Mistaken Identity: The Case for Early, Correct Identification of Fibrosing Mediastinitis

Podcast Transcript

Raed Dweik, MD:

Hello, and welcome to the Respiratory Exchange podcast. I'm Raed Dweik, chairman of the Respiratory 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. My colleagues and I will be interviewing experts about timely and timeless topics in the areas of pulmonary, critical care, sleep, infectious disease, and related disciplines. We will share information that will help you take better care of your patients today, as well as the patients of tomorrow. I hope you enjoy today's episode.

Daniel Culver, DO:

Hello. Welcome to this edition of Respiratory Exchange. I'm your guest host today, Dan Culver. I'm the chair of the Department of Pulmonary Medicine at Cleveland Clinic. Today we'll be discussing fibrosing mediastinitis. I have two guests with me today, Dr. Francisco Almeida, who's the head of the Fibrosing Mediastinitis Program and an interventional pulmonologist at Cleveland Clinic, And Dr. Atul Mehta, who is the section head of General Pulmonary Medicine and one of the leaders in bronchoscopy. Welcome.

Francisco Almeida, MD:

Hello Dan. Great to be here talking to you today.

Atul Mehta, MD:

Hello Dan. Looking forward to it.

Daniel Culver, DO:

So, Francisco, tell us a little bit about fibrosing mediastinitis. How is it defined and what causes it?

Francisco Almeida, MD:

Well, fibrosing mediastinitis is a, as we understand it, mostly a CD20-driven inflammatory reaction in the chest that leads to this exuberant reaction and fibrotic or fibrosis development. This process of fibrosis ends up leading to such a reaction or buildup in the chest that leads to compression of neighboring structures within the mediastinum or hilar structures. You know, as we know, pulmonary artery, pulmonary veins, the SVC, you know, it can compress the esophagus and then the airways, you know, at the main airway level or lobar or segmental level. So, that's sort of what that is.

Daniel Culver, DO:

So, in the US, I suppose the main cause is still histoplasmosis?

Francisco Almeida, MD:

Correct. In the US, it is believed histoplasmosis infection is the most common cause, and, as you know, one of the main places are among or near the Mississippi and Ohio Valley rivers, near us, also and southeastern US and the Mid-Atlantic. So, those are the top places, but it's not the only cause. There are many, many other causes.

You know, many fungal infections can lead to fibrosing mediastinitis, this fibrotic reaction. TB is another cause not very common in the US. IgG4-related conditions also may play a role. Radiation, sometimes, can cause sarcoidosis, SLE, ANCA-related vasculitis. So, there are numerous causes out there that can lead to fibrosing mediastinitis.

Daniel Culver, DO:

So, it seems like sometimes the fibrosing mediastinitis patients that I've seen have been presented quite late, and they often have very severe disease. So, what is it about the presentation of fibrosing mediastinitis that makes it so challenging for clinicians to diagnose and why we see it so late. Atul?

Atul Mehta, MD:

Yeah, that's a very interesting situation. As you mentioned in the beginning, fibrosing mediastinitis, in my opinion, is very much under-recognized because when patients have shortness of breath, they suspect that is because of asthma or COPD, and those symptoms are overlooked, and we are not thinking that this could be fibrosing mediastinitis.

Very often, you know, the x-ray findings are so non-discriminatory, and they are non-specific and hence, the diagnosis is not pointed out. And I don't think it's a difficult diagnosis to make, but it is overlooked for a long period of time until somebody is referred to the pulmonary department or general pulmonary medicine areas and somebody suspects it. So, I think it is more under-recognition than difficulty making the diagnosis. Once you recognize it, once you suspect it, I don't think it is that difficult to make the diagnosis.

Daniel Culver, DO:

Of course, there are a lot of mediastinal processes that we see on CT scanning. Is it a radiographic diagnosis or a physiologic diagnosis or an endobronchial diagnosis? How would you confirm the diagnosis versus just seeing something that looks like an extensive mediastinal process?

Francisco Almeida, MD:

Yeah, so, I just wanted to add to Dr. Mehta's comment. You know, also it's underrecognized, at first, because sometimes patients have no symptoms. You know, it grows very slowly. Some have said that it may grow about one millimeter a year or so, but I'm not sure there's enough evidence to say that is a fact, but historically, that seems to be close to the truth.

Radiographically, when you have a CT scan, you can make a diagnosis in the majority of patients. Yet, we see a number of patients that come to us, and I hear patients coming in and saying, doctor, I came here to see you because I have lymphoma. Hey, why are you saying you have lymphoma? Well, because I have this mediastinal mass, and, you know, sometimes they say, well, for different wording, but it's funny.

Like, I look at the CT scan, and even before I collect a history, let me show this CT. You do not have lymphoma. This is a classic appearance of a condition called fibrosing mediastinitis. Of course, sometimes lymphoma is in the differential.

Daniel Culver, DO:

We all had lymphoma a few times in medical school, didn't we?

Francisco Almeida, MD:

Oh, we do. It's like, when I was in medical school, back in Brazil, it's funny. Our mentors used to say, if you're not paying attention and somebody asks you, what do you think this is? Just say lymphoma or TB.

Daniel Culver, DO:

You're never wrong. So, it seems like there are many pathways for patients to come in to see us, and often, there's a missed diagnosis. What kinds of therapeutic and diagnostic testing have you seen commonly done before patients come to see you and which ones of those have been the most useful for making the diagnosis or for treatment?

Atul Mehta, MD:

Yes. It's a good question, Dan. I think technological advancement in all different sub-specialties has brought up this whole field of fibrosing mediastinitis. As I always say, we are doing more and more CT scans of the chest. So, that is the first step, that's where we consider, or we recognize that this may be a fibrotic process involving the mediastinum. So, that is number one.

We have tremendous, you know, growth or technological advancement in interventional radiology. So, these specialists can diagnose obstruction of the mediastinal structure, such as vascular obstructions, superior vena cava obstruction and collateral formation. In Francisco's field, interventional pulmonology, you know, we are seeing lots of patients with fibrosing mediastinitis-related endobronchial findings, not only branchiostegal obstruction, but increased vascularity and hemoptysis, and so on and so forth.

So, a combination of looking at the CT scans, doing the bronchoscopies and getting the help of interventional radiologists. It's a team approach that we can diagnosis these conditions very easily these days.

Francisco Almeida, MD:

Yeah, to add to that, when patients come to us, not infrequently, patients have an invasive procedure, whether that's EBUS-TBNA, sampling of the lesion, that the findings, not infrequently, outside are non-diagnostic, and we have those slides reviewed here, and our pathologists can see some changes that are consistent. We even have some patients, at times, that have had a mediastinoscopy or a thoracotomy, a VATS biopsy of the lesion.

You know, and obviously, that's clearly diagnostic in virtually 100 percent of the cases, but most patients do not need such procedure to make a diagnosis, and sometimes, they have a CT-guided biopsy. Rarely, do we see patients that may have EUS-FNA of the lesion near the esophagus. So, all these procedures can eventually confirm a diagnosis that we're not sure, but as we mentioned before, most patients do not need an invasive test to confirm a diagnosis that is done just radiographically.

Especially if you see, as Dr. Mehta mentioned, patients have a CT, so there's more CTs are being done out there. If they have classic findings for histoplasmosis, such as calcification of the liver or the spleen, you know, certain calcified nodules. So, that combination, that constellation, along with the patient living in an area that we know histoplasmosis is endemic, that's all you need.

So, when you see a patient in the community, and you see that constellation of findings, very rarely a physician needs to get an invasive test, but it is helpful at times, and it is needed at times, when we can't, as we mentioned before, when lymphoma's in the differential, or a few of these other conditions, sometimes biopsy is necessary.

Daniel Culver, DO:

I'm curious how often you see the sorts of tests that are done to exclude active infection being helpful. Often you see fungal serologies and histo urine antigen and, of course, stains and cultures of any kind of biopsy samples, and I suppose that that's important for completeness sake, but once you see that real fibrosing mediastinitis picture, radiographically and you see the physiology of that, how often do you actually find an active infection in your practice?

Francisco Almeida, MD:

It's very rare to find something active. Sometimes, when the radiological picture is not classic, is not clear cut, those tests may help us. So, now we have a histoplasma antigen or urine antigen is positive, along with those findings. This is most likely fibrosing mediastinitis, but finding an active infection is very rare, and it's not uncommon that we see patients here that come being treated for an active infection, when, clearly, it's not present.

But it's difficult. I don't blame the physicians that see this condition, that they're somewhat limited options in terms of treatment, until a few years ago, and try to do something. That's our reaction of doctors. You know, we want to do something, and historically, many people have tried to treat these patients with antifungals with little benefit, unfortunately. So, I know I don't blame people, as I said, to try. For the most part, it doesn't provide any benefit.

Atul Mehta, MD:

I agree with what Francisco is stating. At this point, I remember my professor, he used to say that old X-rays are a gold mine. So, when you suspect fibrosing mediastinitis and you try to go back as much as you can and look at the old films. If there is histoplasmosis, you'll see the telltale sign that this has been going on for several years. Under those circumstances, doing histo antigen is not going to be beneficial. You know, you may have histo serology positive. This is more or less all the blood tests and serologies, what we do, is for the completion of the workup rather than making a diagnosis in this situation.

You know, I do tend to treat my patients with antifungals irrespective, because most of them come from histo belt, and I also treat them with steroids, but that doesn't mean I know that these patients do not have active infection. This is just for my own satisfaction and to cross all the Ts and dot all the Is. We do that. Maybe there are one or two organisms alive in patients coming from histo belt and that is the reason I do that.

Daniel Culver, DO:

So, we don't really know that there's a big role for antifungal therapy.

Atul Mehta, MD:

Absolutely. It has never been proven that antifungal treatment, or even steroids, do any benefit to these patients.

Daniel Culver, DO:

So, I'm curious about other sorts of treatments. You have both seen a number of patients come in who have had endobronchial procedures, stent placements, lasers, various intravascular procedures. What are the indications for those and how helpful are those in general?

Francisco Almeida, MD:

That's a great question, Dan. I think we are moving towards a more disciplinarian approach to these patients, because putting a stent in a vessel is, for the most part, permanent. Putting a stent in the airway can be temporary. Most of these stents can be removed. So, sometimes that's necessary, but as you know, airway stents are rarely a definitive treatment for any airway stenosis, just because of the many side effects and complications related to it.

And even those vascular stents often occlude, because that fibrotic tissue often keeps growing and compressing that vessel. So, we, not infrequently, see some of those stents placed that end up being occluded later down the line. More recently some have used a monoclonal antibody drug, known as Rituximab, that works against CD20 B-cells to try to halt or stop that inflammation altogether, and some patients will respond.

Some data shows that two-thirds or more patients will either decrease the size of their lesions or get stabilized, you know, stop the growth. So, the question is: when you see a patient that is severely symptomatic from airway occlusion or vascular occlusion or esophageal occlusion, should you wait for that drug to kick in and try to see if it shrinks? Or should you put in a stent or dilate one of these structures that are occluded or narrowed? And we don't know the answer to that question.

That's why I think a multi-disciplinary approach, having a bunch of people discuss from all these fields is extremely important to say, "Hey, maybe we should temporarily stent this patient because this is too severe right now. We should probably not risk waiting until that drug works, and there are the hurdles that we need to go through because there's not an FDA drug for the treatment of fibrosing mediastinitis.

But sometimes the patient is not that symptomatic. You know, maybe we can give the drug now. This is really a discussion between physicians that care for these patients from various specialties, with the patient and the family, discussing the pros and cons. The timing, right now, based on the limited data of what you do first, is not known. If that answers your question.

Daniel Culver, DO:

No, I think that you point out the complexity and really one of the things you highlighted is the importance of the multi-disciplinary approach. I wonder if you can share a little bit about the organization of the multi-disciplinary approach in your program, who's at the table, how do you bring them in, how do they interact, and what have you seen the benefit of that being?

Francisco Almeida, MD:

We're just in the process of starting that. We have many specialties on the table, you know, pulmonologists, I and Dr. Mehta and our team around us. We have pulmonary hypertension, also pulmonologist doctor that helps us when the pulmonary artery is compressed and there's pulmonary hypertension playing a role as well.

We have a couple of thoracic surgeons that are there to help and give their opinion on potentially resectable cases, interventional radiologists that look at the overall radiographic picture and compression of vessels and airways and their opinion related to that. An interventional cardiologist who also deals with some of the therapeutic interventions for vascular structures or pulmonary veins, for example. And infectious disease doctors.

We have this team approach that we're kind of brainstorming, when we see new patients or even patients we've been seeing for a while that we are just observing, so we want to redress. So, should we readdress what we discussed before? We have this team approach that sometimes the patient doesn't need to see each one of them, but for the patient, it's like they're getting all these second opinions and additional consultations without having to go through all those appointments.

So, the team is increasingly working very well together. This is like a classical Cleveland Clinic thing, the team approach. We work well together as a team, and this is another example that we're still in the work of perfecting our work, but I think we're almost there on that perfection of a team approach. I think we'll get better, in terms of brainstorming ideas for not only treatment, but hopefully, future investigations and research in this area. It's been a really short road since we started this program, but it's coming out nicely, and we're getting there.

Daniel Culver, DO:

Atul, you've seen this team in action. What other thoughts on it, you know?

Atul Mehta, MD:

The team is very well formed, actually, just because of the COVID situation, we worked virtually and more with emails and telephones, but eventually we will be having our own conferences and meetings together. The team is getting along extremely well, as Francisco mentioned. Everybody's extremely interested. This is an old disease with new recognition, and everybody realizes this.

Before the CT scans, we never suspected this disease, and now, with all the CT scans, we recognize it. Everybody's using the CT scans and they come up with this diagnosis. I tell you that, interestingly, a couple times, I had suspected the disease on the bronchoscopic findings. The patient comes with a mediastinal mass and patient has got typical endobronchial features.

Daniel Culver, DO:

Which are?

Atul Mehta, MD:

Which are increased vascularity because of the obstruction of the bronchial vessels. You see that there is neovascularization within the endobronchial tree, which we have very well described many years ago. We were probably the first one to describe these findings in fibrosing mediastinitis, and these patients come to us with hemoptysis, and Francisco and his team use argon plasma coagulation to take off these things and some of these patients may even come for EBUS-TBNA of the mediastinal mass, which turns out to be fibrosing mediastinitis.

So, the team works, between the pulmonologists and interventional pulmonologists and radiologists, is working out extremely well. I do want to bring out a couple cases we have done with our interventional radiology team, a stent in the superior vena cava on a young gentleman, 40-something years old. It has been working out extremely well for the last three years. And a similar situation in a young woman from histo belt that we have treated with dual stenting, in this particular situation.

And, as Francisco mentioned, a lot needs to be done in terms of preventing further complications of the permanent stents. Let me ask a simple question: should I leave these patients on lifelong anticoagulation after putting in the vascular stents, considering the complications of these medications? So, there is lot to learn, but, again, coming back to your question about a multidisciplinary team approach, it is working out extremely well.

Daniel Culver, DO:

It reminds me of the old paradigm of oculostenotic reflex that we used to think about in the early days of interventional cardiology. I think one of the things that we've seen over the years is knowing when not to put a device in a patient is, perhaps, even more important than knowing how to put the device in.

Atul Mehta, MD:

Absolutely.

Francisco Almeida, MD:

Yeah. No, as you talk about not doing something, it's important to remind the physicians out there seeing these patients, as Dr. Mehta pointed out, the hypervascularity of the airways. These are not clear-cut procedures to do, when you think about, oh, I'm gonna do a bronch and do an EBUS-TBNA or look at that stenosis or dilate that. Those patients often bleed significantly, just with a little needle or even with a dilation that seems simple. So, if you do not have the experience to deal with those significant bleeds, or have the experience of the tools available, such as argon plasma coagulation or laser or electrocautery, and experience in using those, those can be very challenging procedures.

You need somebody who is experienced in doing bronchoscopies, somebody who is experienced using those tools. You need an experienced team with you, an anesthesiologist for the airway management, and you need to have the support available, in case these patients need to go down to interventional radiology right away, if the bleeding doesn't stop. It's a complex situation when you decide to do a procedure on those patients. So, if you don't have that multidisciplinary team available, sometimes immediately, you should rethink about doing procedures on these patients.

Daniel Culver, DO:

It's like many things in life, the more you learn, the more you see the complexity. I want to draw you out a little bit more, Francisco, on something that you mentioned, which is now the hot treatment, and that's Rituximab. Can you tell me a little bit more about what we've seen with Rituximab and where do you see that going, and do you see it changing, really, the course of the disease?

Francisco Almeida, MD:

Yeah, absolutely. I think we have seen a number of patients in the recent past that Rituximab really changes their lives. I recently had a young patient who was in the ICU. We gave a first dose while the patient was in the hospital, a second dose as an outpatient, and I see this patient now entirely asymptomatic, living their lives to the fullest. So, it's a game changer. The main thing is it is a game changer to everyone? Unfortunately, the answer is no.

Some patients don't respond, and it may be because not all patients are entirely driven by CD20 B-f- B-cell lymphocytes. A recent study suggested that there is a row of CD4-positive T cells also in the inflammation and fibrosing mediastinitis related to histoplasma. So, maybe depending on the condition, there's some other physiopathology related to how the fibrotic reaction develops.

I'm hopeful that as we grow the program, see more patients, we can eventually get together with our translational researchers and start investigating further what are the other potential biomarkers or physiopathogenesis of this disease that we can target with different drugs for the non-responders or eventually find different drugs that, oh, so, this patient is not a responder to the Rituximab, even before we treat.

I think it's quite a way to get there, but I think that should be the goal of this relatively uncommon procedure. It has a tremendous impact on the quality of life of the patients who have it, and their families.

Daniel Culver, DO:

I think that getting together, concentrated expertise in one program is really the key to making those sorts of advances, and thinking about the patient holistically and what questions there are, really, will move the field forward. As we wrap up, I wanted to ask you one more question, Atul, and that is, when nothing else is working, sometimes the patients appear in front of the lung transplant team. Is transplantation ever a viable option for people with fibrosing mediastinitis?

Atul Mehta, MD:

This is an excellent question. This is more a surgical question than a medical question because there is so much fibrosis in these patients, that exploration and anastomosis could be very challenging. We have had few patients who have undergone lung transplantation for radiation fibrosis and radiation-related fibrosing mediastinitis, and those cases are very challenging.

So, to answer that question would be that it is all individualized. We look at every patient's CT scan of the chest. We reviewed this thing probably with our surgeons. If single lung is possible versus double lung is possible versus even doing a heart-lung transplantation, but this is indeed a challenging operation.

Another thing is this, you’ve got to realize that these patients are much, much younger than the patients who usually undergo lung transplantation for, let's say, ILD or even emphysema. Most of these patients undergo lung transplantation for fibrosis involving the mediastinum, and more of these patients are radiation-related thing than truly fibrosing mediastinitis. It’s very, very difficult to do transplants in these patients or justify them for transplant, because the lungs are functioning fine.

If you look at their oxygenation, you know, it is okay. Their DLCO is normal in this situation. So, this is more or less a surgical scenario, a surgical question than a medical question, and decisions are made on an individual basis.

Daniel Culver, DO:

So, again, coming down to volume of the center and expertise and experience.

Atul Mehta, MD:

Absolutely. Absolutely. That is true.

Daniel Culver, DO:

I'd like to get one final word. What message would you like to leave for clinicians as they think about diagnosis and approach patients that they suspect of having fibrosing mediastinitis? Atul, one final word?

Atul Mehta, MD:

One final word is fibrosing mediastinitis is underrecognized. Pay attention to the CT scan of the chest, and we do have several palliative modalities to help the welfare of patients with fibrosing mediastinitis.

Daniel Culver, DO:

Thank you. Francisco, one final word?

Francisco Almeida, MD:

Yeah, one final word is don't give up on your patients. There are some options for them, and seek help, if you need help. Reach out to our team. We're here to help your patient, either from a consultation or sending the patient over for us to work with you and the patient. Don't give up on them, because I see a lot of pessimistic approaches sometimes, when patients come to me. This is from the patients, you know, that they heard from their doctors. But let's give them hope. I think there's hope. So, let's work together to take care of them.

Daniel Culver, DO:

Thank you. Thank you all for listening today. This is Dan Culver. I've been just chatting with Drs. Almeida and Mehta. Thank you for joining us for Respiratory Exchange.

Raed Dweik:

Thank you for listening to this episode of Respiratory Exchange podcast. For more stories and information from the Cleveland Clinic Respiratory Institute, you can follow me on Twitter @RaedDweikMD.