BTK 7.15.24 Journal Review Thymectomy

Hello and welcome back to another journal review in thoracic surgery with your with your Swedish thoracic surgery team. I'm Chloe Hansen. I'm a third year general surgery resident currently in my research year here at Swedish and I'm joined by my co host PGY4 Dr. Doss and our attendings Dr. Brian Louie and Dr.

Peter White. Hi everybody. Hi, great to be back. Today in Journal Club we'll be discussing a paper out of the New England Journal of Medicine discussing the health consequences of thymectomy in adults published in August of 2023. Yeah, I chose this paper for this podcast even though it's not necessarily a surgical paper because it was published by a medical group primarily in HEMONC and regenerative medicine but it was picked up quite widely by the media.

If you look at their citations, over a hundred different media outlets picked it up and because of that, it sparked a lot of interest with our patients and we've had several patients both with Brian and myself bring the paper into clinic and ask, are they getting a total or a partial thymectomy. and asked about the results of this paper.

So we figured it'd be a great one to

discuss so we can talk about some of the potentially concerning findings and highlight some of the things that the paper does that may make some of their results less relevant to our surgical populations and, but may give us some better long term health outcomes to counsel thymectomy patients.

You know, that's true, Peter. We've there's been a number of patients here wanting to talk about the results. The paper and the consequences of the thymectomy. But as you know, the congenital heart disease literature that we've seen for the effects of removing the thymus in children, we've known about that for a while.

The thymus is critical for the normal development of the immune system. An early thymectomy can have devastating effects on the immune system, which can lead to increased infections, autoimmune issues, and even some malignancies. I know we're all surgeons here, but before we jump into the meat of the paper Kelly, can you give us a brief refresher for the role of the thymus in the immune system?

Medical school immunology has been a long time for me, and I know I'm not the only one who could refresh

what the consequences might be after removal. Of course. So, the main role of the thymus is that it's facilitating the maturation of T cells. And it's a critical step in cell mediated immunity.

So T cells begin in the bone marrow, and then they eventually migrate to the thymus, where they undergo a process of maturation that involves ensuring the cells are reacting moderately against antigens, a process called positive selection, but that they don't react too strongly against self antigens found in the body tissue.

This is called negative selection. I think of the thymus as kind of where the T cells go to school to figure out what they should be fighting against in the body. So each T cell has a T cell receptor that's matched to a specific antigen. And most T cell receptors bind to MHCs or major histocompatibility complexes.

MHC class 1 tends to produce a CD8 cytotoxic T cell, while MHC class 2 tends to produce CD4 positive T cells. And all the T cells have to make it

through both this positive and negative selection in order to mature. Mature T cells then leave the thymus and go out into the body and do their work.

The thymus continues to grow after birth. By about puberty, it reaches its maximum, maximum size, but it subsequently starts to decrease in size and activity as patients move into adulthood. And this is a process known as thymic involution. The generation of these new T cells declines, the body maintains its existing population of T cells and has its pretty much set T cell repertoire.

The age related contraction of this T cell receptor repertoire may hinder immune surveillance as patients age, and this can increase the risk of infection, cancers, and it could be a risk factor for older patients developing autoimmune diseases. Well, Kelly, that's a great review. And as Peter said, I think we all needed that review to understand some of the role of the thymus.

As thoracic surgeons, this paper is relevant to us,

as Peter mentioned in the introduction, because of the implications for patients who might be getting a total thymectomy if they have myasthenia gravis, or those who have a thymoma and undergoing resection. And there's been some debate over the last little while between partial and total thymectomy in patients who have smaller or early thymomas and this could influence that decision process as well as help provide informed consent to our patients.

Great Brian. So with that setting up the context, let's move into our paper discussion. So it involves multiple groups, some matching, some separate sub analysis. So we'll really try and break it down and simplify it as best as we can. And Chloe, why don't you start us off? Yeah, as mentioned, this was published in the New England Journal of Medicine in 2023.

It's a retrospective chart review of all patients who underwent thymectomy at MGH between 1993 and 2020. They excluded patients who died within 90 days of the procedure or those who had non laparoscopic cardiac surgery within 5 years

after thymectomy. They call it non laparoscopic in the paper, which likely points it to not being a surgical group and we can presume it's referring to thoroscopic or robotic surgery.

A separate control group consisted of patients who had undergone non laparoscopic cardiac surgery between 2000 and 2019 and had no history of thymectomy. The exclusions for the control group included patients who died within 90 days of the procedure, those who had pre operative heart failure, or who had a second cardiac surgery within five years after the procedure.

As they reported, preservation of the thymus is unlikely in repeat cardiac operations. Yeah, so basically they were taking patients who had undergone a thymectomy and comparing them to someone who had just undergone an open cardiac procedure. And so after exclusions and one to one matching to the control group, their primary cohort consisted of 1, 146 patients who had undergone thymectomy and then the same number of age, race, and sex matched

controls.

Of those patients that had undergone thymectomy 511 were for cancer, 370 for a suspected thymic mass. and 183 for parathyroid excisions. The remainder were cardiac or for indeterminate reasons. Um, their supplemental data also showed that the majority of these patients underwent a total thymectomy, 997 out of the total cohort.

Thymectomy was done either by sternotomy, thoroscopic, or a transcervical approach, and their control group of patients undergoing open cardiac surgery primarily included cabbages, valve surgeries, aortic root or arch repairs, or a combination of all of those above. Yeah, it's, to note, they don't actually say how many patients underwent sternotomy, thoracoscopic, or transcervical for their thymectomy patients, but all of the cardiac were open.

Yeah, and to get a little bit more granular in their analysis of the characteristics of the cancers and the autoimmune diseases

of their patient cohort. They did a deeper chart review of 75 patients who underwent thymectomy 75 of their control patients who had post op cancer, and a separate 75 control patients who had post op autoimmune disease.

And these weren't matched according to any demographic characteristics. It was just a little bit of a more deeper dive that they took. They also did a separate 5 year mortality assessment using all thymectomy patients with at least 5 year follow up, and the mortality of the thymectomy group and the control group were compared with values reported in the general population from the CDC.

To obtain immune assays, blood was obtained from 20 thymectomy patients and 19 controls and was used to perform lymphocyte and cytokine analysis, in addition to examining the T cell receptor excision circles and TCR sequencing. Thanks, Kelly and Chloe. To briefly summarize, we have a retrospective study from a single institution over almost 30 years that included 1146 thymectomy patients with varied surgical

approaches, 87 percent of which were total thymectomies.

These were compared one to one to match controls who had undergone cardiac surgery during a similar time frame, presumably without thymectomy. Yeah. Thanks, Brian. So, when you have a study that has to go to this length in order to get matched controls and exclusions, it always makes you wonder, what is the actual group that we're looking at?

And we'll get into more of that later when we talk about some of the limitations of the study. But now that we've finished that study design, let's jump into the results. So really the most significant finding in my view is that patients who underwent thymectomy were almost three times as likely as their control group.

To die within five years after surgery from any cause that relative risk was 2. 9 This equated to a five year mortality of 8. 1 percent for the thymectomy patients compared to only 2. 8 for controls and this finding was preserved

Even when they excluded patients who had pre operative comorbidities such as myasthenia gravis Thymoma cancer infection or autoimmune disease.

But obviously that group that was then studied was a much smaller cohort of population, and they also found that the all cause mortality over the five years after surgery was higher in patients who had undergone thymectomy. Then, when compared to the general population using the CDC data, but remember, they did end up modifying those results to try and deal with the fact that patients in Massachusetts may have a baseline higher survival rate.

And so they actually reduced their rates by 17 percent to try and match the general population. So they did a little bit of manipulation of the data there in order to come up with those numbers. Okay. Now, in terms of the risk of cancer, they found that patients who had undergone thymectomy were twice as likely as controls to have a cancer within five years after surgery

with a relative risk of two, 7.

4 percent in the thymectomy group and 3. 7 percent in the control group. This was also preserved at 20 years with a hazard ratio of 1. 6. The risk of cancer among controls was similar to the general population. Kidney Syndrome was 1036. And, what, what is kidney syndrome? Okay. So, again, I forgot exactly the answer to that but let's talk a little bit about what Now, what is siamo syrup?

What is a siam syrup? Well, what you're going to notice with this is that some of the components Of what we What did they find when they did a deeper dive into the 75 post thymectomy cancer patients? Yeah, so they were really trying to better understand what was going on with these patients and tried to characterize the types of cancer they were getting and the aggressiveness of these cancers after thymectomy.

Overall they found that the thymectomy group had more cancers per patient and a more diverse array of cancers. Specifically when they looked at patients who developed a breast cancer.

Those in the thymectomy group had a higher histologic grade, on average. And the thymectomy group also had a higher percentage of cancers that had distant tissue or nodal metastasis.

Patients who had undergone thymectomy and got cancer afterwards also had a higher rate of cancer recurrence. Yeah, so with the risk of cancer after thymectomy I think the thought is that the thymus gland continues to be a functioning part of the immune system. We know that the immune system, by recognizing self versus not self, can recognize cancer cells as not self and potentially attack them.

And that's part of the basis for immunotherapy when we're treating our other cancers like lung cancer and esophageal cancer. So in this setting, I can see how those results could make sense but we have to take it in context of what their control was and what they kind of did with their, with their matching and how they may or may not have been completely matched groups.

So then let's move on and we'll discuss their findings with regards to post thymectomy

autoimmune disease. So Chloe, what were those results? Yeah, as a whole, the thymectomy group was no different than the controls, but in order to minimize Pre operative confounders, they excluded patients with pre operative infection, cancer, and autoimmune disease.

This revealed a 1. 5 times higher risk of post op autoimmune disease at 5 years in this thymectomy group, at 12. 3%, compared to controls at 7. 9%. However, this difference dissipated when evaluated over a 20 year period, leading researchers to conclude that thymectomy appears to have a transient and modest increase on the risk of autoimmune disease.

They also found that patients in the post thymectomy group had a higher number of post op autoimmune diseases per patient. The blood draw and immune cell results are less relevant to our surgical discussion. So Kelly, can you give us a quick one liner on this aspect? Sure, I think this was a really interesting thing to look at, but obviously something very challenging to do on a large scale.

So they

took blood samples from 20 patients and 19 controls. And they showed a higher new T cell production in their controls compared to the thymectomy group. Now, granted this is a very small, very small cohort but this supports that the thymus continues to contribute to new T cell production in adulthood and that removal of the thymus could affect T cell mediated immunity.

Great. Thanks Kelly. Absolutely. So the, the paper goes into a lot more detail about. T cell clonality and receptors and cytokines both in post slamectomy and in these pro inflammatory states compared to control. So if any of you are super interested in that, and I know there may be some out there, you can go and read the paper for all those details.

So, that was a lot Chloe can you take us through and really summarize what all of these findings show? Yeah, definitely. So this paper found that patients across all age groups who had undergone thymectomy were two point times more likely to die at five years

compared to controls, and 1. 7 times more likely compared to the U.

S. general population. Among patients with post op cancer, thymectomy was associated with more aggressive recurrent disease. In subgroup analysis, excluding confounding pre surgical conditions, an association between thymectomy and post operative autoimmune disease was found. Finally, patients who received a thymectomy had a pro inflammatory cytokine profile compared to controls that has been associated with cancer and autoimmune disease.

This paper brings up a fairly common surgical topic. Everything we do to a patient has an outcome, and we need to balance the potential benefit and risks of everything we do. While this paper brings up questions of mortality and cancer risk, we've known about the autoimmune risks for longer. Kelly, briefly, 2020 show?

Yeah, so this paper included about 2, 500 patients and they did a retrospective review of patients who had undergone thymectomy. Just under about 50 percent were 4 myasthenia

gravis. And they matched them to a non thymectomy group. And their overall result was that they found a 2. 68 times higher likelihood for any type of autoimmune disease in patients who had undergone a thymectomy.

Switching back to the New England Journal of Medicine paper, Dr. White, what do you feel are some of this paper's limitations? Yeah, so I think we have to start by addressing the way that they chose their control group. And it's really not a true control. I know why they chose those patients, because they were trying to remove the confounder of undergoing surgery and the potential autoimmune and inflammatory and cytokine response of the operation.

But in doing that, they chose a control group that was actually undergoing a separate life preserving intervention. We know that almost half of those patients underwent coronary artery bypass grafting. underwent CABG with a valve and that the rest either had a valve or they had some sort of

aortic root or arch operation.

All of these operations inherently confer a survival benefit to that individual patient population. And then when they matched them, They only matched on age, sex, and race. They didn't match on anything of potential comorbidities that would affect survival like diabetes and underlying heart disease, lung disease, kidney disease, any of the things that you would normally expect when you're matching to try and get equivalent cohorts and then the control groups.

So I think that really brings in a question, do the results that they have actually correspond to what we would expect to see. In our clinics with the patients that we're seeing, and I'm not sure it does because there may have been a fair number of patients as part of the thymectomy group that did have underlying heart disease or diabetes that never had any heart intervention, and then they would have potentially had a lower survival simply for that rate, completely

unrelated to the fact that they had a thymectomy.

The other thing that you have to mention is when they were doing that five year survival comparison using the CDC data and the general population, of which we already mentioned they did some statistical changes to try and make it more equitable for the Massachusetts population, the five year survival rate was 1.

7 times less likely for those that had thymectomy. compared to the general population, but then 2. 9 times less likely compared to those compared to the control. So the question is, why did the control group, which was a group inherently that had heart disease, have a much higher survival rate than the general population?

And so something is going on with the way that these groups were constructed that I don't think makes it a true control. When you look at mortality rates CABG and PCI over a nine year rate there's about a 9 percent mortality rate for all

ages, just in those undergoing those procedures. And so for the risk to not equate to what we would expect in that heart disease group, it seems like just something's not panning out with the way it was done.

Yeah, and I, I think the fact that this paper was in the news so much and patients are hearing about it in a, explained to them in a non scientific way without all of these details and discussion of bias and limitation has to be really challenging when Dr. White and Dr. Louie, you're seeing these patients in clinic and they're bringing up this data.

So how does this paper impact your practice? How does it impact your conversation with patients? Well, I think, you know, you, you need to address this paper when having an informed consent discussion but because it doesn't necessarily prove causation I usually tell patients there's some signal here, but we don't really have the full answer and our decision making for your thymoma should be based on other characteristics about whether we

would do less than a total thymectomy and for patients who have myasthenia gravis.

There really isn't much discussion because those folks benefit from a total thymectomy, at least at least based on our, our experience and most others. Peter? Yeah, so I think that it's important to understand what the goal of this paper was and then look at their results in that light. And so they said right from the beginning that the hypothesis was that the adult thymus is needed to sustain immune competence.

That was their number one. And then to look at overall health. for those who have had thymectomy long term. So it was written on the base of this hypothesis, and it was not designed to comment, well, do you do a partial versus a total thymectomy? Do you talk about indications for the operation in the background of well, maybe there's an increased risk of death with the surgery long term?

Do we even do it? None of those were It was not designed to address those concerns and those are the concerns that patients really have they want to know

well What is the benefit going to be to do this thymic surgery for my thymoma? Well, obviously we know the risk is they have a cancer and if you don't treat it Well, that can potentially lead to decreased survival, whereas the operation may be curative.

But the, this paper was not framed in that way but patients read it in that way. And the news outlets have reported it as a survival when they get a thymectomy reduction in survival with thymectomy, but they don't have all the background history, which is part of the reason why picking this paper to actually discuss in this format, I think was so important.

When you review some of the data that has been published over the last few years, partial versus total thymectomy for early stage thymoma, I do think it makes a lot of sense to consider a partial thymectomy as long as you feel like the margins are going to be appropriate. Could this paper impact some of those thoughts?

It may, because as Brian said, there's a signal that says, well maybe

there is a decrease in survival, maybe there is an increase in survival, So if I have two equivalent operations, will I want to do the one that has the least amount of morbidity or mortality associated with it? So this paper may factor some of those decisions, and I think it also comes into play when we talk about counseling patients.

If you have a myasthenic patient, and you know they need a total thymectomy, could this paper play into how you describe what some of the long term outcomes are? It could, not to say that it would change the operation that you do. But it may change how you counsel patients about it. You know, Peter, the other thing that I think this paper suggests, not from a thiamectomy standpoint, but for the trainees who listen to the podcasts, are that even though papers are in the New England Journal of Medicine, a lot of trainees will assume that, Oh, this paper has been well vetted, and there are no limitations to the paper because it's in the New England Journal of Medicine.

And I think this is a good example and a good lesson to the residents and the

trainees who listen to our podcast that, you know, Just because the paper is in a high impact journal doesn't mean it doesn't have limitations and needs to be carefully thought through in order to apply it to your patient population and how you practice medicine or surgery.

Yeah, and we're not saying that the paper is inherently wrong or bad, it's just that it was designed to look at something that's different than what we're looking at. And I think that's really important for the context of the paper. Why you have to have a hypothesis ahead of time. You can't data mine and then come up with a hypothesis afterwards because that guides the entire way that research is done.

I was a little bit disappointed though in their discussion because they really didn't get into any of these details. There, they only gave a one liner about limitations saying it's a retrospective study, so it can't imply causation. But there was so much other things that they could have talked about that really would have flushed out these details that I think would have been important.

So it sounds like to summarize, you guys are really looking

at the individual disease processes that your patients are coming to you with. Are they coming to you with myasthenia gravis? What type of thymoma are they coming to you with? And then counseling your patients on what surgery they should have for their disease process and using this paper to kind of help discuss some of the caveats and long term consequences after surgery.

Thanks, you guys. That was a great discussion. To wrap up our thoughts, this is one of the first papers published examining the long term health consequences of thianectomy in adults, a topic with relatively little research. While the study design certainly has some flaws with regard to their choice of controls, their outcomes have given thoracic surgeons something worth thinking about by reporting an increased risk of death, post op cancer, and post op autoimmune disease in patients undergoing thianectomy.

This paper was not designed to answer the question about partial versus total thymectomy, and we don't necessarily think it should be used as such. It does, however, enable us to have a more complete risk versus benefit discussion with patients and adds an additional layer of consideration in early stage thymomas.

I

think we can all agree that more research is needed on this topic before any significant conclusions can be made. As always, thank you for listening to another Swedish Thoracic Surgery Journal Review. We hope you furthered your knowledge and understanding of the long term health consequences of thymectomy.

Now go out and dominate the day.