Episode 004: Current management guidelines for Barrett’s esophagus
Guests: Dr. Christopher Teshima and Dr. Thurarshen (TJ) Jeyalingam
SHOW NOTES
Huaqi Li
Thanks so much for tuning in again to Scope Notes, your gastroenterology focused medical education podcast created by learners for learners!
For any new listeners, I’m your co-host Huaqi Li, current first year Internal Medicine resident at the University of Toronto in Canada. I am joined today by Jack Yang, current 3rd year medical student from Western University. Our amazing faculty advisor is Dr. Parul Tandon, a Staff Gastroenterologist and Clinician Scientist in inflammatory bowel diseases at the University Health Network/Sinai Health in Toronto.
With Scope Notes, you can look forward to monthly episodes covering all things GI including practice guidelines, research reviews, and special career topics! We’ll be specifically featuring prominent Gastroenterology staff from the University of Toronto and across Canada for their expert opinions. So come join us from your favorite podcast streaming app!
We would like also to extend a big thank you to the Division of Gastroenterology and Hepatology at the University of Toronto for their generous support of this podcast. With all that being said, let’s move on to our episode! April is Esophageal Cancer Awareness month! So, today’s episode will focus on the treatment of Barrett’s.
We’re very fortunate to be joined today by two leading experts in the field, Dr. Christopher Teshima and Dr. Thurarshen (TJ) Jeyalingam. Dr. Teshima is an advanced endoscopist at St. Michael’s Hospital and Co-director of the Advanced Endoscopy Fellowship training program. Dr. Jeyalingam is an advanced endoscopist at UHN and Education Site Director at Toronto Western Hospital. Dr. Teshima and Dr. Jeyalingam, very excited to have both of you on today’s Scope Notes episode. Thank you so much for joining!
Jack Yang:
Before we get started on discussing this important topic, could you tell the audience a bit about yourself? Where did you start training, how long you've been in Toronto, and a bit about your clinical and research interests?
Dr. Christopher Teshima:
Thank you so much for having me and inviting me to join this exciting new podcast. My name is Chris Teshima. I am a therapeutic endoscopist at St. Michael's Hospital at the University of Toronto. I trained in medical school at U of T, internal medicine at U of T. I did my GI training in Edmonton, the University of Alberta, and then I did advanced therapeutic endoscopy fellowship in the Netherlands. I then worked as a GI staff at U of A from 2010 to 2015 and then I've been here at St Michael's from 2015 until now. I've been in practice for 15 years, and at St. Mike's for 10 years.
My practice is focused on predominantly luminal therapeutic endoscopy, and I run our Barrett’s esophagus and upper GI neoplasia clinical and research program. We have the largest population of Barrett's esophagus patients in Canada and one of the largest in North America. And we see mainly patients who've been diagnosed with dysplastic Barrett's esophagus elsewhere, who are then referred to us for various endoscopic treatments and other interventions. A lot of the research that I've been involved with over the last decade has been derived from Barrett's esophagus, or focus on Barrett’s esophagus, and we have been looking at various clinical outcomes with respect to types of treatments of Barrett's and how that affects patients in the long run. We can maintain a large prospective database going back now more than 20 years, following hundreds and hundreds of patients with Barrett‘s esophagus. So we have a wealth of data that we can use to help treat these patients. I think this is a really exciting illness. It's one which is really challenging, because the average endoscopist doesn't see very many Barrett’s esophagus patients and it’s a unique illness because it has a real inflammatory component, and this means the diagnostic assessment of Barrett’s esophagus with endoscopy is quite challenging, and we see a real discrepancy about how it's assessed in inexperience hands versus experienced hands. And I think that's one of the advantages of coming to a tertiary center like ours.
Dr. Thurarshen (TJ) Jeyalingam:
Yeah, thank you Jack and Huaqi for having me on this episode of Scope Notes. So I'm a gastroenterologist and therapeutic endoscopist at U of T, based at UHN. I formerly did my undergraduate and medical school studies at Queen's University. I then did internal medicine and GI training here at U of T and when I was doing my GI training here, I also did this thing called the clinician investigator program and clinician educator training program because medical education has always been an area of academic interest for me alongside my GI training. And then once I finished that, I actually did an advanced luminal therapeutic endoscopy fellowship at the University of Calgary, and subsequently returned to U of T to join the faculty. And to answer your question about how long, I guess I would have started in 2022 now. So, this is now three years into it!
Jack Yang:
Perfect. Thank you so much for that great introduction! Dr. Jeyalingam, could you start us off with a brief introduction now to Barrett's esophagus. For instance, the epidemiology, pathophysiology, and also its relation to esophageal cancer.
Dr. Thurarshen (TJ) Jeyalingam:
Yeah, great, great question. So Barrett's esophagus is essentially a condition that is associated with gastroesophageal reflux disease, also known as GERD. So GERD is just something that a lot of people experience in our population. It manifests most commonly with heartburn that actually has a wide set of manifestations outside of heartburn as well, and in patients that have long standing chronic regular GERD, somewhere between 5 and 10% of them may develop this condition called Barrett's esophagus. And Barrett's is actually a cellular change in the bottom of the esophagus, where the esophagus meets the stomach, where the normal lining of the esophagus, which is made up of something called squamous epithelial cells, actually is replaced by something called columnar epithelium, usually associated with another cellular change called intestinal metaplasia. So there's cellular change that happens in the area that's constantly exposed to acid and that is known as Barrett’s esophagus, and is a precursor to esophageal adenocarcinoma, which is the most common type of esophageal cancer in North America.
So basically there are a few known risk factors for Barrett’s, and so in addition to having chronic GERD symptoms, other risk factors that we know increase patients chances of developing Barrett's esophagus include being male, being over the age of 50, being white, smoking, obesity, having a family history of Barrett's or esophageal cancer in a first degree relative, all of those factors will increase the chance of a patient developing Barrett’s.
Jack Yang:
Thank you for that explanation! I think some of what you've touched on is essentially the 2020 American College of Gastroenterology clinical guidelines outline of the diagnostic criteria for Barrett’s esophagus. Could you also touch on this a little bit more? What exactly is on the guidelines?
Dr. Thurarshen (TJ) Jeyalingam:
Okay. So basically, the diagnosis of Barrett's esophagus requires that there is a histologic finding of intestinal metaplasia in the esophagus. So histologic meaning under the microscope, there is a change in the normal squamous epithelium of the esophagus to a columnar type epithelium, which is a different shape of the cell that typically doesn't happen in the esophagus, and that is often associated with an intestinal type goblet cell, and that is referred to, I mean that cellular change usually is associated with a finding called intestinal metaplasia. Metaplasia meaning a change in the cell type, and that itself is a precursor for esophageal adenocarcinoma. So if you look at different jurisdictions around the world, the histologic definition is slightly different, but those are sort of the main characteristics, and certainly patients in some parts of the world, patients can be diagnosed with Barrett’s esophagus in the absence of histologic intestinal metaplasia, but we know that intestinal metaplasia is a risk factor for the development of esophageal adenocarcinoma. So generally in North America, we require that patients have intestinal metaplasia to make a diagnosis of Barrett's.
The other thing that's worth mentioning is the length of the segment. So sometimes patients can have a finding of columnar mucosa that is less than a centimeter in length. So the bottom of the esophagus, less than one centimeter is involved. And in that setting, we actually call that an irregular Z line, or an irregular Zed line. We don't call that Barrett’s esophagus. And generally speaking, those patients don't require biopsies. They don't require any sort of surveillance, because they are sort of at the baseline population risk for esophageal adenocarcinoma. So just because someone has columnar mucosa in the distal esophagus, doesn't mean they automatically have a diagnosis of Barrett’s. You really need at least a centimeter or more of that columnar finding before you make the diagnosis.
Jack Yang:
Yeah, thank you so much for clarifying. I think a key point here is really those cellular differentiation and mucosal changes there. Would you mind speaking a little bit more to the different classification systems for Barrett's such as the Prague C & M criteria, and how and why is it used?
Dr. Thurarshen (TJ) Jeyalingam:
Great question! The Prague criteria actually outlines the endoscopic appearance of Barrett’s, so it's not based on the histologic findings. It's based on the way it looks when you put the scope in the patient's distal esophagus. So in Barrett's, the normal squamous epithelium, as we discussed, is replaced by a columnar type epithelium, and you can actually tell that there's a difference in color. The columnar type epithelium is more salmon colored epithelium. So if you are looking at someone's esophagus endoscopically, you can actually differentiate where that color change happens. And that tells you where the Barrett’s segment potentially starts, the distance from which the top most aspect of the Barrett’s segment, the top most aspect of the columnar epithelium, the distance between that and the top of the gastric folds, which is where the esophagus ends and the stomach begins. That tells you the maximal extent, or the maximal length of Barrett's and in the Prague classification that's referred to as, it’s designated by the letter M.
Now, there's some patients in whom although the maximal extent is long, the amount of esophagus that's involved by circumferential columnar epithelium. That means there's columnar epithelium all the way around that is shorter than the maximal involvement. This is like sort of difficult to describe without actually having a picture in front of you, but basically the extent to which the esophagus is circumferentially involved is referred to with the letter C, and the maximal length of the Barrett’s segment is referred to with the letter M. So you'll come out with measurements like C1M3 which means that there's one centimeter of circumferential involvement of the Barrett’s and three centimeters of maximal involvement, where at the longest point, it's three centimeters long, but at that longest point, it's not circumferential all the way around. The M3 includes that 1 of the C. So it's one centimeter of the bottom that's fully circumferential, and then two centimeters above that circumferential segment, that where it's not fully circumferential, and that's where you get the M3 from, it’s that one plus two.
So we use the Prague classification to, characterize, again, endoscopically, how the segment looks. And we want to know if that segment is changing or evolving over time. And this gives us a standardized way of characterizing that. We do know that long segments of Barrett's are associated with it, increased risk of esophageal cancer that you know, that makes sense because the more cellular changes that you have, the more columnar mucosa there is there, the more intestinal metaplasia that there is, the higher the probability that things are going to progress to dysplasia and then subsequently carcinoma. So we care about the length of the segment, this gives us an opportunity to characterize the length of the segment, and also, when we start doing endoscopic therapy, we want to be able to follow how the segment is changing over time, and particularly with, you know, a treatment like RFA, where patients are brought back multiple times for multiple sessions. You want to know if over time, if the segment is changing, because we like to treat some of these patients, at least those that have high-grade dysplasia, for instance, we like to treat them to an endpoint where they no longer have any intestinal metaplasia in their esophagus. So it helps us sort of follow the trajectory of someone's disease segment over time.
Our pathologist friends look at the biopsies under the microscope, and they look for something called dysplasia, which is an early cancerous change, depending on if the patient does not have dysplasia, if they have low-grade dysplasia, or if they have intramucosal carcinoma or an early esophageal adenocarcinoma - that also tells you about someone's risk of progressing to like full esophageal cancer, and it also helps inform management decisions regarding whether we do endoscopic eradication therapy, or whether patients get, RFA, or EMR, or ESD, or esophagectomy, or whatever the case may be.
Jack Yang:
Perfect. Thank you for clarifying Dr. Jeyalingam!
Huaqi Li:
So last month, on the podcast, we spoke about screening guidelines for colorectal cancer in the setting of upper GI neoplasia, endoscopic detection of Barrett's can be invasive, expensive and difficult to access. As such, to our knowledge, the ACG doesn't really recommend screening of the general population for Barrett's and so we're hoping Dr. Teshima, if you could walk us through what the current practices are for screening of Barrett's.
Dr. Christopher Teshima:
So the issue with Barrett's esophagus is that it's a relatively uncommon condition, and even amongst patients with Barrett’s esophagus, the actual cancer risk is relatively low, in the range of one person per 500 per year. So most patients, when you do endoscopy for symptomatic assessment will not have Barrett's esophagus. And when you've, when this has been studied from a cost-benefit perspective, there hasn't been any demonstrable benefit for screening for Barrett’s at a population level. So because the prevalence of the disease is too infrequent, screening has never really been shown to change outcomes. As a result, basically every guideline from every country’s society will recommend against population level screening, which is quite different from what we see in colon cancer, where obviously there's a clear benefit for screening. So right now, there is no recommendations to perform screening endoscopy, or screening interventions of any type for Barrett’s esophagus. That said, we do know that when there are at-risk patients, there may be benefit in performing an evaluation to determine if selected patients have Barrett’s esophagus.
So for instance, patients who have long standing GERD, and particularly patients aged 50 or older with gastroesophageal reflux disease or new onset of gastroesophageal reflux disease may benefit, particularly if they have any sort of additional epidemiological risk factors, such as male gender, Caucasian ethnicity, smoking, and alcohol history and a family history of esophageal cancer. When we look at our database of the patients we've been following for the last 20 years who have dysplastic Barrett’s esophagus or esophageal cancer, shockingly, 86% of our patients are white men, so it's a real disproportionate distribution. So you can see how some epidemiologic factors may affect some screening. It's not really screening. It's kind of diagnostic endoscopy assessment, but in essence, a patient with long standing GERD over the age of 50, and one or two of those other risk factors, or a patient who's having new onset of GERD, particularly if not immediately responsive or quickly responsive to PPI, or even if responsive to PPI, but over the age of 50, we think there will be benefit of a once in a lifetime diagnostic endoscopy. So that patient who even with response to PPI, but has had a history of GERD for some time, and is now 50, we think that by that time period you'll have either manifested with Barrett’s esophagus or not, because the genetic polymorphism immune-mediated response to the acid injury will determine whether you get Barrett’s or not. So you can assess these people in middle-age, do the endoscopy, they don't have Barrett’s, they don't need any follow up endoscopy, or identify that they have Barrett’s esophagus. But right now, that's kind of focused on patients who've had symptoms of acid reflux.
The problem with this strategy is that when you take patients who've been diagnosed with esophageal adenocarcinoma and you ask them about their GERD history, approximately half will deny having had a history of acid reflux. So quite clearly, although we know all those patients had acid-mediated injury leading to Barrett's leading to cancer, half will say they never recognize or don't recall having had that. So clearly, there's a problem in this approach, because it's going to miss a lot of patients, and unfortunately, most patients with esophageal cancer in the West present with late-stage disease.
Huaqi Li:
Understood. Thank you! So it sounds like there's no population level screening, for some specific patients that you outlined their recommendations to go forward for a once in a lifetime endoscopic surveillance, but there's no program then really for patients, it's more they have, the primary care provider has to be aware of these and then refer onwards. Is that correct?
Dr. Christopher Teshima:
Yeah, correct. There's no screening programs in clinical practice in the West for Barrett's esophagus and esophageal adenocarcinoma. This is quite different than gastric cancers, where there's clear screening programs, particularly in Asia, where the prevalence of the disease is high, but for Barrett's esophagus and esophageal cancer, there isn't any screening programs in clinical practice, there are, have been research led initiatives for screening, looking at less invasive means of determining whether there’s presence of Barrett’s esophagus. So there's various types of cytosponges or these types of, various sponges that can be swallowed and attached to a string of some type, and then that can be pulled up through the esophagus, scraping the surface of the esophagus, collecting cellular material, which can then be tested for the presence of Barrett’s esophagus. So these are things that have been done with quite a lot of research from the UK initially, but also there’s several American firms as well. And we were part of these studies maybe five to eight years ago, where we were trying to help validate the technology. And this is something that's in the works and in development, but really now is still only being used in a research setting, and hasn't really been rolled out in a primary care clinical practice perspective. But maybe in the future, this could be something that could be done, you know, in a GP’s office, the problem is that because it's just swallowing this syringe, this sponge attached to a string. It's not so comfortable to do, and not so easy to do. So we're still looking for a better, non-invasive test that could be done in a primary care setting.
Huaqi Li:
Thank you, that's really interesting! I wonder how logistically they coordinate those sponges. Do you think you know that's close to being included in clinical practice, or is it still very much in the research phase at this point?
Dr. Christopher Teshima:
Yeah, I don't think we're going to see this type of screening in clinical practice in the next five years for sure.
Huaqi Li:
Gotcha. Thank you.
Jack Yang:
Dr. Jeyalingam, you’ve worked with AI when Toronto Western Hospital became one of the first centers in Ontario to acquire an AI system for use in colonoscopies. What are your thoughts on the application of AI in upper endoscopies, and specifically in the setting of Barrett's?
Dr. Thurarshen (TJ) Jeyalingam:
Yeah, that's a great question. I actually think that AI and CADI systems, that's like computer aided detection systems, will make the biggest difference in upper GI neoplasia. I think it'll make a bigger difference in Barrett's and the detection of early gastric cancer than it will and that it has in the colon. And that's because early cancerous changes in the upper GI tract are generally speaking more subtle than in the lower GI tract. They're more obvious in the lower GI tract because generally they present with polyps. In the upper GI tract, they may present with flat changes where there's no protuberant polyp or other lesion that's easily detectable at the time of endoscopy. And sometimes those changes are actually not even visible unless you're using like, a special type of high-resolution camera, and you're doing some sort of a magnifying exam of the cells to look at the microscopic pit pattern and the vascular pattern to see if there are features that would be associated with cancer. So we are really bad at this in North America. I think in Asia, they're much better, and they're much better trained than North American endoscopists are, so this is definitely an area I think that CADI and AI are going to make a big difference in helping us detect these early cancerous change.
In Barrett's in particular, it takes a long time to be able to actually detect these very subtle findings of dysplasia optically. And that's part of the reason why we have these biopsy protocols. I don't know if we talked about it before, but there's like this protocol that we use called the Seattle protocol, where we biopsy, we do random biopsies of a Barrett’s segment to look for dysplasia. Arguably, a lot of dysplasia is not invisible. It's actually visible if we have the skills and the equipment, and maybe with AI, the technology to detect it, we don't have to rely on random biopsies picking up the dysplasia. It might actually be that, you know, when we look at the Barrett’s segment, with the assistance of these technologies, that we might be able to make a spot diagnosis of dysplasia and then decide how to appropriately manage that on that basis.
The other problem with biopsies is that, by their very nature, they're very random and haphazard, and you might not biopsy the area, like the correct area. If you're dealing with, you know, a three-dimensional structure, like, the tubular esophagus, where there's, you know, like a big Barrett’s segment, you can't biopsy the whole thing. You’re essentially sampling a very, very small amount of the entire Barrett’s segment when you take these random biopsies. So if we can improve our optical diagnosis, and we can use, we can leverage these technologies to help us improve our optical diagnosis, that's definitely going to be a net positive for patients, because certainly things can be missed on biopsies.
Jack Yang:
Absolutely, that is so cool! Thank you so much for that discussion. Hopefully we'll get to adopt more of that in the future and really make it a standard practice there.
Huaqi Li:
And then lastly, we want to touch on the treatment for Barrett’s. So Dr. Teshima, there's more conservative management therapies to treat the underlying GERD, and also endoscopic therapies, which you're an expert in. So could you walk us through some of these options?
Dr. Christopher Teshima:
So the types of treatment intervention that should be considered really depend on the state of a patient's Barrett’s esophagus and the risk of cancer that's predicted in relation to that state of disease. So, if you have Barrett’s esophagus itself, but no cellular dysplasia, dysplasia meaning biopsies demonstrating cellular irregularity. So if there's just Barrett’s esophagus without dysplasia, then we think that the harms related to the treatment exceed the likely benefit of intervening, meaning that the risk of cancer is so low that we don't think we should do any intervention or treatment other than effective acid suppression. So the most important thing for all Barrett’s esophagus is that we stop their acid reflux. Ongoing acid exposure to the esophagus will continue the inflammatory insult that leads to the cellular injury and the mutation process that drives the disease. And we know from even randomized controlled trial studies that patients who are on high dose PPI versus low dose PPI versus no PPI had statistically significant differences in progression to higher grade dysplasia and cancer. So these patients need to have maximal acid suppression thus completely stopping their acid exposure. So all patients with Barrett's esophagus need to be on PPI, and if they have ongoing acid injury, despite once-a-day PPI, then they need to be on twice a day PPI. And then sometimes I have my patients on additional histamine-2 receptor antagonist in addition. So we really want to turn off their acid, so non-dysplastic Barrett's patients really only need to have surveillance endoscopy every three years or so. There's some studies suggesting some patients could have longer intervals if they have low clinical risk, but right now, we would still say on average, three years interval for all patients with non-dysplastic Barrett’s with medical therapy with PPI.
Now, then you get in degrees of dysplasia. And this is tricky, because this is such an inflammatory disease, the pathologic determination of the presence of dysplasia is quite challenging. So we have these grades of dysplasia, from no dysplasia, to low-grade dysplasia, to high-grade dysplasia, to cancer. And the assessment of low-grade dysplasia is really tough, because low-grade dysplasia we're talking about more minor structural changes to cells that can be very similar to what's seen from active inflammatory injury. So you can see cellular irregularity from inflammation, and you can see cellular irregularity from true dysplasia. And we know that there is a lot of discordance between pathologists in determining for a given patient's biopsies whether or not they have low-grade dysplasia or not. This is why it's strongly recommended that anytime a patient is found to have low-grade dysplasia that it needs to be confirmed by an expert GI pathologist, of which there’s really only a handful in the GTA, so the biopsies at one particular site saying low grade dysplasia should be sent out and to be confirmed by another pathologist with the expertise and training in GI pathology to say, yes, this is truly low-grade dysplasia.
There are really interesting studies that show if a patient has been diagnosed for low-grade dysplasia by a general pathologist and then downgraded and said not to have low grade dysplasia by the expert, in follow up, they have no increased risk of cancer compared to patients without dysplasia. And similarly, where you get this kind of gray line, gray area diagnosis of indeterminate dysplasia, meaning the pathologist can't tell, again if the expert says that it remains indeterminate and is not actually low grade, those patients don't have an increased risk of cancer compared to non-dysplastic Barrett’s. So low-grade dysplasia that's not confirmed by expert pathologist, or indeterminate dysplasia that's not confirmed by expert pathologist, should be treated the same as non-dysplastic Barrett’s, meaning only acid suppression. Oftentimes, if there is this uncertainty that persists, I may bring these patients to the expert center to have a second opinion and to make sure that nothing has been missed on the endoscopy, that the biopsies are truly representative of the worst state of what's going on in the Barrett’s. If we can confirm there isn't actually low-grade dysplasia, then they don't need an intervention.
When we have confirmed low-grade dysplasia, and nothing more advanced than that, then these patients benefit from eradication of their dysplasia by getting rid of the Barrett’s esophagus. So there are different methods of ablation or to have endoscopically directed therapies to basically kill the dysplastic cells by destroying the Barrett’s esophagus tissue. So this requires a series of endoscopic procedures where the tissues can either be burned with thermal energy, or frozen with cryoablation, so you either freeze the tissue or burn the tissue to kill those dysplastic cells. And we do this in iterative sessions of multiple repeat procedures until, ideally, we get something called CRIM or complete remission of intestinal metaplasia, at which point we think the Barrett’s esophagus is gone. Now, not all patients with low-grade dysplasia need to have ablation. So if there's patients with a lot of Barrett’s esophagus, so longer segment Barrett's and multifocal areas, so more than one spot with low-grade dysplasia, we think that's a good patient. Or patients who have low-grade dysplasia that seems to persist over time. These are like stronger indications, or patients who have those other epidemiologic risk factors I mentioned before, like a family history, or maybe longer segment of Barrett's. Because if there's isolated one biopsy shown in low-grade dysplasia, it's also reasonable to just do an annual follow-up endoscopy and monitor that patient.
Another interesting thing about low-grade dysplasia is that, what many medical trainees will read is that the risk of cancer is relatively low, and you have these wide ranges of cancer risk predicted anywhere from 2% to 30% and you’re like, what does this mean? And this is because, again, studies have so much heterogeneity about who really has low-grade dysplasia. They showed in the Netherlands that the cancer risk increases proportionally to the number of pathologists who agree that it's low-grade dysplasia and the extent of low-grade dysplasia, so that if you have two pathologists who say that this patient has low-grade dysplasia, they have higher cancer risk than if only one. And if four pathologists say, yeah we all agree, then that patient's cancer risk goes up. So the more confident we are that this is truly dysplastic, the greater likelihood the patient is to benefit from this type of intervention where we go in endoscopically and burn the tissue. This matters because these treatments can be uncomfortable, you know, as you burn the tissue, my patients will often have some chest discomfort for 7 to 10 days, and during which time we have to have them on, you know, pureed or liquid diet. So it is really disruptive to their quality of life, because they have to come in every three to six months for treatments, and then every time you do, you're kind of out of commission for one to two weeks. So you know, they have to understand what the undertaking is and determine that risk-benefit trade off, which for low-grade dysplasia can be a fine line.
Now, it's much different for high-grade dysplasia. When patients are diagnosed with high-grade dysplasia, meaning there's pretty substantial cellular irregularity, this doesn't have the same inter-observer disagreement. It's pretty consistent when we say this is high-grade dysplasia on a given biopsy, so we know that patient has a real problem and with a fairly substantially increased risk of esophageal cancer. One of the things with high-grade dysplasia that's interesting is that oftentimes these patients have visible lesions that can be seen when assessed by an expert. We know when I get a referral for high-grade dysplasia, in my mind, I'm thinking this patient probably has cancer, and we have data, not just our own, but from multiple US centers. When the patient is sent from a community setting to a tertiary expert center with an endoscopy report saying there's no visible lesion, but biopsy show high-grade dysplasia, that at least two-thirds of the time the experts will see a visible lesion, and nearly 50% of the time the patient will have cancer. So when a patient is diagnosed with high-grade dysplasia, the most important thing is to determine do they actually have a cancer.
So how do we know this? This happened to even two patients today. So the patient has to come to an expert center to undergo a meticulous endoscopic exam. We talk about withdrawal times as a quality indicator of colonoscopy, how slowly we examine the colon as we do a colonoscope withdrawal, there's similar evidence in Barrett's of esophageal inspection time so that for every centimeter of Barrett’s esophagus, we should spend approximately one minute examining esophagus. So if the patient has seven centimeters of Barrett's, you need to spend seven minutes looking at the esophagus, which in most endoscopies are under 10 minutes, and that's probably not happening. So a meticulous, high quality exam, thorough rinsing out of all the mucus, closely using high definition endoscopy with electronic chromoendoscopy techniques like narrow band imaging or BLI on Fuji scopes, and to look really closely if we can see a visibly demarcated lesion, if we can see a visibly demarcated lesion, it doesn't mean the patient has cancer, but they could have early intramucosal cancer. And if you do the ablative techniques that I described for low-grade dysplasia, which are the standard of care for high-grade dysplasia, if you do those on top of an area where there's cancer, you can burn over it, bury cancer cells, have new esophageal tissue heal over and then you've buried their cancer, which then doesn't show up and then they present at a later stage disease.
So the most dangerous thing that could happen is an inexperienced person doing radio frequency ablation for what they think is high-grade dysplasia, that actually is cancer. Now, if a patient truly has high-grade dysplasia and there's no visible lesion, then they should undergo the ablation options that are the same for low-grade dysplasia. So we burn the tissue. Each time we're doing surveillance biopsies as well to make sure that there's nothing being missed, and they come back every three to four months and we do ablation, usually with radio frequency ablation, but also potentially cryoablation. But we only do that once we've looked and said, yes, there's no lesion. If we look and say there is a lesion like this patient today, then, instead of doing the radio frequency ablation for which he was referred, we do endoscopic resection of the areas of interest to cut it out. So if we see a lesion, it has to be cut out by endoscopic resection. And once the lesion of interest is cut out by endoscopic resection, we say, nope it was just high-grade dysplasia, then we bring them back for subsequent treatments and continued RFA to ablate the rest. Then beyond that, sometimes you see these patients referred for high-grade and they actually have pretty notable early esophageal cancer, then that may be a whole different discussion of how we do endoscopic resection, because there's techniques of EMR versus ESD, where we're cutting off all in one piece, versus whether we’re moving in multiple pieces. And there's merits and disadvantages to both.
The one thing I can say about the previous thing, which can be quite overwhelming, is I think AI is really going to help change this. There is a lot of research efforts in Holland looking at AI systems for Barrett's and the systems are being taught to, being trained on expert data sets. So in the not-too-distant future, when we're doing an endoscopy, the computer will project an image on the screen with a heat map showing where our lesion is, and that will then tell the endoscopist that they need to look at that area. And they may not see that area, but they need to biopsy that area, and then they can be sent to the expert center to have it cut out. So right now, it's really difficult, because most people to no fault of their own, don't see where these lesions are because they're very subtle, and it's really challenging. You know, when we're in a tertiary center and we're seeing 10 to 15 patients with Barrett's a week, then it's a whole different game. But if we're seeing one or two patients with Barrett's a year, it's really challenging - to no fault of anyone's practice. It's just a really tough disease.
Huaqi Li:
Thank you, that was super clear! I think, being able to know the different treatments for the different risk factors, essentially, if it's indiscriminate, if it's early, if it's a bit later, and they actually have cancerous lesions and the different types of therapies that we would offer either medical or endoscopic or ablation versus kind of removing the actual lesion. In that vein, could you just touch a little bit about ESD versus EMR?
Dr. Christopher Teshima:
Yeah, so when we talk about endoscopic resection of a lesion, this is not surgery, so we're not actually removing the esophagus, which, you know, esophagectomy has lots of morbidity and mortality and in very early-stage cancer of the esophagus, the risk of death from esophagectomy exceeds the likelihood of lymph node metastasis from the cancer. And so that is really the tipping point when you're at a stage of early esophageal cancer where the predicted risk of lymph node metastasis exceeds the predicted death rate from esophagectomy, that's when we tell patients to have esophagectomy. If the risk of lymph node metastasis is negligible or very low, then we're going to try to do endoscopic resection, where we're cutting out mucosal and submucosal layers of the esophagus only, and preserving the deeper muscle layer so that the integrity of the esophagus is maintained.
The problem with endoscopic resection is that there's no capability of lymph node assessment, and so that's kind of the whole dichotomy of when we do surgery, when we do endoscopic resection, and when we do endoscopic resection, we can cut it out in various pieces, which is called endoscopic mucosal resection, or we can cut it out from a type of endoscopic endo-surgical procedure called ESD, where we're using a type of knife to remove it in an en bloc fashion, in one piece, means cutting around the entirety of the lesion and then cutting underneath it, within the wall of esophagus to undermine it. So there's advantages and disadvantages to each. The advantage of EMR is that it is relatively straightforward to proceed, so it's something that can be done at most hospitals by most people who've had training to do so. So it's easily accessible to most places. It can be done in real time, so the patient is being seen today, they're found to have a visible lesion in their esophagus, the EMR can be performed right now. It's low cost, so it doesn't require a lot of special devices, and it is faster, so it doesn't take that long, maybe 15 to 20 minutes.
So there's also, a wealth of data over the last 15 to 20 years supporting its use, and we know that for really early intramucosal cancer, it's an effective treatment. So it's effective for most patients, it's relatively easier to perform, it has a fairly similar complication rate, it's lower cost, doesn't require overnight stay in hospital. So the disadvantage, however, is that from an oncologic perspective, we ideally want a pathologic assessment that determines whether you got the whole thing out, meaning you cut out one piece, so that you can determine that the margins of what you cut out are free of cancer. When you're cutting things out in pieces, it's kind of like pieces of a puzzle, and you have cancer at the edges, so you're intentionally cutting within the cancer, so you're going to have positive margins, and is the margin that's positive in the center of the lesion? I mean, you've cut around adequately that's clear, or is that positive margin at the edge, and you've actually left cancer cells behind. And this has been the long-standing criticism of this technique, because you're having to potentially cut right through the middle of cancer. So we can't tell the patient that you have an R0 resection. We can't say that it's all out. So instead, you go back and you have to call in ongoing repeat procedures, and if there's more, then you got to try cutting out more. This has worked for most patients over the years.
When we looked at our data spanning 2005 to 2020 about 19% of patients who underwent EMR had non-curative findings on their pathology, and that means that those patients are having to be recommended to go on to have esophagectomy. And we know that in the SEER database in the United States, which monitors outcomes for cancer and procedures, that between 6 to 8% of patients who undergo esophagectomy will die from complications of the surgery, and then that mortality rate over the age of 70 increases to 10%. So, if we could prevent some of these patients from having non-curative findings on their EMR by doing a more aggressive endoscopic resection, then that might be a benefit. So the other way of treating this, which is what we would do for early gastric cancer, or for squamous cell cancer of the esophagus is the endo-surgical procedure of endoscopic submucosal dissection, or ESD, in which the tumor is removed in its entirety in one piece. So we're using a special knife to cut around it with wide margins, and then cut underneath it, just above the surface of the muscle, to remove it all in one piece, to allow for definitive oncologic assessment of the margins so we know that we got it all out, presumably leading to reduction in local recurrence. It also allows us to cut deeper within the submucosa so that we can get, a deeper negative margin, but then a deeper, deep margin. So that's the advantage of having been able to get out a wide piece oncologic pathology assessment, deeper resection margin, and to be more successful in cutting out areas of fibrosis.
So in patients who have lots of bad GERD, sometimes they have really scarred esophagus, and in those patients, EMR techniques can sometimes fail, whereas they can be overcome with ESD. The disadvantage with ESD is that it's technically much more challenging. We think that ESD in Barrett's is more difficult than in other types of esophageal cancer because it's been an inflammatory state, so it's more, it has lots of vessels, it bleeds more, it's more fibrotic, so it's more challenging. There's not a lot of ESD expertise in North America. It's, you know, clearly developing. But this is not something that's available in most centers. We typically do this under general anesthesia. So if you're having your endoscopy today, and I find a lesion, I could have EMR’d it today, and you go home and you're happy because the lesion is out, whereas, if we're going to do ESD, you have to come back on another occasion to have your procedure under general anesthesia. It's more resource intensive, it involves more tools and supplies, and for our patients, at least, we admit them to hospital for observation, and so then it's more resource drained on the medical system because of that need for inpatient care. In an expert’s hands, the complication rate is not higher, so I don't think there's a safety difference between ESD and EMR, but it does require this increased technical expertise.
That said, if that expertise can become more widely disseminated, I think it would become increasingly advocated for. And for us now, we think that there are definite patients who will benefit from ESD over EMR. So for us, we think if: the tumors are bulky, it's hard to get out completely with EMR and get deep enough, if there's bigger tumors, perhaps bigger than two centimeters, if there's multi focal cancers distributed in many ways throughout the esophagus, it's kind of impossible to do in pieces, and you have to cut it all out at once, or if there's suspicion of invasion into the submucosa based on endoscopic features, you're able to get deeper within it/beneath it, with ESD. So we think that's in our practice, what we're advocating in terms of ESD. But admittedly, this is the American Gastroenterology AGA guidelines 2024 do not state what I just said, and those guidelines would say that EMR should be used in the vast majority of cases of early esophageal cancer in Barrett's, and ESD should be reserved for cases with failed EMR or ones where submucosal invasion is suspected. We particularly disagree with those guidelines, but that's what the guidelines state.
We have our own data comparing our patients over the last four years, about 160 patients underwent EMR or ESD for Barrett's cancer, and our EMR groups were more likely to have recurrence of high-grade dysplasia or cancer in follow-up, even after all the dysplasia was eradicated. You can imagine that if you're cutting pieces you might miss some and you need to come back and get more out. But even once the patients were considered to be cured and everything, regardless of number of procedures of techniques, got everything out and there was no evidence dysplasia, then in long-term follow-up, there was a statistically significant difference in recurrence over time. And the Kaplan-Meier curve showed about eventually 18% recurrence of high-grade dysplasia or cancer after EMR extending out follow-up of four to five years, and less than 4% after ESD. And we also recently published a meta-analysis showing the similar findings of increase recurrence after EMR versus ESD. So we think this paradigm will begin to change, and that patients should eventually be considered for aggressive, more definitive upfront endoscopic resections with ESD rather than EMR. But as said, that does not represent current guidelines.
Huaqi Li:
Thank you so much Dr. Teshima and Dr. Jeyalingam for a very engaging conversation on Barrett’s. That’s it for our episode today! Thanks so much to our listeners for tuning in and join us again next week!
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