Robert M. Kotloff, M.D., Chairman, Department of Pulmonary Medicine at Cleveland Clinic, and Professor of Medicine Emeritus at the University of Pennsylvania, presented "Lymphangioleiomyomatosis: A Tale of a Mother, a Child, and an Orphan Disease" at University of Louisville Department of Medicine Grand Rounds on October 23, 2014.
The talk focused on understanding the clinical and radiographic manifestations of LAM and the differential diagnosis of cystic lung disease, the molecular pathogenesis of LAM that has led to targeted drug development, and learning about the current treatment options for LAM.
Presented by the UofL Division of Pulmonary, Critical Care & Sleep Disorders Medicine.
Good morning, um, I'm, obviously, not.
Dr, roman he's out of town and uh asked me to start our training rounds.
Um, one thing I wanted to remind everyone of and I'll reiterate this at the end of grand rapids is that next thursday both before and after grand rams, there will be flu shots distributed around here.
So if you have not yet gotten your flu shot, and I do know that we do have crew in the community already is that great for us.
Make sure you take time to do that you can go online there's a forum to fill out.
And if you can do that in advance, it will expedite that in dr, roman's absence.
And to continue his tradition, I have a few historical facts that happened on this day in history.
The first is in 1814, the first ever plastic surgery was performed by a physician named joseph carpone.
And he performed this on a british soldier who had lost his nose due to the toxic effect of mercury treatments.
So talk about side effects to drugs.
And this was the herald for plastic surgery as we know it in the modern era.
Also in this day on this date in 1879, thomas edison was successful creating the first light bulb.
And that is probably arguably one of the most transformative things that has happened to us and has allowed us to not burn with midnight oil than to stay up late.
And we can thank you for our sleep deprivation.
Because we all are now able to see you very late as late as we want and, um, uh, also, michael crichton was born in 1942 on this day.
And as you guys know, he was actually a harvard training physician who wrote numerous books, uh, some of them.
Notably the drama, the strength, which is somewhat question for our ebola hair that we're having and also jurassic park.
And then lastly, in 1986, the nobel prize winner.
Edward joycy died.
He was actually credited with the discovery of vitamin k.
So a fairly recent discovery that again has allowed us to care for our patients and right away.
Both blocking vitamin k, but also repleting them.
So, um, lots of interesting things in history.
Today, and I will now invite.
Dr, david not only to come forward and introduce our great advancement good morning for the last two and a half decades have seen quite an evolution in the approach and treatment of pulmonary diseases, our understandings now of inflammation and reparative and remodeling processes have certainly changed the whole paradigm of how we treat patients with advanced lung disease.
Our speaker today is someone who has been very very much involved in that transition over those years and has seen it firsthand is actually I believe his talk today is going to express some of those things that we've learned in the last 25 years.
Dr, robert kotlov attended brown university and matriculated to yale university school of medicine.
After completing his medical degree, her medicine resident at temple university in philadelphia, and then went on to the prestigious university of pennsylvania pulmonary critical care program.
And after completing his training, there has actually remained there for 27 years.
And recently has moved on to become the chairman of the department of pulmonary medicine at the cleveland clinic while at penn.
Dr, kotla was instrumental in not only leading their cystic fibrosis program, but also making their lung transplant program, one of the premier programs in the united states.
And when he left the university of pennsylvania earlier this year, he was the chief of the advanced the section of advanced lung disease and a lot of transplantation.
Um, dr, podluff has published more than 60, peer-reviewed articles multiple book chapters and served on many societies and task force task forces for many of the major societies in the united states.
I had the good fortune of serving with him on a couple of uh, committees and task forces.
And I can tell you that I've always been impressed with his, uh, his presence and his leadership.
And so I'm, very privileged to present him to you today.
So please join with me in welcoming from cleveland clinic.
Dr, robert is it possible to get the lights down a little bit.
So david, thank you very much for that gracious introduction and also kind of invitation to come here and see your beautiful city and your wonderful medical center.
And I had the opportunity to have dinner with a number of members of the pulmonary division.
And in particular with jesse roman last night, he's announced his delightful individualism.
So I picked a somewhat usual topic.
And I always have to make a few apologies, particularly when I'm talking to non-pulmonologists in an audience, because why would you want to hear about a disease that you may never see? In fact, you may never be able to pronounce, and even as a practicing pulmonologist, if you see one or two cases in your entire career, it may be a lot.
The reason I like to talk about this disease is I think it has a number of important lessons? One lesson is the importance of basic science and the insights.
It provides in understanding disease pathogenesis and then in defining and introducing rational treatment.
And the second is, I think there's a remarkable tale behind this that I'll talk about in just a minute, the power of motherhood and the power of uh, lobbying congress to move forward in a disease that was neglected for many many years.
So hopefully, by the end of this you'll, uh, you'll, enjoy at least learning a little bit about a very unusual, uh disease.
So let me just give you some basic, uh, basic overview of what I'm now going to call lamb instead of having to continue to study angiolymiatosis.
This is a disease that has some unusual characteristics, it's almost exclusively seen in women.
And typically during childbearing years of peak incidence is between the ages of 20 and 40.
it's characterized by smooth muscle proliferation and infiltration that involves predominantly the lungs.
And within the lungs, the airways the blood vessels and the lymphatics and is also characterized as we'll see by cystic destruction of the lung parenchyma.
It has three characteristic features that certainly the oncologists in the group here will recognize as characteristic of cancer unregulated cell growth, vascular lymphatic, spread as I'll show you in some subsequent slides and local tissue, invasion and destruction.
And for that reason, the paradigm of this disease has shifted from looking at it as an interstitial lung disease, or diffuse parenchyma lung disease to what is now being described as and I'll quote from a recent review article.
Lamb is the simplest of human cancers.
Let me tell you a little bit about the history of this disease, and this gets into the mother child and orphan disease story here.
So the first case of what we recognize as lamb was published in the medical literature in 1919.
It took another 50 years until enough cases were recognized that a case series was published.
So in 1966, the first case series appeared in the literature and um to that time.
It was basically recognized as a medical curiosity was also recognized as a lethal disease.
And in fact, the what was uh observed in the 1966 case, series and a couple others that ensued was that from diagnosis to death was basically 10 years.
So this was a disease that was felt to be lethal and to basically robbing young women of a normal life expectancy.
So here's where the story of the mother and child come in.
So in 1994, andrea burns who was then a 22 year old young woman was diagnosed with lamb.
Her mother sue burns took her around first to a number of community criminologists.
And then some of the major academic medical centers in ohio.
They actually lived in the cincinnati area.
And sue burns was very frustrated to realize that no one knew anything about this disease.
She delved a little further into the medical literature and realized there was absolutely nothing in the literature that provided any answers.
So now she was dealing with a daughter who basically had been told that she had 10 years to live.
And no one knew anything about what to do beyond that obviously a very frustrating situation.
But this was a mother who was not to be stopped.
And what she did was she created grassroots effort lobbied a number of other mothers involved in organizations throughout the country, um ended up collecting a large number of signatures and ultimately lobbied congress to provide funding at the time.
In the 1990s.
Congress was very interested in funding, women's health initiatives, which largely meant breast cancer initiatives.
She managed to get some money committed to starting a registry at the nih and providing some seed money for pilot studies looking into the pathogenesis of this disease.
And from there, we have an explosion in the understanding and attacking treatment of this disease.
So in 1995, sue burns established the lamb foundation in cincinnati.
It remains there to the present time in 1997.
Congress came through with nih funding to fund a registry where women from around the country would be paid to come to the nih every six months to donate blood.
Other tissue specimens get various pfts and other testing performed so that we could understand better the natural history of this disease.
In 1998, the underlying genetic mutation was identified by 2001, the signaling pathway through which this mutation acted was identified and then impressively in 2003.
And 2005, the two clinical trials that demonstrated the clinical efficacy the therapeutic efficacy of ceralymus or rapamycin in treating this disease.
So from a grassroots efforts in 1995 to 2011, we now understand the pathogenesis of this disease and have effective treatment so let's go into a little bit about the epidemiology of this disease.
There are actually two forms there's.
One form that occurs in the setting of an equally unusual disease that you may have heard about in, uh in medical school or subsequently and that's tuberous sclerosis, a neurocutaneous syndrome that in its full-blown form is characterized by severe cognitive impairment in seizures.
But in its mildest form, you would not recognize that a patient necessarily had the disease.
But curiously patients with tsc about 30 to 40 percent of them will develop cystic changes that are characteristic of land, there's a second form of lamb, so-called sporadic lamb that occurs in the absence of tsc importantly, lamb may be the only manifestation of tsc.
You may not see the other characteristic cutaneous lesions, seizures cognitive impairment.
And as I mentioned about several patients with tlt will have lamb changes.
And then in terms of sporadic lamb, it was initially estimated to be quite rare three to five cases per million.
But I can tell you from having established the land clinic at the university of pennsylvania where we grew from 12 patients to over 80 patients in just a three year span.
This is clearly an under recognized disorder and where we're starting to recognize it more and more is with incidental detection of the disease for women who are undergoing cts for abdominal pain, kidney stones, etc, where we'll stumble across cystic changes that we otherwise would never have known about.
So we are discovering the whole end of the spectrum that uh, very often would otherwise remain subclinical.
Um, both forms that are negative are seen almost exclusively in women in the tsc variant.
There are a handful of cases that have been reported in men.
And in the sporadic form there is this one curious case that was described in one of the pulmonary journals of a patient, a male patient with uh.
And in fact, genetically proven to be male who developed the sporadic forms lamb to this day that remains unexplained.
The average stage of diagnosis is 35 years.
Although many of these patients have had symptoms for a number of years and were misdiagnosed.
So this is not age at onset.
This is age of diagnosis at least to the present time.
This seems to be a disease that has a high predilection for caucasian women.
But some of this may be under reporting due to differential access to health care and also to the internet that may actually view our perspective on the ethnic distribution of this disease.
How about the clinical features as with many lung diseases, they're relatively non-specific, virtually all patients who have lung disease are short of breath.
So that certainly doesn't help us in narrowing down the differential.
But you can see a presentation about almost half of patients will present with this beyond exertion, uh.
During the course of the disease, the overwhelming majority of patients will develop some degree of dyspnea, the other characteristic presenting feature.
The common way that women will present is with the spontaneous pneumothorax that is often ascribed to the usual.
Benign pneumothoracies that we see in young adults.
And at some time in the course of the disease about two-thirds of women will develop at least one pneumothorax and then there's a number of other, um non-specific functions, the the one that I will point out that's very characteristic.
And that should make you at least think about the disease is the development of a childish effusion in a young woman.
Most of us when we think of chilo's effusions, um, we think of lymphoma as the most common cause, or there are also traumatic forms of kylos effusion.
But I want you to at least remember that if you stumble across a young woman with a kylos effusion that you should be thinking about lamb as one of the etiologies in the differential.
This is the radiographic presentation of lamb.
This is a very characteristic ct scan.
And what you can see are these innumerable cysts that are generally relatively round in appearance and vary slightly in size.
In this case, if you look closely, you can actually see the walls of the cysts, but they're, not always that obvious.
And for that reason, you can see that to a relatively inexperienced, radiologist, they're much more likely to call this emphysema than they are to call this lamb.
And in fact, one of the common disorders that the lamb is often misdiagnosed as is a precocious onset of emphysema.
You have to wonder why a 25 year old woman would develop emphysema, but at least radiographically it's often confused in terms of functional impairment of the lungs early on in the disease.
Studies may, in fact, be normal.
And in fact, in the nih registry that was created to track women across the country with this disease about a third of patients at the time of diagnosis actually had normal pfds when pfts become abnormal, and they do so in the vast majority of patients, the characteristic pattern is of air flow obstruction.
And you may also see a decrease in using capacity.
This is important, because if you think about it, a young individual with shortness of breath who has a spirometry done in the office that shows airflow destruction, the most common diagnosis that's going to be made is what asthma common things occurring.
Most of these women are told they have asthma before someone stumbles across the correct diagnosis.
In many cases, as I've mentioned, the disease is progressive and general rate of decline is about on average 100 cc's per year.
But there is a wide variation.
There are some patients who have a very aggressive form of the disease that does in fact, rapidly progress and unfold over about a 10-year period.
But there are other women who over an equal amount of time will show absolutely no change in bond function.
And it may, in fact, maintain a lot of function.
The histology of flam is shown here.
And I've learned as a nonpathologist that if I just sort of show my pointer like this you'll, all believe what I say, so what I am going to tell you is that what you're seeing here is a dramatic proliferation of smooth muscle appearing in cells.
This is a higher power view.
But one of the important points I want to make here is that if you just get small snippets of lungs, so if you subject patients to bronchoscopy and take a biopsy very often, the pathologist will look at this, and think they look like fibroblasts.
So it's, not uncommon in the past with trans-bronchial biopsy to get the impression that the patient has a fibrotic lung disorder, rather than lamb.
And in fact, transparency biopsies until recently were abandoned as a diagnostic procedure in establishing the diagnosis here that's changed a bit with the recognition that there's actually a specific stain hmv45, which curiously is a statement was developed for diagnosing melanoma.
But for some reason, the smooth muscle cells that proliferated them and not all of them.
But just for some reason, a smattering of them will take up this immunostain.
The advantage is twofold.
It makes it much easier to establish the digestive diagnosis and importantly, it makes it easier to establish the diagnosis with very small tissue specimens.
So we've revisited the notion of using trans-bronchial biopsies and there's, a recent report that actually suggests that you can make a diagnosis in about 50 of cases, simply by doing a transformative biopsy and therefore sparing the patient, a thoracoscopic surgical biopsy there's, a second feature of this disease that occurs outside the lungs.
And that is a benign lesion of the kidney known as an angiomyolipoma or aml.
The overwhelming majority of patients who have the tsc form of lamb will in fact, have renal amls along with multiple hamartomas throughout the body, but even patients who have sporadic land while this was initially thought to be a pulmonary only disorder in fact, anywhere between a third and fifty percent, depending on the series that's been published will have renal amls.
These amls are basically benign tumors.
They have no potential to transform into malignant tumors and they're composed of basically three constituents they're, highly vascular.
They contain a large number of blood vessels.
They contain the characteristic lamb, smooth, muscle cells that stain positive for hmv45 and importantly, the overwhelming majority of cases they contain fat, which when this is radiographically apparent.
We take advantage of because you can make the diagnosis simply from its radiographic appearance on cat scan.
The problem is that there are lipid poor amls that appear as solid renal lesions.
So another way that lamb patients get to us or enter the medical system is actually through the urology clinics where patients are referred, because they have a mass on the kidneys, there's, a suspicion of renal cell carcinoma.
They end up getting a surgical biopsy and a diagnosis of aml is established.
And then if you have a an astute urologist they're going to know that if you have a woman with an aml, you need to get a cat scan, not all amls are associated with lamb.
There are isolated amls that can occur.
But in many cases, aml was the first sign of an underlying diagnosis of lamb.
Amls are usually clinically silent, but they can present with flying pain hematuria.
And in rare cases with loss of renal function.
There is a risk of hemorrhage.
I told you these are highly vascular.
They do tend to grow.
And if they grow beyond about four centimeters in diameter, there is a significant risk of hemorrhage such that we preemptively will address the issue and I'll show you in some subsequent slides how we do.
So this is the characteristic radiographic appearance, ct appearance of android amls or ancient violin homeless of the kidney.
You can see the kidneys are not only enlarged.
But you see these areas that have characteristic attenuation of fat.
And really you don't need to go any further.
In this case, there's, nothing else that looks like this in the kidney.
So this would be considered diagnostic of an aml.
Sometimes these lesions can become quite large.
Um, this was a patient of mine who, um, you can imagine you could actually palpate on physical examination.
This is the loving disease, and at least on this portion, there's, no recognizable renal parenchyma.
This is all going to be placed by fat.
And on this side, not quite as dramatic and there's.
Also some areas of increased attenuation, which are actually due to an embolization procedure that I'll discuss in a few minutes.
Amls can also be tricky.
They tend to recur if resected and actually the prior treatment for this was surgical resection when they grew to be too large, um and here's an example of the patient who had had a prior right nephrectomy.
And then in the prior surgical bed, you can see this fat density mass here, soft tissue density that is recurrence of the aml in the surgical bed.
I want to spend a few minutes talking about another to me fascinating part of this story, which is our current understanding of the molecular pathogenesis of this disease.
And as I showed you on that timeline, all this came about with an explosion of interest in the disease between around 1995 and present time.
The other thing that's happened that has really advanced the understanding of this disease is by re-characterizing it as a cancer.
We've really gotten not just the pulmonary community, but the oncology community and some very very smart scientists in the oncology community to have an interest in this disease.
Elizabeth, henschke who's at harvard is one of the leaders in this area.
And in fact, she was the first to describe the genetic mutations.
These are mutations in tsc-1 and tsc2.
These genes are tumor suppressor genes that encode for two proteins, tuberin and hammerton respectively.
These proteins as I'll show you on the next slide are involved in a signaling pathway and dysfunction or inactivation of these proteins leads to loss of normal control of cell growth and proliferation.
These mutations, uh, in the setting of two of patients who have tuberous sclerosis are germline mutations.
So they affect all cells throughout the body, whereas women who have the sporadic form of lamb.
The mutations are only found in affected tissue.
So only in the lung or in renal aml, would you find these mutations? If you biopsy the skin or look at other tissue, you would not detect these.
So this is my one and only signaling pathway that I'll show you here and I'll stumble my way through this.
Uh, this was probably probably the most important discovery that was made.
So after it was noted that the genetic mutations involved tsc1 and tsc2.
The question was, how do these genetic mutations? Ultimately lead to disease pathogenesis? And what came about was an understanding that these proteins, the protein products of these genes are intimately involved in the akt signaling pathway, which is basically a pathway that controls normal cell growth proliferation, also angiogenesis.
And these proteins actually exert an inhibitory influence on mtor.
The mammalian target of rapamycin dysfunction of these proteins actually allows the signaling pathway to continue in a constitutive fashion in an ongoing fashion that then leads to unchecked cell proliferation.
This same pathway has now been implicated in a number of malignancies as well as in lamb.
And the important point here is that we now have some potential therapeutic targets in particular mtor to consider in developing rational treatment approaches to this disease.
Another issue that came up.
We've gained an understanding in is.
Why is this a destructive process? Why do you see those cysts throughout the lung parenchyma? The previous theory was that this actually was a post-obstructive phenomenon that if you obstruct a small airway that you get dilatation of the airway distal to the obstruction that actually is not true.
This is not those are not airways in any way.
Those are actually destructive areas of lungs.
And in fact, what we've now seen is that if you look at lung tissue from patients with lamb, there's evidence of upregulation of a number of mmps or matrix metal proteinases that are destructive proteinases that lead to cis formation.
And not only does it cause local destruction, but it may actually, uh, be responsible for promoting metastatic spread of of lamb cells and I'll talk about that in just a minute as well.
So this is something I alluded to uh earlier, which is that we've shifted our paradigm, our understanding of this disease from looking at lamb as an interstitial lung disease to looking at lamb as a cancer.
I showed you that there are the three cardinal features that define cancer can actually be applied to this disease as well.
I just want to show you some additional evidence that has really fueled this newer approach that we're actually dealing with a low-grade malignancy, rather than a benign interstitial process.
So several groups have shown that you can see lamb cell clusters that start to bud off of lymphatics.
They can also be found in oral fusions in the in the pilot's, fluid it's tapped from the chest, and they can be found in regional lymph node groups.
So there's evidence that these cells are occurring outside of the lung itself.
The nih group has shown that lamb cells would be isolated from the bloodstream, certainly a characteristic feature of metastatic disease.
And in their study published a number of years ago about half of patients with lamb were shown to have circulating hiv, 45 positive smooth, muscle cells in the bloodstream.
This is perhaps one of the most fascinating observations that's been made, which is that lamb actually recurs in the allograft after lung transplantation and the lamb cells that are found in the donor how graft are actually of recipient origin.
So they have to get there somehow and the feeling is that they probably migrate or metastasize either from the bloodstream or from regional lymph nodes.
And then they infiltrate the donor allograft.
So that dates the question of if this is a metastatic disease to the lung what's, the primary site of origin, and there are two theories both of them still speculative.
One theory is that actually the kidney is the primary site of infection arguing for that is the presence of angiomyelipomas and the notion that you can then get cells breaking off from the kidney traveling through the lung, which as you know, serves as a major filtering mechanism for debris and cells.
So that theory sort of makes sense, except for the fact that aml's are only seen as I mentioned in about a third to a half of patients with sporadic lamb, even on careful microscopic inspection of kidneys.
So you can't find the aml in the kidney, how can you blame the kidney as the primary site there's? Now, newer evidence evolving that actually the uterus is the primary site.
And in fact, there was a recent publication showing that women with lamb who have undergone hysterectomies.
You can actually find these microscopic nests of lamb cells within the uterus.
And maybe, in fact, that's the primary site of disease, let's talk, a little bit about the diagnosis and start with just some general statements.
I mentioned before that the average age of diagnosis is 35 years.
But again, pointing out that that's, not the average age of onset of symptoms.
In fact, most women have had symptoms for a number of years.
And in fact, many women unfortunately have gone through at least two, spontaneous pneumococcis before the diagnosis has been definitively established for reasons that I mentioned before very commonly, the initial diagnosis can be asthma.
Again, young woman with some airflow obstruction on pfts.
That would certainly be the first thing I would think about and we're, not in a habit of subjecting all people who are short of breath with mild airflow obstruction to cat scans.
So in the absence of that, you really would not detect the disease.
And if you do image, the chest very often the radiologists looking at that cat scan that I showed, you will not think of lamb, although more recently now that we've become more aware of the disease.
I think that's not as true, but very commonly.
And I still see this these patients are I'm told they have emphysema, even though the overwhelming majority are non-smokers.
And in fact, the first thing that's done by the homeologists who sees this patient is they get alpha-1 antitrypsin levels because they're thinking, why should a young individual develop precocious emphysema? Well, how do we make a diagnosis? This is an important point.
And one of the reasons that we're really trying to send the message out here that these patients need to go to specialized centers.
Even before the diagnosis is firmly established.
The reason is that there's still a tendency to take these patients to a surgical lung biopsy.
And in the current day, it's, actually unnecessary in the vast majority of cases, because there are non-invasive or minimally invasive ways of establishing the diagnosis and I'm just going to highlight those in this slide.
So if you have a cat scan that shows cystic lung disease in combination with an aml, you have established your diagnosis.
So the first thing we do as pulmonologists when we see that chest ct is we get an abdominal ct where you can even very simply get an abdominal ultrasound, and you will pick up afls that is considered diagnostic.
Additionally, if you have cystic lung disease in association with tylose effusion, and you've ruled out lymphoma, you've made your diagnosis.
And finally, in patients who clearly have an established diagnosis or whom you can establish a diagnosis of.
Ts, you've also established your diagnosis without ever having to get any tissue.
Second way that we have a strong suggestion of the diagnosis.
I won't say, it's, always definitive.
But if you have that characteristic-looking cat scan in a non-smoking female that's, not because the absence of smoking rules out emphysema again, that's, not in the differential it's because the absence of smoking actually rules out a second form of cystic lung disease that we see that radiographically can be very similar something called langerhans cell histiocytosis previously known as eosinophilic granuloma or histiocytosis x, um.
That is an increase of cystic lung disease, almost exclusively in smokers.
So young woman, cystic lung disease, non-smoker.
You have pretty compelling evidence of what you're dealing with there is now a biomarker that was first identified by the group at the university of cincinnati order here and that's vegfd vegfd is a lymphangiogenesis factor and I'll show you on the next slide, some pretty compelling data showing that we can now use this as a non-invasive diagnostic tool.
The problem with it is it's, not yet commercially available.
It does require a little bit of extra effort because you have to send the patient to a lab the blood's drawn.
But then it has to be shipped off to the university of cincinnati.
Many insurance companies are not covering for it.
So very often the patient will bear the burden of the cost of the test.
I mentioned the trans-bronchial lung biopsy.
The old adage was it's, not worth doing.
The new lesson is it's probably worth doing.
If these other methods are either not applicable or fail to establish a diagnosis, because at least in certain centers they're now, recording about a fifty percent yield in a transfer biopsy and only in cases where you could not establish the diagnosis in any other way, there's still significant diagnostic uncertainty.
Would you now subject a patient to a surgical lung biopsy? So that clearly has become the exception.
This is data from the cincinnati group, although I believe young has since moved.
But this is frank mccormick's group at the university of cincinnati, looking at uh, serum-vegfd levels and importantly, they did this study the right way which is, they took not just healthy individuals as a control group.
But they looked at other groups that are frequently in the differential diagnosis of cystic lung disease, emphysema being one, which is as we said, not a true, cystic disease, but then birdhouse sjogren's, langerhan cell histiocytosis.
And you can see there's a pretty nice cutoff here beyond which.
And this is about 800 micrograms per ml beyond which, um, none of these other diseases seem to cause elevations in that range.
So if you have a veggie level that exceeds 800 that seems to be rather compelling evidence that you're dealing with lamb.
The problem is that there are a number of land patients who fall into a gray zone or clearly have so called normal edge of d levels.
So the absence of a markedly elevated level is not helpful.
The presence of a mark of the elevated level is now considered diagnostic in the appropriate clinical and radiographic context, what's the differential diagnosis and I'm, not going to go through this very busy slide.
What I tell my pulmonary fellows is the good news is you don't have to learn an extensive differential diagnosis of cystic lung disease.
There are only four diseases that cause this.
The bad news is that they're all incredibly obscure diseases that you can forget 100 times before you remember what they are, but I will at least go through them with you they're all fascinating diseases.
And I have to say one of the fascinating things for me as I've gotten involved in the lamb community is you start out learning about one obscure disease.
And you end up learning about four because not only do, I have patients referred to me who have lamb, but I have patients referred to me who are misdiagnosed as having lamb because they have cysts.
And suddenly you do have to learn about these other disorders that can mimic the diagnosis.
So the other diseases are linear on cell histocytosis, a newly described disease at least in the pulmonary community, but a disease that's been known to dermatologists and actually oncologists for a number of years because there's an increased risk of renal cell cancer with this disease.
This is a disease known as birdhog dubai, actually named after three canadian dermatologists who first describe the disease and then something called lymphocytic interstitial pneumonia.
Let me at least show you some imaging that's associated with these.
But point out on this slide that in addition to imaging characteristics that differ between the four diseases you have to look for other manifestations, very often outside the lung that will clue you into alternative diabetes.
You have key findings lamb and langerhans share in common airflow obstruction.
But these other two disorders in birdhog, dubai, pfts are normal in lip typically restrictive and then there's some adjunct labs that can be used.
I've talked about vegfd in lamb and there's, actually a follicular mutation analysis that can be done to diagnose this disease.
So let me show you radiographically.
Some of these other diseases.
This is my uh, new fascination, a disease called bird.
As I mentioned that is characterized by some subtle, but characteristic skin lesions and by the development of cystic lung disease.
But you can see already that these cysts look, nothing like lampsis, they're, large they're irregular in shape.
They tend to hug these subplural regions and they're, very few of them compared to the lamb cysts.
This is where confusion sometimes comes up, because you can also see dermatologic manifestations of tuberous sclerosis with lamb.
So if a woman presents with, um, a rash on the face, these sort of hard nodules, often this could be misdiagnosed as ts associated lesions.
But in fact, these are called fibromoleculomas.
These are the characteristic skin matter to take manifestations of birdhout duvet.
And you can actually make the diagnosis of birdhouse simply by doing a very simple skin biopsy.
Sometimes these lesions are very subtle.
This is some lesions on the ends on the neck of one of our patients.
And if you didn't look closely, you would miss these, or you might want to just misdiagnose these skin tags, for example, this is langerhans cell histiocytosis, which is a disease, almost exclusively of smokers in its earliest presentation.
It looks nothing like lamb because it's very nodular in its appearance.
But you can see that you occasionally will start to see cavitation or cyst formation.
Here, it's a little bit more obvious.
We sometimes call this the cheerio sign, which are these small thick-walled, little cysts, just starting to form.
But as the disease progresses, it progresses to a purely cystic form in its classic form.
It looks different from lamb in that.
The cysts are more irregular in their shape and they're more variable in their size.
And the walls are somewhat thicker than what I showed you in the typical case of lamb.
But I can tell you there are cases of langerhans cell that are radiographically indistinguishable from lamb.
This is lip that you may know as in in a couple of its forms.
So it's a hiv, defining illness, um, particularly in children.
It's also seen in a number of immunologic disorders, including lupus, jogern syndrome, common variable immunodeficiency.
And again, in its classic radiographic form.
You don't see a lot of cysts.
And you also see, in addition to cysts parenchymal changes.
So here you see ground glass, opacity surrounding the system very often.
This will start as brown glass.
And then as you as the disease evolves, you'll see the cysts subsequently appear.
But you know, nothing follows the textbook.
So here's the case of lip that I came across that I thought was lamb because all there was was cis without accompanimental changes.
But in fact, this proved on biopsy to be lip so that's, the differential all relatively obscure diseases.
In many cases, if you pay attention to the cat scan alone, you can actually differentiate between these well, once we've made the diagnosis of lamb.
What are you obligated to do as the clinician? And there are a couple things one is we do a at least a preliminary screening for plain.
Ts, I mentioned that not all patients with ts will have cognitive impairment seizures.
So sometimes you have to look very hard to find it.
Why is it important to find it doesn't change your approach to the patient? It does change your approach to the patient's desire to have children because there's genetic counseling that goes along with that.
This can be an absolutely devastating disease.
And you want to at least be able to provide appropriate counseling to the patient, should she decide that she wants to have children? So we screen, and that includes a careful physical examination, I'm, one who absolutely loves physical exams and all the little clues that you learn from it and I'll show you some of the characteristic findings.
If you look closely that you can see on a patient with.
Ts, we also in a patient who's been diagnosed with lamb.
We also want to screen for amls, because if they are of a certain size we're going to want to intervene preemptively as I'll mention in a second.
And then we want to get a sense of if there is impairment in lung function if so how severe so that basically means screening pfts and ambulatory oxymetry, looking for evidence of desaturation.
If the option level is normal at rest, these are some of the characteristic changes of.
And we've probably had a single lecture in medical school that you've since forgotten that goes over a number of these, but I'll remind you what these are.
These are chagrin's patches, which are these raised roughened lesions, very often on the trunk.
These are uh, hypopigmented, uh, macules that commonly occur in clusters.
So they're called confetti lesions, because they look sort of like this used to be called, uh, adenomas, sebaceous on the face in a malware distribution it's now called uh angiofibromas.
This is a very characteristic feature.
This is the one that when I showed you the fibro folliculars of birdhog duvet, they often can get confused.
This is the most subtle sign.
But one of the things that I ask all my patients who present with lamb to do is they have to take off their shoes and their socks.
And you have to look at all 10 toes, and you have to look at all 10 fingers because very often the only sign that you'll see of ts is this little heaped up area on a nail called an angle broma.
And you may simply see a single one of these, but that's, all you need to raise your suspicion with the patient sts, a second way to screen in a more definitive way is actually to do a an mr or a head ct.
And even in patients with normal cognitive function, and no seizures you'll very often come across characteristic changes these, uh, cortical, tubers, um, or some dependable calcifications.
And occasionally you'll see astrocytomas, these are all characteristic neurologic imaging, manifestations of ts, and for women who really want to know whether they do or don't have the disease.
This is the second step.
Third step would be to send them to a geneticist and there's.
Now, a commercially available test to look for tsc1 and tsc2 mutations.
How about treatment to me? This is the most fascinating part of the story and I'll actually go through this relatively quickly.
So we don't run out of time here, and there are four approaches hormonal manipulation.
And the reason I've graded this out is that this is largely fallen out of favor sirolimus also known as rapamycin, which is a specific mtor inhibitor.
And based on the pathway that I showed you previously understand why there was a tremendous interest in looking at this drug in the treatment of this disease simvastatin seems like statins do everything it should be in our water supply and there's, actually some evidence that stats may have a role in treating this disease I'll show you that in a minute.
And then ultimately for those patients who do progress to advance disease transplantation, well, how about hormonal therapy? This was the initial therapy that was tried.
And there was certainly a sound logic to this.
I mentioned that this is a disease, almost exclusively of women suggests that there's a hormonal hormonal, underpinning to this.
The estrogen receptor actually works through the akt pathway.
So it's the same pathway that I showed you before.
So it makes sense that maybe estrogen is involved in the disease.
There are studies showing that lamb cells actually contain estrogen receptors on their surface, and then their anecdotal reports of lamb, worsening during pregnancy, or when women are given exogenous estrogen as was commonly occurring in the past with post-menopausal hormone replacement therapy.
However, and until recently, all patients with lamb would be put on the droxy progesterone for a period of time.
Many patients with lamb were told to undergo oophorectomies, um all of these intended to lower estrogen levels.
But there is absolutely no compelling evidence that hormonal manipulation is beneficial.
And for that reason it's been abandoned well, how about sarah limas? This is the big story, the big news in this disease.
Once we understood that this disease works through the mtor pathway.
It was also nice to know that there was a drug that had been introduced.
And in fact, fda approved, it was an mtor inhibitor.
It had absolutely nothing to do with lamb.
In fact, it is not fda approved for lamb.
It was introduced in the organ transplant world because the m24 pathway is also involved in t, cell proliferation, that's a component of cellular rejection.
So rapamycin was developed as an anti-rejection medication and solid organ transplantation and was then subsequently applied to the land population in a study that appeared in the new england journal in 2011, with frank mccormick from cincinnati being the lead investigator.
It was a prospective randomized trial.
You can imagine it took a long time to enroll because you're talking about a relatively rare disease.
And in the first year, women were randomized to either receive, uh, rapamycin or placebo in the second year.
The treatment group, the drug was stopped, and they were observed off of drug.
There are two important points that were that can be shown on this curve here.
The first is that there was a significant difference in lung function at the end of one year between the treatment group.
And the placebo group, such as treatment group, maintained a higher fep1 during that entire year, compared to declining fev1 in the placebo group.
Notably once the drug was stopped the rate of decline in lung function.
Then parallel that the placebo group.
So the drug works while it's given.
But unfortunately, the effect wanes after the drug is stopped.
Initially grappa was thought that maybe it would actually improve lung function.
And there were some initial anecdotal reports that it did.
But if you actually look at the spectrum of changes in the treatment group, shown in blue bars here, most of the patients had very little change in fev1.
So it was a lung function stabilizing drug.
It was only a very few patients who experienced significant improvement in their lung function.
But this is in contrast to the placebo group where most of these patients actually declined over that year, rapa is not without its side effects.
And the most common are nuisance side effects.
Mouth, ulcers, virtually all patients develop hyperlipidemia.
Rash is not uncommon.
Lower extremity edema.
But two of the most feared complications have really not materialized.
You can imagine that a drug that was developed for prevention of organ transplant projection has immunosuppressive effects to it.
So there was a concern that there would be an increased risk of infection.
But at the point of fact, there was no difference in the rate of infection between the treatment and placebo groups, there's also a very concerning.
But unusual side effect called rapid meningitis that lymphocytic infiltration of the lung fever parenchymal infiltrates on on radiograph.
Um, we see this in in our lung transplant patients who start on rapa.
But there have been few if any reports of pneumonitis developing in lamb patients who are treated with the drug probably because we're using much lower doses of the drug well, how about statins right now? Most of that data comes from a mouse model of lamb that was actually developed at my former institution, uh, vera krumskaya and her colleagues at penn, uh, developed a mouse model, where tsc know that the gene has been inactivated.
Tsc, null cells are injected into the tail vein of a mouse.
They gravitate towards and take up residence in the lung.
And they create a disorder that looks very much like lamb in humans in that.
You see these collections of lamb cells that develop, and you also see airspace enlargement.
And this is just some quantitative techniques that ferra used to document the development of these lesions.
And also to document airspace enlargement.
This is mean, alveolar, airspace area.
So it's, a quantitative way of defining the extent of aerospace enlargement, you can see development of these lesions and aerospace enlargement over time.
This is a complicated slide, but I'm going to show you some simple lessons that were learned.
So what she did was compare the controls.
They looked at the effect of giving wrapa versus the effect of giving synthestatin and then I'm going to ignore the last part, which is combination therapy, but they looked at it on regional growth and on development of airspace enlargement.
And if you look at the growth of these lesions, these collections of uh, hmv45, positive cells, rapa has a profound effect on reducing the size.
And number of these lesions simvastatin had a lesser effect, but still some effect compared to controls.
This was the important observation.
If you look at airspace enlargement using either a technique called mean, linear intercept that I won't go into here, we're actually quantifying the area of these air spaces.
You can see that rapid lysine had very little effect on cyst formation.
Whereas the statin had a relatively profound and statistically significant effect the same when we used a different.
Quantitative measure rapamycin really did not affect cis formation in the lung, whereas the statins did.
So this has generated an interest in giving combination therapy rapamycin to prevent or diminish the growth of these hmv45 lesions and simvastatin to actually prevent or attenuate the development of cysts in the lung.
And we are now in the process of a phase one trial that started at penn and several other centers.
Now, looking at the combination of these two drugs to see if it would have a synergistic effect, compared to wrap up one, a few words on lung transplantation.
And then I think I will wrap up and skip some of my last slides here.
So this is reserved for patients who have life-threatening disease.
Typically, an fev1 that's come down to very severe levels.
If you look at patients who are transplanted who are in the national database, their fpp one is around 24 percent of predicted, very limited functionally.
In terms of six minute, walk distance importantly, prior pleurodesis, which is done for many of these women because of pneumothoraxis, it does complicate the procedure.
It makes it very hard to explain the lungs, but it does not preclude or contraindicate transplantation.
You just need an experienced surgeon, who's capable of handling a complex pleural space, there's evidence that replacing two lungs is actually a better outcome than one.
But this dab is not yet conclusive and survival is among the best of any patient population for which we offer lung transplants, probably because these are young otherwise healthy individuals with about a 90 one year survival and about a 50 10 year survival, a couple of observations that we've made in the transplant population.
Um, I've mentioned one, which is that you very often encounter extensive, pleural adhesions at the time of explanation of the lungs and very often that will occur even in the absence of chlorogenesis.
So the disease itself seems to engender the development of pleural adhesions.
And this leads to intraoperative bleeding.
But ultimately, if you get the patient through the operative and perioperative phase, as I showed you they've done quite well, they can develop complications of their native disease.
So kyle's effusions can occur post-transplant.
If you leave along in place by doing a single lung transplant, then you potentially raise the risk of metabolism in the native lung.
And curiously, as I mentioned, there can be disease recurrence in the allograft here's, one of our patients at 10 who you can see some early cyst formation in the new allografts.
And one important point to mention.
And this has become very controversial is rapamycin.
So many of these women you can imagine who are on transplant tests are on rapamycin.
The problem with rapamycin is as an antiproliferative drug.
It also inhibits fiber left fibroblast proliferation, which is key to wound healing.
One of the key wounds that you have to heal with a lung transplant is the bronchial anastomosis.
And when rapa was looked at as an immunosuppressive drug in lung transplant patients, there were reports of case series of fatal bronchial dehiscence.
So the drug has to be stopped before transplant.
And in the perioperative period until you have documented complete healing of the bronchial anastomosis I'm going to skip through this and conclude, because we are running out of time here and I'll just talk about where we are.
Now, as my last slide, I think we've come a long way with this disease in terms of understanding its pathogenesis.
And in terms of introducing some very effective at least disease, stabilizing therapy.
So we've gone from a disease that in the past.
The the adage was diagnosis to death in 10 years, you will still see this all over the internet.
And the first thing that patients come to my clinic with is the absolute fear that they have 10 years to live.
They've been given a death sentence with this disease.
But in point of fact, at present, the 10-year survival, approximates, 90 that has nothing to do with lung transplantation.
It has nothing to do with raphamycin and everything to do with the fact that we now recognize there's a whole spectrum to this disease, including mild reforms, the future up in the air.
I would hope that with the widespread use of graphomycin.
The transplant will become a thing of the past, and the end-stage disease will become a thing of the past.
And I hope that as we intervene earlier and earlier with less toxic agents that this will no longer be a disease that will in any way strike fear in the hearts of young women, I'm going to end there and I'm going to thank you for your patience.
And hopefully you've enjoyed learning about another disease.
Um, as you said there in your conclusion, we all hope that all these end stage lung diseases, no longer need transplant ultimately for us transplanters out of business, but do you have any concerns that? Maybe what will happen with this disease is a little bit what we saw with ipf earlier was when some medications came out that looked promising that referral transplant sometimes got delayed, sometimes maybe even fatally delayed.
Do you have any concerns that this may happen with the carolinas and transplant? Um do a little bit, although I'll tell you what potentially will mitigate that fear is somewhat like the cf community.
There are now specialized lamb centers.
So many of these patients are being referred early to these lamb, designated centers or lamb foundation, designated centers.
And I think most the physicians participating in those specialized centers are aware of these issues, and hopefully will not be referring late plantation, but you're right, it's always clear that when you introduce a therapy that it's going to lead to delayed referral for transplant when in fact, it might be appropriate and not to get off track.
But I think that's one of our concerns about professional coming out with homeostasis, is that going to save those patients or is it going to delay them coming to a more definitive therapy? So yeah, and we've certainly learned with pulmonary hypertension, another, treatable disease that the problem with that, the good news is we're treating patients.
The bad news is that when they're finally referred for transplant, they are really serious questions, um.
So I thought in here, or one of the earlier slides, you said that it was a tumor suppressor signaling pathway involved in disease.
So generally the textbook story about that is that there's, some second hit that has to come along to initiate.
So I was curious as to of the number of people who have the genetic defect, how many ultimately have a disease.
And since you pointed out, the uterus and females, I was curious about the connection to pregnancy, whether women who have to who develop clinical disease can be nulligraphic or good have they become afraid.
So to answer the first question it is at least in the sporadic form of the disease.
It is felt that there's probably a two-hit phenomenon there that many of these patients are probably genetically heterozygous and intersect something that creates a homozygous state in the particular tissue that's involved through a spontaneous mutation.
But no one really knows more about it than that.
So it's, just a theory that there's a two-hit phenomenon to cause the disease in terms of pregnancy, it's a big controversy.
So there are clearly case reports of exacerbations of the disease with pregnancy.
But if you really look closely at those reports it's, mostly chylos effusions or pneumothorax, it's, very hard to find documentation that the lung function itself deteriorates dramatically under the influence of estrogen for that reason you get two schools of thought you get some clinicians who tell patients they should never become pregnant.
And you get other physicians such as myself who tell women with well-preserved lung function that the documentation is weak and that as long as they're willing to accept some uncertainty related to the pregnancy that we would fully endorse it and help them through their pregnancy.
We have seen many many women with lamb successfully navigate pregnancy without any changes.
I I just was curious about two things.
One is the symptom burden.
Um, even though we've prolonged, um life and these women.
Fortunately, I just wonder what is their quality of life? And you know, especially during those years when when people are very active working and such, uh, the second question is what happened to the woman's daughter? So the first question about quality of life is or women who have reasonably well, preserved lung function quality of life is quite good.
I can tell you in general for patients with mild disease.
I see them once a year in clinic and even for patients on rapamycin while it has a number of nuisance side effects.
I don't think it significantly impairs quality of life for most patients, taking the drug obviously for women who have very advanced disease, it dramatically impairs quality of life and is, you know, that's, obviously a major issue.
The second question was, uh to andrea I'm happy to report that andrew is actually doing quite well, she's very actively involved in the lamb foundation.
Her mother sue just retired last year, but she and she's also benefited from the development and introduction of rapamycin that has stabilized her disease, it's, very interesting to the point very specific like it.
I have one or two observations from your presentation about the progression and the pathogenesis of the disease.
It seems that the oxygen tension has to do with the overall disease progression because lung is the more is the most important key direction side here.
But when it takes the form of aml and to survive there, those cells, they recruit too much of blood vessels for vascularization.
So it seems that at the molecular level, probably the conditions of hypoxia is recreated in the lung where it should not be and stabilizes those factors, which is basically meant for the upper regulation of psychical control pathways.
So my question here is because it's basically called predominantly your pulmonary implications here.
If something of the targeted therapeutics is developed where it can only affect the lung where you can restore the ps2 functions there, and it should be all right so you're talking about selectively targeting the mutation in the lung as opposed to systemically.
Yeah, it doesn't matter, even if it is germline right? So the only thing I can tell you there is there's a strong interest and there's about to be a clinical trial looking at inhaled therapy.
So, um, a company has developed inhaled rapamycin.
And you would think that if you want to target the lung that using the inhaled group would be ideal, because you get very high concentrations within the lung, hopefully minimal absorption within the bloodstream.
So there are individuals who are thinking exactly like you that maybe that's the appropriate way to go in.
I mean, aml's are in general very benign process.
So we really don't care about them, but let's focus on the mutation within the lung itself.
So in the interest of time, if you want to have I'm sure you'd be happy to answer questions, uh, it is a tradition in our for our grand rounds that each of our presenters from your other institutions actually goes home with a gift.
And um, I won't take any credit for this.
Dr, roman to hear this.
But this is a little slugger bat, which has your name and the date on.
Thank you very much.