So, good afternoon, everyone. My name is Mary Jo Farmer. I'm Associate Professor of Medicine at the UMass Medical School up in Springfield, Massachusetts. So welcome to this session, which is called Unusual Manifestations of Unusual Diseases. So I guess it goes without saying we will be hearing about some unusual things. Let me just read a few of the ground rules. Just a reminder that all these sessions can be evaluated through the mobile app and or the online program. And don't forget to evaluate this session when it's done. Presenters are required to verbally disclose any or no financial relationships relevant to their presentations. And what we'll do, since I believe there are going to be six presenters, each presenter will have eight minutes each. So I thought what we could do is I'll call up the first three presenters, and you can have a seat at the table, and you can each present. And once those first three presentations are done, then we can open the floor up for questions. If you do have questions, I invite you to approach the microphone and identify yourself, and then direct your question to the appropriate presenter. So I guess we can begin. So first off, I have on my list, I have Malsha, hi. And then I have Tom, Thomas. And then is Zainab here? Okay. So then I'll move up John. So Malsha, we'll move you up here. And you can obviously introduce yourself when you begin your talk, what institution you're from. Okay. You should be ready to go. Hello. My name is Malsha Walgamage. I'm one of the PGY-2 internal medicine residents in Danbury Hospital. I wanted to come with an element of surprise, but my topic was right there, so that's fine. Okay. I have... It's okay. I have nothing to disclose. So I want you guys to think about a differential when you see this CT scan. Think about it, and then we'll discuss my case. Okay. So my case is the traveling fibroids, a case of a benign metastasizing leiomyoma. Probably it was in your differential, or maybe it wasn't. But I know one of the suspected would be, we'll talk about the differentials when it comes to it. So these are my objectives. Okay. So a 45-year-old female presented to the outpatient pulmonology office for incidentally found multiple lung nodules. She has a past medical history of uterine fibroids. She is an ex-smoker. So a month ago, she underwent a total abdominal hysterectomy and oophorectomy. And during the anesthesia emergent state, she had a transient hypoxemic episode. So they did more investigations. They did a chest X-ray, I'll tell you about it. But when she walked into the clinic outpatient, she was asymptomatic. Her vital signs were normal. She had no indication of any pathology is going on in her lungs. So they did a chest X-ray, and it showed multiple lung nodules. And they did a CT scan, and it showed what we saw before. It showed multiple enumerable lung nodules in bilateral lungs, predominantly in the hematogenous zones. And comparing the prior imaging she has done, 10 years ago, she had an abdominal CT scan. And in the lower lung basis, she also had some lung nodules that had gone uninvestigated, which was in a similar presentation like the current CT scan. So at this time, we were clearly worried this could be some sort of a metastatic malignancy. She didn't have any traveling history or anything like that. So tuberculosis was not part of our differential. But then there could be sarcoidosis or things like that. But we wanted to rule out the most concerning ones, like malignancy. And the PET scan, thankfully, showed negative FDG avidity. However, because it's negative doesn't really mean that we can rule out any potential malignancies. And we wanted to do a biopsy and see what was going on. So we did a transthoracic needle biopsy of the lung nodule. And the pathology showed that it was benign lung parenchyma. And it had smooth muscle proliferation. And histology showed it was desmin-positive. It was actin-positive, estrogen receptor-positive, progesterone receptor-positive. And we looked at the proliferative index, which is the K167, and it was 0%. So that's a good sign. And I'll tell you why later. So if the abdominal hysterectomy she did, the histology samples of that showed proliferative endometrium to leiomyomas. And they did extensive sampling to see if there was any intravascular invasion of these leiomyomas or anything like that. But they could not find anything like that. So I'll tell you why that's important later as well. So given the imaging findings, clinical presentation, the pathology findings, we came into the diagnosis this could be a benign metastasizing leiomyoma. And basically, the pathology is in the name itself. So one important thing that we have to do when we encounter BML is that we have to rule out leiomyosarcoma, which is a very malignant, aggressive pathology. And the K167, which is a proliferative index, it tells you how fast the cells proliferate. In this sense, it was 0%. But if it was leiomyosarcoma, it would be much more higher and much more aggressive. And leiomyosarcomas, there have been case reports where they thought it was BML. But then it turned out to be a leiomyosarcoma later onwards. So BML is a very rare disease. And that's why I'm here talking about it. There was a review paper published in August 2023, only 385 documented cases. And it's characterized by the benign widespread proliferation of smooth muscle cells. And we think that this is originating from the uterine leiomyomas. And usually, you find this in premenopausal women who have a lot of hormonal activity ongoing in the body. And also, you find this in women who have undergone surgical intervention for leiomyomas with myomectomy or hysterectomy. And the time gap is years, decades, or more even. Or even uterine dilatation, curettage, any of these procedures. You will have a history of these women undergoing any of these procedures. So how does it spread? The most common and the most popular theory is that these leiomyomas, they invade the vasculature or the lymphatics. And that is why we were looking for angioinvasion in other leiomyoma sample, which we couldn't find. So the coelomic metaplasia theory is that anything that originates from the mesenchyme, they can undergo metaplasia and transform into leiomyomas. And that could be independent and in multiple locations. And the last one, peritoneal seeding, it can happen when, again, when you undergo any instrumentation, any surgery that allows these leiomyomas to seed into the peritoneal cavity. But then there's also a theory of a parasitic leiomyoma, which is essentially that a subserious leiomyoma in the uterine cavity, it goes and attaches itself to the peritoneum. And then at a later stage, it detaches itself. And then it starts to proliferate in the peritoneum itself. But that kind of does not explain how it can go to the lungs, because there is no connection between the peritoneum and the lung itself directly. So where does it travel to? The most common place is the lungs. But it can go to the peritoneum, like we spoke before, the pleura, the pericardial cavity. And there was also cases about the leiomyoma being in the atrium. So the urinary and digestive tracts, inguinal canal, lymph nodes, and even the brain. So all of these kind of gives us an idea that probably there is multiple pathophysiologies that is underlying this pathology, interesting pathology, actually. So why is our case unique? Most of the literature that we have currently shows that benign metastasizing leiomyomas, and finding it, discovering it in the person, happens years after hysterectomy. But because it takes time for it to seed, and proliferate, and grow. But in our case, we actually found it while the patient underwent hysterectomy. And probably she had these years ago as well, because of the abdominal CT scan findings 10 years ago, shows some lung nodules in the bases of the abdominal CT. So if our theory is that it undergoes vascular invasion or lymphatic invasion, she didn't undergo any instrumentation until we found it. So maybe there are other, it's multifactorial perhaps. And we couldn't find any angioinvasion in other leiomyoma samples as well. Doesn't necessarily mean that that's not the case. But it's interesting. OK, so how do we treat it? Hysterectomy is the mainstay, and hormonal suppression. The idea is that if we stop the ER and PR positive receptors from getting stimulated, we can stop the leiomyomas from growing. OK, so how did our patient fare? So we did a CT scan three months later. And the lung nodules was stable. And in fact, some lung nodules seemed much more better. She also underwent an oophorectomy as well. So she has been asymptomatic all throughout this journey. And you saw the CT scan, which was quite a lot of tumor burden. So what is the clinical significance of BML? This is rare. So not every person would have this in the differential. But if you have a female who is premenopausal and has these multiple enumerable lung nodules and has a history of fibroids or a hysterectomy, this could be part of your differential. And also, we have a lot of unanswered questions, like, can these tumors undergo maturation? And we don't know the clinical significance of like we don't have the answers. We don't have the easy tests at our fingertips. There are limitations for histopathology. We don't know if this is a tumor of unknown malignant potential. So how do we keep treating the patient in the future? We don't have guidelines. So it's important that we research this more and take this into consideration. So these are my references. And I would like to thank Dr. Golovian, my mentor, for guiding me throughout this. Thanks very much. Good afternoon, everyone, and thanks for coming to this session. For the classicists out there, I named my title caveat mTOR, and this is a curious case of nodular lung disease. My name is Tom Bollig. I'm a fellow at Northwestern University in Chicago. I have nothing to disclose, financial or otherwise, and wanted to acknowledge my co-authors on this, Dr. Esposito, who's in the audience, Anjani Aldandi, one of our wonderful pathologists, and Dr. Jane Damani. So there are my objectives. Basically, it kind of all applies to the case, and I kind of want to walk you through it without kind of bearing the lead here, but basically kind of formulating our differential, looking at the role of next-gen sequencing to help in an undifferentiated case, and kind of reviewing kind of the results of that, basically, and its implications for pathology and potential role of disease-modifying therapy. So for the case, this is a 67-year-old gentleman who came to clinic, actually, our ALD clinic, for incidental CT chest findings. As far as his history, so he actually underwent a surveillance CT scan of his chest for staging of fairly recently diagnosed thyroid cancer. It was referred to us due to concern for diffuse parenchymal lung disease. The patient, like I said, since it was incidental, he was really asymptomatic, no shortness of breath, no—he reported no exercise limitation, maybe some intermittent kind of throat clearing and cough, but otherwise really no concerning symptoms otherwise. Notable past medical history, he did have a renal cell carcinoma about a decade prior to presentation, and like I said, the recently diagnosed thyroid cancer, which he had a total thyroidectomy and radioactive therapy, and again, another history of multifocal meningiomata status post-proton therapy about a year before he presented. So and then partial nephrectomy for that renal cell carcinoma, which is thought to no longer be active, and then like I mentioned, the thyroidectomy. His family history, no history of cancer, notable, no thyroid disease prior to this, no respiratory disease, no history of pneumothorax, even spontaneous or otherwise. He is a former smoker, quit, you know, a couple decades ago, no other drug use. He is retired. He used to work in the gypsum business with some dust exposure. He wasn't like directly involved in the business. He was more kind of, I think, selling or some kind of office job related to it, and he did previously own parrots. His only medications are Tamsulosin and Synthroid daily. As far as the exam, nothing really notable on vitals, 98% on room air. His exam, really nothing notable other than some flesh-colored papules over his forehead and on the palms of his hands. His six-minute walk was normal. Pulmonary function tests, so you see some flow limitation there, and, you know, kind of this borderline mild obstructive ventilatory defect, no restriction, no decrease in his DLCO. Shout-out to Tim Rowe in the audience who made this video for the CT scan. I'm going to try to play it now, and it's not working. There we go, there we go. So I'll let it play through. Kind of got choppy there. I don't know why it's doing that. We'll let it go one more time. It's going to come back up. Hopefully it looks better. Great. Well, maybe I'll pause it. When it gets, the pathology is really in the upper lung zone, so you kind of see some ground-glass nodules. It might be hard to see, but there's some scattered thin-walled cysts in there. All right. And then just after visiting us, I'm just going to show you some laboratory values. So really nothing significant. I mean, it's not a big deal. It's not a big deal. So after visiting us, I'm just going to show you some laboratory values. So really nothing remarkable on his CBC or his chem panels. LFTs were also normal. Got some autoimmune stuff. His quantitative immunoglobulins were normal. INC and ANA negative. SSA and B are negative. Again, just thinking about the cysts. RF, CCP negative. HP panel, very weakly positive for penotautum and cerebrum. So kind of walking through the differential. So 67-year-old man, history of these cancers. Tobacco use. Former smoker. Had this remote bird exposure. Doesn't have parrots currently. With incidental findings on his CT concerning diffuse parenchymal lung disease. He had the skin findings on exam. You saw the PFTs. Nothing on his lab. So basically, CT with upper-low predominant ground glass nodules and cysts. So kind of thinking narrowly, just given that presentation, we do have an initial differential that we kind of were thinking of here. Again, with the upper lung predominant ground glass nodules, thinking about HP and the bird exposure most notable, more so than those weakly positive HP labs. Bird hog duvet. He had these skin findings. Maybe they were fibrofolliculomas. Again, this is a cystic lung process, as well as the history of renal cancer kind of put that high on the list. You think about lamb, sporadic lamb, but that would be kind of an odd presentation in a man, but not impossible. And then PLCH is certainly there. Upper lung system changes and nodular abnormalities. Typically, we'll see kind of more of a bizarre cyst pattern. I know it's hard to see on the imaging, but they were very small kind of normal-appearing cysts. And then thinking about like RBI-LD, which diffuse and patchy ground glass central labular nodules, did not have air trapping. And he's not really an active smoker. And then given his cancer history, thinking about maybe some neoplastic process. So you end up going for VATS lung biopsy. And the arrows here are showing a numeral nodular foci of atypical pneumocyte proliferation. And the pathologists reported that as of uncertain nature and uncertain biologic potential. We actually had, I think it was Mayo who also looked at this. And basically, they couldn't decide whether it's a benign or potentially like a neoplasm cancerous process. So he ended up going for genetic testing of that lung tissue. And it actually came back for this mTOR mutation. The nucleotide changes there. It was a missense mutation in kind of the phosphokinase domain of mTOR. And this putatively led to, given other reports in the scientific literature, of increased S6K1. So this is serine kinase phosphorylation, which then leads to downstream a gain of mTOR function. And I'll kind of talk about the significance of that. So given this mutation, and I'll kind of explain why, the predominantly nodular pattern, as well as the cysts, that kind of led us to thinking about pulmonary manifestations that we typically do think of in TSC. So predominantly, you think of classically LAM, right? So that's this diffused cystic lung disease process, much more predominant in women than in men. And then this kind of less commonly discussed process, which we were kind of zoning in on, which is MMPH, or multifocal macronodular pneumocyte hyperplasia. It's a rare manifestation. And it's really a benign hamartromatous process, which is proliferation of type 2 pneumocytes along the alveolar septae. And they can appear as multiple discrete lung nodules on CT. So the red arrows are showing you those nodules. And then that asterisk in the upper right is showing you one of the cysts. There's a handful of cysts as you scan up and down. So kind of reviewing the mTOR pathway in tuberous sclerosis. So in the upper right is your TSC1 and 2. And you kind of think of that as putting the brakes on mTOR. And in TSC classically, when it's inherited, you take the foot off the brake. So there's no brake anymore. And what it shows is basically you get that downstream activation of mTOR, S6K1, leading to cell growth, ribosomal biogenesis, and protein synthesis. You did have cysts. So we're like, well, is this LAM or not? And we did do follow-up VEGFD testing, which was negative. So what we think really, again, is this mTOR mutation that we found is leading to this increased phosphorylation of S6K1. And we're really putting our foot on the gas leading to increased cell growth, biogenesis, and protein synthesis. We were kind of wondering, well, is this activity, can we kind of show these downstream effects somehow? It's actually been kind of difficult to get a good immunohistochemistry staining. This is 1 to 400 of anti-S6K1 phosphate, basically, to show that activity. And basically what they're showing is weakly positive staining of those type 2 pneumocytes in an area of these hyperplastic nodules. And this was kind of the best level that we could get. We had issues with blocking and things like that. But we're trying to show that this actually is driving this patient's presentation. So in summary, this is a 67-year-old man, history of cancer, came in with the incidental findings that I discussed, with a novel gain-of-function mTOR mutation leading to what we think is MMPH. As I mentioned, it plays a central role in these pulmonary manifestations. And I mentioned its role downstream to promote cell growth. And I showed you the immunohistochemistry that was positive in these hyperplastic foci. And again, this is a rather benign process. And really, it's a lot of watchful waiting. So kind of in the 1 to 2 years follow-up, he's actually had stable imaging in PFTs and remains asymptomatic. The reason I bring this up, and again, because we were thinking possibly LAM, thinking about the role of serolimus or something potentially in him. But again, our suspicion for LAM is a lot lower. And he remains asymptomatic with really pretty reasonable PFTs and stable imaging. So that's my talk. And looking forward to any questions. Thanks. Thank you. Good afternoon, everyone, and thank you so much. My name is John Fanos. I'm one of the fellows in Mayo Clinic, Phoenix, Arizona. I have nothing to disclose. Today we'll talk about my presentation. It's called ACD and ABCA3 variants presumably associated with lung fibrosis and the importance of genetic evaluation, especially in cases of familial pulmonary fibrosis. So as you guys know, 20% of patients with pulmonary fibrosis fulfill the definitions of family pulmonary fibrosis, which is defined as having two or more cases within three degrees of relationship. Patients are usually younger and have more progressive lung disease. Previous genetic studies have attributed familial pulmonary fibrosis to multiple genetic variants in genes encoding mostly telomere-related components and surfactant proteins, respectively. However, to our knowledge, we present the first case of heterogeneous variants in both alleles occurring in adult with ILD, and we'll speak about it in the next few slides. So our case, we had a 50-year-old female, never smoker, presented to our ILD clinic, to our Dr. Samaras Clinic, with progressive accessional shortness of breath for the past three years. She had a strong family history of ILD. Both her mother and brother were diagnosed with pulmonary fibrosis at the ages of 70 and 49, respectively. Her father and ancestor had also alpha-1 antitrypsin deficiency. They later passed away in their 50s. She reported premature graying of her hair as early at the age of 17. Upon physical exam, she was noted to have bilateral crepitus up to two-thirds of her hemothorax, but she didn't have any associated clubbing or cyanosis. Workup was unremarkable, including LFTs, alpha-1 antitrypsin levels, and autoimmune serologies. CT chest showed scattered reticulation, patchy, ground glass opacities, architectural distortion, with relatively equal upper and lower lobe predominance. Now we'll see that in the next slide. And the PFTs showed a restrictive pattern, with a FVC of around 38% predicted, and the DLC was 50%. So as you can see here in the CT scan, the architectural distortion, the ground glass opacities and reticulation. And as you can see, it's fairly equal, both bilaterally and upper and lower lobe distribution. So we did further workup, including mean leukocyte telomere length measurement, which showed that her mean telomere length was actually lower than expected. It was below the first percentile. And we ran genetic testing, which showed two heterogeneous variants in ABCA3. Usually it's related to surfactant hemostasis, and another in ACD, which is associated with telomere protein TPP1, respectively. Both variants were classified as uncertain significance by the ACMG criteria. However, the variant in ACD was located at the end of axon 3, which potentially impacts splicing. We ran SPLICE-A1, and it indicated a low prediction score of donor gain 7pb downstream for that position. So as you can see here, the telomere length is less than first percentile, according to her age, which was 50. And as I mentioned, ABCA3-related variant, and ACD variant as well. So coming to discussion, family clustering of pulmonary fibrosis with similar phenotypical characteristics, like premature graying of hair, young age at diagnosis, and associated hematological or liver disease has led to further genetic evaluation. And the discovery that around 20% to 25% of cases were related to genetic alteration, leading to either shorter telomere length or defective maintenance, including or defective maintenance, including the surfactant. As you can see here by this review done by Zhang et al. in CHESS 2021, familial pulmonary fibrosis, and if you look individually, like an IPF, around 25% were familiar. The rest were sporadic. The same with chronic hypersensitivity pneumonitis, around 15% were familiar. With unclassified ILD, we had also around 15% that was familiar. And connective tissue diseases-related ILD had around 5% familiar causes. Collectively, telomere-related genes serve to protect, maintain, and elongate telomeres. Although telomere shortening is a normal function of age, damaging variants within these genes often result in pathological shortness. Pulmonary fibrosis is the most common manifestation in adults with heterogeneous rare telomere-related gene variants. However, less frequently, variants in surfactant-related genes have been identified in only less than 5% of patients, with only a handful of cases surviving beyond puberty. The variant found in ACD is novel. And as I mentioned, although there was a low in SLISO prediction of impacting splicing, the significantly shortened lymphocyte telomere and the familiar pulmonary fibrosis phenotype in our patient make it a very appealing variant. So in conclusion, although there's growing appreciation of the role of inherited genetic variants and familiar pulmonary fibrosis development, around 60% to 70% of cases remain unexplained and possibly related to yet to be identified genetic mutations, epigenic alterations, or non-genetic factors. Combining telomere length evaluation with sequencing of telomere and LD-related genes can provide additional information and evaluation of familiar cases of pulmonary fibrosis in the future. These are my references. Thank you so much.

Unusual Manifestations of Unusual Diseases

lung diseases

benign metastasizing leiomyoma

mTOR mutation

multifocal macronodular pneumocyte hyperplasia

familial pulmonary fibrosis

genetic evaluation