible for this disease, and there are more than 150 different mutations have been identified across all the exons of this gene. Diagnosis is usually made in third or fourth decade of life with no sex predilection. Pulmonary manifestation, which is cystic lung disease, is the most common presentation present in 80% of cases diagnosed in fourth or fifth decade. Pulmonary function tests are usually either normal or they are minimally affected, and patients are usually asymptomatic. The cystic lung disease associated with Birdhug-Dubay syndrome does not progress to respiratory failure. The most common presentation is spontaneous pneumothorax, which is present in 24% to 38% of cases, but there is high rate of recurrence of 75%. Therefore, it is very important if we see a case of spontaneous pneumothorax in a young person to obtain a CT scan of the chest and to obtain a family history about pneumothorax and look for other manifestations of Birdhug-Dubay syndrome, which could be skin manifestations presented with fibrofolliculomas, trichodiscomas, or acrocordons, which are skin tags. They are present in 80% in Caucasians ranging from age 15 to 60 years, and they could be presenting sign in some patients. They are usually present perinasal, retroauricular, knuckle, or upper chest. Renal tumors are present in 14% to 34% of the cases. Interestingly, the histology in Birdhug-Dubay syndrome of renal tumors is more commonly hybrid chromoform renal cell carcinoma and onchocytoma or chromophobe RCC as compared to clear cell or papillary renal cell carcinoma seen in general population. So diagnosis of Birdhug-Dubay syndrome, there are at least three different diagnostic criteria being proposed. I have put here one of them. Amongst the major criteria, at least five fibrofolliculomas or trichodiscoma and at least one histologically confirmed or presence of pathogenic FLC and germline mutation. Amongst the minor criteria, the typical CT scan as we discussed here, and renal cancer which is present in younger patients, present bilaterally or multifocal, or the interesting histology that we talked about, mixed chromoform and onchocytoma histology, or a first degree relative having Birdhug-Dubay syndrome. So if you have one major and two minor of these criteria, you can make the diagnosis of Birdhug-Dubay syndrome. Amongst the management, there is no specific management. The management of Birdhug-Dubay syndrome mainly revolves around preventing and treatment of pneumothoraces and screening and surveillance for renal tumors. Coming specifically to these manifestations for pulmonary, we talk about patient education about pneumothorax, smoking cessation, to be up to date with the vaccination, diving is discouraged. It is unnecessary to advise against air travel. It is not recommended to do regular pulmonary function test and CT chest as the disease does not progress rapidly. Consider pleurodesis after the first episode of spontaneous pneumothorax. For renal tumors, screening of renal tumors should be started at the time of diagnosis or earliest at the age of 20. MRI is recommended imaging modality. After initial imaging, follow-up is recommended every three to four years. If one or more tumor is detected, it is recommended to postpone surgery until the largest mass is greater than three centimeter in diameter. A delayed nephron sparing surgery is favored to preserve kidney functions. Radiofrequency ablation or cryotherapy are alternative nephron sparing techniques. The skin lesions are usually benign, but they can be disfiguring and can cause a lot of psychosocial burden. So excision, debulking, ablative laser surgery, or electrodissection can be proposed, but recurrence may occur. With that, we will switch gear to lymphocytic interstitial pneumonia, or LIP, which is a clinical pathologic condition associated with expansion and infiltration of bronchus-associated lymphoid tissue called BALT. What happens is that some inflammatory cells, like T and B lymphocytes, histiocytes, and plasma cells would enter into the interstitium. There could be a number of triggers that can cause it. Lebo and Caddington were the first ones who described this in 1966, and after that they had additional 17 cases, and they wrote it down in diffuse pulmonary lymphoreticular infiltration-associated dysproteinemia. But after this seminal paper, a number of papers were published looking at the inciting triggers, like what causes LIP. On top of the list are autoimmune conditions, such as Sjogren's, SLE, rheumatoid arthritis, Hashimoto's thyroiditis, myasthenia gravis, pernicious anemia, chronic active hepatitis, or primary biliary cirrhosis, followed by viral infections, especially EBV, HIV, HTLV, combined variable immune deficiency. There are other infections that can cause LIP as well, which are not viral, such as Legionella, tuberculosis, mycoplasma, and chlamydia. After that are rare causes, such as a complication of allogenic bone marrow transplant, or phenytoin or diaphenylhydretoin use, pulmonary alveolar proteinosis, or pulmonary alveolar microlithiasis. If you do not find any cause, then we will label it as idiopathic. The presentation is nonspecific, and it also depends on the underlying disease. If you read the literature, the recommendation is to obtain a surgical lung biopsy to make the diagnosis, because you need to do immunohistochemical staining to rule out any monoclonal proliferation of the cells. But it depends on the scenario. If you encounter LIP in a case of Sjogren's disease, I do not think you need to do surgical lung biopsy. Similarly, if you see a case of LIP in a patient who has HIV, you do not need surgical lung biopsy. So I would say that it depends on the case that whether you really need to do biopsy. So after the LIP is diagnosed, then you look for underlying diseases. And this is the suggested list of laboratory tests that you can do. Number one would be to rule out autoimmune conditions. So you can start with ANA, CCP, or rheumatoid factor, Sjogren's antibodies. You can also look for viral etiologies. So you can check for EBV, titers, HIV, or immunoglobulins. You can do serum and protein electrophoresis and thyroid function tests. The treatment is, there are no randomized controlled trial. It is based on anecdotal experience. You may see improvement even without treatment. Generally, LIP is considered steroid responsive. And in 50% to 60% of the cases, it does response to steroid, but relapses occur. Other immunosuppressants have been used, but they have variable results. For combined variable immune deficiencies, cyclosporine A, IVIG, and steroids have been used. For HIV-associated LIP, multidrug antiretroviral therapy sometimes cured LIP. But mortality in HIV is not associated with the presence of LIP. Prognosis is also variable and is often unpredictable from the clinical parameters that we have. Death has been described in one third of the cases in the first five years after the diagnosis. And the most common cause of death would be infectious complications related to treatment, progressive pulmonary fibrosis, and transformation to malignant lymphoma, which is seen in 5% of the cases. Now switching to LAM, LAM comes in two forms. One is sporadic LAM, and the other one is due to the germline mutations of tumor suppressor gene TSC1 or TSC2. Now when it is associated with TSC-related gene, it causes the suppression of this tumor suppressor gene, which causes activation of mTOR pathway, which is responsible for cell growth and proliferation. LAM is seen in women of childbearing age with estimated incidence of 3.4 to 7.8 per million. And it is associated with proliferation of smooth muscle cell-like LAM cells, which cause the cystic destruction in the lung, chylospiral effusion, AML, and other lymphatic complications associated with proliferations of these cells. The frequency at which these complications happen is tabulated here. Renal AML is more common with TSC or tuberous sclerosis-associated LAM, which is 80% compared to sporadic LAM. When we obtain the biopsy, there are certain receptors like HMB45, estrogen receptors, and smooth muscles that we stain for to make the diagnosis. So the most common complication or presentation of LAM is spontaneous pneumothorax and progressive dyspnea. In 10% of the cases, it can present as renal AML in an undiagnosed case. When we encounter a case of typical CT scan showing LAM, it is important to look for features of tuberous sclerosis, which could be hypomelanotic macules, chagrin patches, angiofibromas, ungual fibromas, oral fibromas or dental enamel pits, bilateral renal AML, and renal peritoneal lymphangiomas. So in order to make the diagnosis, WEGFD of greater than 800 nanograms per ml is diagnostic. Otherwise we do biopsy and immunohistochemical staining for the receptors that I talked about earlier would be diagnostic. But you don't have to do WEGFD in every case. There are certain conditions in which you do not need WEGFD to make a diagnosis, such as if you have presence of AML, presence of lymphangioleomyomas, chylus pleural effusion, presence of tuberous sclerosis, presence of LAM cells on pleural fluid or lymph node biopsy. So after Myles' trial published in 2011, the cystic lung disease associated with LAM has – the mTOR inhibitor has been approved – mTOR inhibitor serolimus has been approved for the treatment of cystic lung disease associated with LAM. And the indications would be FEV1 less than 70% predicted. There are cases where FEV1 is greater than 70%, but the person's FEV1 is declining, or there is elevated residual volume or decreasing DLCO or desaturation. In those cases, you still can give that person serolimus. In 18 to 26% cases, there is bronchoreactivity. In those cases, consider adding inhaled bronchodilators. If despite treatment with serolimus, the lung functions are declining or due to some reason, a person is not able to tolerate serolimus, then lung transplant obviously is an option. For pneumothorax and air travel, pleurodesis is recommended after the first pneumothorax. The incidence of pneumothorax is 2.9% by air and 1.3% by land. It is seen that it is the incidence of pneumothorax after air travel is higher when there are larger cysts and there is decreased lung function. Current recommendations do not prevent stable LAM patients from air travel. Regarding AML, if the size is less than three centimeters, then surveillance imaging every one to two years are recommended. Large and symptomatic AML, for example, if there is bleeding, hematuria, or aneurysmal dilatation or pain, then MRI with or either selective embolization or nephron-sparing surgery is recommended. Otherwise, mTOR inhibitors are very useful and helpful in shrinking the size of AML. Lymphatic manifestations, if there is pleural effusion or chylocystitis, then drainage would be recommended to relieve dyspnea or abdominal distention. Again, mTOR inhibitors would be the first-line agent. If recurrent or refractory, then thoracic imaging followed by thoracic embolization or ligation may be needed. Regarding pregnancy, women with LAM should be informed about the risk of pregnancy and possibility of disease progression. In this study, in 353 pregnancies, 16.7% had spontaneous abortion, 15% had therapeutic abortion, 1.4% had stillbirth, and 25% had exacerbation of symptoms. Sirolimus is regarded as pregnancy category C drug. More studies are coming regarding that. Amongst the general measures, pulmonary rehabilitation in various studies have shown to be very helpful in LAM ladies. And long-term oxygen assessment should be done as soon as possible. Special attention should be given to bone health. And lastly, a special plug to LAM Foundation, which is an excellent resource for providers as well as for patients to look up anything regarding LAM. Thank you. Thank you, everyone, for staying for the last talk of the session. The other speakers have made my job easy for me. Mine will be just case discussion, but we'll see whether they have done their job well. This is going to be an ARS session. I just wanted to introduce myself. My name is Rachana Krishna. I'm an ILD physician at MUSC in Charleston. And I don't have any disclosures. So we'll go to... So this is the QR code for your ARS questions, if you want to answer. All right. So the first case that I have, these are all cases from our clinic. So very true cases. And I'll show you their scans also. So this is a 35-year-old woman, went into the ER with acute chest pain. She had a CT, which showed cysts, and was referred to the clinic, pulmonary clinic. And by the time she came to us, she did not have any chest pain. It had resolved spontaneously, didn't have any pneumothorax. She was asymptomatic, was hiking several miles without Dyspnea, and review of systems was pretty unremarkable. She did have a history of migraines, and she was trying to get pregnant with IVF but didn't have any success yet. She worked as a schoolteacher, was not a smoker. She did give a significant family history. She told us that her sister was diagnosed with neurofibromatosis. And the sister had skin neurofibromas, skin lesions with cafe au lait spots, had some skeletal abnormalities, which were corrected surgically, but didn't have any developmental delay or seizures. And her nephew also had neurofibromatosis. And the physical exam was pretty unremarkable. She did not have any skin lesions to note. And lung function was fairly OK. She did not have any obstruction. FEV1 was 72%, and no air trapping or increased residual volume here. I'll show you the CT scan next. Hopefully this will play. I guess one more time. Am I supposed to comment on this? No. I can try. Well, we'll let you comment on it after. OK. So she did have some lab scent, most of which were negative. She had an alpha one level also scent, which was not reduced. So we'll come to the question next. Let's see. The options are not showing up for some reason. Sorry. Alright, so sporadic LAM, TS-LAM, and neurofibromatosis, okay. So let's see, what is the next step for this patient? All right, this is what we did, but I see that there are several of you who would have done slightly differently. But so I wanted to bring this case up because we did discuss some other etiologies outside of these three main categories for cystic lung disease, and she had a family history of neurofibromatosis, so I just wanted to bring up this case because she had, you know, family history, and our dilemma in the clinic was her imaging, as Jonathan would agree, was suggestive of LAM, and so we were not sure, and she was wanting to have kids, wanted to know whether the diagnosis was accurate, she wanted a clear diagnosis. So we did send her to HFT level, and it did come back high, and she was diagnosed eventually with sporadic LAM. But something to note is that neurofibromatosis can also be associated with diffuse parenchymal lung disease, and this case series by Dr. Zamora looked at lung involvement in neurofibromatosis, and about 50% had Buller's disease, and 25% of those cases had cystic lung disease, so something to keep in mind. But this patient did not have neurofibromatosis, and she did end up actually having genetic counseling prior to becoming pregnant, so we found that out also. Next case, 50-year-old woman having dyspnea for a year, and she presented to the ER with abdominal pain. She had a CT abdomen, and the lower lung fields caught some nodules, but the abdomen imaging showed diverticulitis, and she was treated with antibiotics for the diverticulitis and got better, but her shortness of breath continued to get worse, and was referred to the clinic, in Pulmonary Clinic, one of our nearby hospitals. She did have some weight loss, but the rest of the REVF system was negative, and she worked in a grocery store. She used to be a smoker until three months before she came to the clinic, and she didn't have any family history of pneumothorax. She did not have any skin lesions, but her lung exam had visas, expiratory visas, bilaterally. A lung function showed obstruction, severely obstructed, severely reduced FEV1. She had elevated residual volume and reduced diffusion also. And I'll show you. She had two CT scans, one at the time of her CT abdomen, which I'm going to show you now, and I'll show you the one when she came to the hospital nine months later. So this is the first CT. So as you can see, there's a lot of nodular opacities. And then this is the next CT when she came in nine months later. Okay, so, and she had some labs done also, and these were all pretty unremarkable. Okay, let's find out what you guys think. All right, great. So most of you think it's Pulmonary Langerhansel Hysteocytosis, which is, if Dr. Chung would agree, is that what you would say? Yeah, it's ugly, right? So it's ugly cystic lung disease, almost always that's going to be LCH, yeah. And the cost for gangles, they were like relatively spared. So she was diagnosed with Pulmonary Langerhansel Hysteocytosis. She had already quit smoking by then and didn't have any other extra pulmonary symptoms. She was started on oxygen by the time she came to us. And we did get a screening echo, and she did have mild pulmonary hypertension, and she was eventually referred to lung transplant. But a brief overview on this, I think some of it is already touched on. But as you saw in the previous presentation, it's upper lobe predominant, irregular, bizarre shaped cysts with nodules. And this case clearly showed the nodules evolving into cysts, which is why I showed both the CTs separately. And you can diagnose that with a biopsy, but most of the times you don't need to. And if you do end up doing a biopsy, you can see CD1A positive cells. And the important thing to remember is a minority of patients with PLCH will have extra pulmonary manifestations, which like I said, it's rare, but something to screen for. They can have pituitary involvement with diabetes insipidus, and so you look for urine output and sodium. They can have cystic lesions in the bone. And they obviously, with the smoking history, have a higher incidence of lung cancer than other cystic lung diseases, so something to look for. And they also have a higher incidence of pulmonary hypertension, so screening with an echocardiogram. And management is primarily smoking cessation, but as we are getting to know more of the disease, some people progress despite smoking cessation. And hence, there have been some studies showing the use of cladribine, which has been successful. And with certain individuals who have positive mutation for BRAF and V600E, there have been reports of using Vemurafenib, which is another chemo agent to help with the progression of disease in these folks. But that's mostly for when there's multi-system involvement and significant progression of disease. So I actually would like to stop before we do the third case, since we are out of time, since I anticipate that people may have questions. So I'll not do my third case, and we can pause and take questions at this time. Thank you.

diffuse cystic lung disease

sporadic lymphangioleiomyomatosis

LAM management

pulmonary Langerhans cell histiocytosis

LCH management

cladribine

Vemurafenib

VEGF-D

serolimus