Understanding LAM: Insights into this Rare Lung Disease

Podcast Transcript

Dr. Raed Dweik, MD (00:01):

Hello and welcome to the Respiratory Exchange Podcast. I'm Raed Dweik, Chief of the Integrated Hospital Care Institute at Cleveland Clinic. This podcast series of short, digestible episodes is intended for healthcare providers and covers topics related to respiratory health and disease in the areas of lung health, critical illness, sleep, infectious disease, and related disciplines. We will share with you information that will help you take better care of your patients. I hope you enjoy today's episode.

Dr. Les Tolle, MD (00:33):

Hello, welcome to the Cleveland Clinic Respiratory Exchange Podcast. My name is Les Tolle, and I am the Section Head for Diffuse Parenchymal Lung Disease at Cleveland Clinic. I am happy to be joined by Dr. Joy Ussavarungsi, who is the Head of the Rare Lung Disease Clinic at Cleveland Clinic. Joy, would you like to introduce yourself?

Dr. Joy Ussavarungsi, MD (00:57):

Hi, uh, and thank you so much for having me today. It's a pleasure to be here as we recognize Rare Disease Awareness Month this February. I am the director of the LAM Clinic at Cleveland Clinic. In addition to treating LAM and other cystic lung diseases, our clinic also provides care for patients with various rare lung conditions. And we work as a team, focused on providing personalized, specialized care for patients facing these unique health challenges. I am excited to discuss LAM in more detail today and contribute to the effort to raise awareness about this rare disease.

Dr. Les Tolle, MD (01:45):

Excellent. So yeah, the topic of this podcast, as you mentioned, will be LAM or lymphangioleiomyomatosis. It's quite a mouthful. What can you tell me about LAM? Like, how do you describe it to patients? How do you describe it to other providers? What do you know about it?

Dr. Joy Ussavarungsi, MD (02:02):

Yeah. So, LAM is a rare, slowly progressive cystic lung disease. It is characterized by the infiltration of the, uh, lung parenchyma by abnormal smooth muscle-like cells and epithelioid cells known as LAM cells or LAM lesions. And it leads to the destruction of lung tissue and the formation of lung cysts. LAM was previously considered an interstitial lung disease, but with increased knowledge and discoveries, showing multi-system involvement and the presence of LAM cells in blood and lymphatics, a genetic component, and there are reports of LAM lesions or LAM cells recurring in transplanted lungs. So, it is now recognized as a low-grade metastatic neoplasm.

Dr. Les Tolle, MD (03:10):

Yeah. I mean, that's super interesting because that sort of shifted the whole, whole dynamic and the, and the whole thought process for LAM [Yeah.] that, that's sort of new and recent. In light of that sort of low-grade metastatic neoplasm, how, how do we think LAM starts? Where do, where do patients get it from?

Dr. Joy Ussavarungsi, MD (03:30):

Yeah. So, talking about the ... We'll start from the knowledge that the LAM cells carry mutations in the tuberous sclerosis complex or TSC genes, and there are two forms, uh, TSC1 and TSC2 genes. A loss of function from this mutation in LAM cells will lead to the hyperactivation of the MTOR signaling pathway. And this pathway is important for regulating cell growth and cell survival. So, its activation can cause uncontrolled cell growth, cell proliferation, and irregular cell function. So, there are two forms of LAM: sporadic LAM and LAM with tuberous sclerosis complex (TSC). And TSC is an autosomal dominant genetic disorder, and the disease characterized by a benign tumor called hamartomas in multiple organs, for example, in the brain, skin, kidneys and lungs. But, uh, interestingly, LAM cells originate from an unknown source, but there's a recent hypothesis suggesting that the uterus is likely the source as LAM lesions have been observed in the uterus.

(05:00):

And supporting this idea, there was a research study using a single-cell RNA sequencing that shows a population of morphologically similar LAM cells in both the lung and uterus and, uh, sporadic LAM patients. And these cells also share a, uh, identical TSC mutation in both organs. And we believe that this LAM cell also travels and spreads to the lung via the lymphatic system or bloodstream because they also express angiogenic or lymphangiogenic growth factors. And these factors can promote the growth of the blood vessels and lymphatic channels around the LAM lesions, which may facilitate the entry of LAM cells into the circulation.

Dr. Les Tolle, MD (05:57):

That's really interesting. And you sort of mentioned that there's, you know, two types, genetic and sporadic cases. So, can you talk a little bit about how these patients present? You know - do the two types present differently? Are they similar? What are the demographics of these patients? And speaking as a pulmonologist, right, what are the things that we have to look out for from a pulmonary perspective from these patients?

Dr. Joy Ussavarungsi, MD (06:23):

Sure. So, LAM mostly affects women of childbearing age, and the estimated prevalence is around three to seven per million women worldwide, but this number is likely underestimated now as, um, awareness grows and, uh, diagnostic capabilities improve. And most LAM patients, usually sporadic LAMs, are diagnosed in their third or fourth decade of life, and most of them are premenopausal women. However, the conditions can affect individuals from pre-adolescents to the elderly. When talking about TSC-LAM, lung cysts consistent with LAM are present in about half of women with TSC and in only a few, like 10%, of men. And, uh, we may detect more, uh, LAM cases because, uh, international TSC guidelines have recommended CT screening for LAM in women with TSC starting at the age of, uh, 18. And if talking about symptoms for LAM, pulmonary manifestations are the most common presentation because, uh, they often present with shortness of breath, which can be progressive or pneumothorax.

(07:55):

In addition to this, LAM patients can present with extra-pulmonary features such as an abdominal mass. A common one is a benign tumor known as, uh, angiomyolipomas or AMLs, commonly found in the kidneys, but another unique feature is a lymphatic involvement, as we know that the lymph cells can spread through the lymphatic system. So, this may present as a lymphadenopathy colors effusion, either pleural effusions or ascites and lymphatic mass called lymphangioleiomyomas, typically found in the, um, abdominal, pelvic or retroperitoneal areas.

Dr. Les Tolle, MD (08:47):

Yeah, that, that's super interesting. One of the things I actually had a question about is when I learned about LAM, we thought of it as an exclusively female disease, and you mentioned that even men can have LAM. Can you talk a little bit more about that, or is it just pretty unknown in its sporadic, rare cases?

Dr. Joy Ussavarungsi, MD (09:06):

So yes, um, because there is also a thought that hormonal influences seem to play a role in the LAM disease and LAM progression as like, you say that this disease predominantly affects women and LAM cells also express estrogen and progesterone receptor. So that sometimes this is severity often worsen with estrogen supplementation or during pregnancy and additionally from LAM repository data, they show that the rate of lung function decline can slow down after menopause, which, uh, further supporting the role of estrogen in this disease.

Dr. Les Tolle, MD (09:51):

I just had a sort of a separate question about that. So now I have someone who's, you know, generally a younger woman in my clinic that I'm suspicious of LAM. How do I make a formal diagnosis of LAM? What, what am I looking for in terms of imaging, spirometry, tissue diagnosis, all those things?

Dr. Joy Ussavarungsi, MD (10:10):

Yeah. CT plays a major role in diagnosing LAM, and when talking about it, usually the CT will show a round, uniform, thin-wall cyst, usually distributed in both lungs, and usually we will see normal lung tissue in between, but to keep in mind, uh, many conditions can, uh, mimic LAM. For example, lymphoid interstitial pneumonia or LIP in autoimmune disease, especially Sjogren's syndrome, or syndrome, which is one of the genetic conditions that can cause a scattered lung cyst with skin lesions or kidney tumor, or sometimes it's confused with ultra-rare lung category like amyloidosis or light chain deposition disease, which can also cause scattered lung cysts. So, we cannot rely solely on CT [unintelligible] for a LEM diagnosis, but in addition to this imaging feature, uh, fortunately, LEM also has a serum biomarker called vascular endothelial growth factor D or VFD.

(11:27):

If the level is above 800, uh, LAM can be diagnosed confidently without a biopsy. And nowadays, um, we can diagnose LAM with a thorough evaluation without the need for a biopsy. For example, if the patient present with a characteristic CT findings, we need to try to look for one or more of the supporting features, for example, the presence of tuberous sclerosis complex, AML lesions, uh, lymphatic mass, lymphangioma lesions, colors effusions from pleural effusions orascites and elevated serum, um, which FD level. But in cases with atypical CT findings or when supporting features of LAM are absent, yes, a biopsy may be considered, but personally, the decision to proceed to carefully balance the potential benefits of a definitive diagnosis in guiding or changing management with the risk of the, uh, possible complications. For example, if our patients have no symptoms or only a few cysts or very mild disease burden, probable clinical diagnosis of LAM with serial monitoring is reasonable, especially if a pathology will not change our management at this time, but when tissue sampling is deemed necessary, LAM guidelines recommend considering transbronchial biopsy first before proceeding with a surgical biopsy, but in my opinion, cryobiopsy can, can be considered to increase the yield, but the decision will depend on the center's expertise.

Dr. Les Tolle, MD (13:38):

Yeah. I had one quick question about the VEGF-D testing because traditionally it used to be sort of a challenge to get VEGF-D levels. Has that process gotten easier? Is that a readily available lab or do you need to be at a specialty center in order to get that?

Dr. Joy Ussavarungsi, MD (13:55):

That's a challenging <laugh> question because, um, uh, in the US right now, it needs to be done at University of Cincinnati because there's no available reliable commercial tests, um, at this time. And it's good to let everybody know that the, uh, commercial test that everybody may order is a VEGH or VEG-A, which is not the VEG-D.

Dr. Les Tolle, MD (14:25):

So that, that, that's important to kind of, to recognize that if you want to send the VEGF-D levels, you sort of have to have some experience [Right.] ... able to do that. And you sort of touched on this earlier, sort of switching gears a little bit, but, like, what does the clinical course look like in LAM patients? You know, how do they, how do they progress throughout their lives?

Dr. Joy Ussavarungsi, MD (14:46):

Yeah, so there is a known data in, uh, LAM community. There's a LAM repository that shows that lung function in LAM patients declined approximately three times faster than in healthy individuals, with FEV1 typically dropping 40 to 120 CC per year or faster in some patients, for example, in premenopausal women. And like I said, um, sometimes if talking about a TSC LAM patients, they usually diagnose in earlier age and they tend to have a fewer respiratory symptoms or come with a normal lung function test, but anyway, usually the percent of fewer lung cysts or normal lung function in TSC patients does not predict a favorable outcome because TSD LAM patients can also decline rapidly with age and follow a similar progression pattern as a sporadic LAM as well. And over time, they also, um, can have extra pulmonary complications or progression. For example, the AML lesions, if they are small, usually they are asymptomatic, but they can continue to grow and impair kidney functions, and if they are larger than four centimeter in size or contain aneurysmal blood vessel, they become at risk for hemorrhage.

(16:23):

Uh, same theory with a lymphatic mass or lymphangioleiomyomas, it can continue to grow and compress, um, surrounding organs and cause a variety of symptoms. For example, new symptom of abdominal, um, distension, um, if it's compressed bladder can cause urinary, uh, frequency or they cause a, uh, lower extremity edema, if it compress, uh, IVC, and in some cases, all this lymphatic mass can, um, rupture and cause a chylous leakage and cause a chylous ascites.

Dr. Les Tolle, MD (17:03):

Okay. And, and sort of the next question is sort of a two-parter related to, to, to clinical course is sort of what, what's the prognosis of these patients and, and sort of a necessary adjacent question would be what treatments do we use? How does the treatment affect prognosis?

Dr. Joy Ussavarungsi, MD (17:23):

Yeah. So, uh, that will be, um, a long talk <laugh>. But fortunately, that <laugh>, uh, fortunately, there is a treatment available for LAM. Yeah. So, there's a landmark clinical study well known in our field. It is called the MILES study that, um, that randomized patients to receive sirolimus or a placebo for 12 months and followed by a 12-month observation. And, um, the results showed that sirolimus treatment will stabilize lung function and also improve their functional performance and, uh, quality of life. So, building on this finding, for patients with LAM who have abnormal lung function, which we define as an FEV1 less than 70%, we recommend treatment with sirolimus rather than continued observation. But in some cases, we, we consider offering treatment for patients with normal lung function, but if they experience a decline, usually from the registry data, if the annual FEV1 decline 90 cc per year or more, it's considered declined faster, uh, at least three times faster than the normal rate of FEV1 decline.

(18:45):

We will consider treatment as well. Or in some patients that we can’t, um, see a sign of a LAM disease burden, for example, elevated residual volume, reduced diffusing capacity, the LCO exercise-induced desaturation, or they have hypoxia, this is considered high disease burden, and we also offer, uh, treatment. And for extra pulmonary fissures, mTOR inhibitors, sirolimus or everolimus, also, uh, shown to reduce the volume, the size of the mass, either AMLs or lymphangioleiomyomas and also chylous, uh, reaccumulations. So sometimes each case may present with unique showings and should be discussed with a LEM provider. For example, chylous effusion, um, can be refractory and require thoracentesis, uh, first to relieve symptoms, but later on we suggest, um, considering sirolimus before proceeding with a more invasive procedure, for example, thoracic duct ligation or, uh, surgical resection for abdominal lymphatic mass or nephrectomy in growing AML lesions.

(20:10):

And I mentioned the prognosis that you asked about earlier [Yeah.] uh, we all know that it's a slowly progressive disease, but the prognosis varies, depending on several factors. Uh, for example, premenopausal women tend to, tend to experience a faster decline in, in lung function if compared to postmenopausal women, and they generally have a poorer prognosis if they present with more severe symptoms indicated by their lung functions or CT findings, and there will be some research data saying that elevated VEGF-D level is also associated with a poorer prognosis. And in the past, when LAM was diagnosed, it was considered fatal without a lung transplant, but today, the median survival for patients is estimated to be over 20 years after diagnosis. And the data say that, uh, transplant-free survival probability is more than 90% at five years, so patients now have much better outcomes, and we also believe that with sirolimus or everolimus, uh, both of them are, uh, mTOR inhibitors, a significantly improved survival rate for LAM patients.

Dr. Les Tolle, MD (21:41):

Yeah. I mean, that's remarkable in terms of the advancement of science and how we've truly helped patients over the years with these new treatments. Where do you think the field's going next? I mean, what's on the horizon, what's in the future? Where would you like to see this field go before we wrap up today?

Dr. Joy Ussavarungsi, MD (22:03):

So, the LAM community is highly active in research. So, uh, I think there's potential for the development of new biomarkers or new methods to better differentiate LAM from other cystic lung diseases. In terms of treatment, we all know that current treatment with mTOR inhibitor, either, uh, sirolimus or everolimus, they are suppressive therapy is not a curative option. So, the researchers are, uh, focused on trying to find a new target or exploring an innovative approach trying to find a cure. One current example of exploration is immunotherapy, or the potential role of nintedanib or OFEV, which is well known in our pulmonary fibrosis field, because OFEV has resolutions promise in stabilizing FEV1 over a 12-month treatment period in LAM patients. So, with ongoing research and advancement, optimistic that our LAM patients will have more treatment options available in the future.

Dr. Les Tolle, MD (23:23):

Yeah, that's great. I just want to sort of put in one final plug to anyone who may be listening, that if you do have a patient that you're suspecting has LAM, there are LAM centers all over the country and really the field in general would benefit from trying to collect as many of these patients as we can so we can learn as much about the disease we can. And so, please send anyone you suspect of having LAM to one of the LAM centers so we can do our best for these patients going forward. Joy, I just wanted to thank you for doing this podcast. l personally learned a ton, hopefully everyone else listening learned a ton, and we really appreciate your time.

Dr. Joy Ussavarungsi, MD (24:08):

Thank you. It's a pleasure.

Dr. Raed Dweik, MD (24:11):

Thank you for listening to this episode of the Respiratory Exchange Podcast. You can find additional podcast episodes on our website, clevelandclinic.org/podcasts or wherever you get your podcasts.