So now we'll proceed a little farther down the GI tract into another controversial area. Robert J. Huang from Stanford University will be presenting a practice update on the management and surveillance of gastric menoplasia. All right. Good morning, everybody. First, I'd like to thank the ASGE and the course directors for inviting me to talk today about the management and surveillance of gastric menoplasia. I think, as you'll see in my talk, that we're about 10 to 15 years behind Barrett's esophagus. So we have a lot to do. But a lot of the principles that were discussed by Drs. Wani and Shaheen, I think, apply to the stomach as well. I'm supported currently on a K08 award from the National Cancer Institute. So in this talk, I'd like to achieve four objectives. I'd first like to discuss the epidemiology of gastric intestinal metoplasia, or GIM. I'd like to discuss endoscopic and histologic considerations for diagnosing and risk stratifying GIM. I'd like to then discuss surveillance strategies for GIM. And finally, I'd like to compare our existing sparse U.S. guidelines with international guidelines for surveillance. So first, the epidemiology. GIM represents a critical precursor along Correa's cascade. This is a cascade of inflammatory insult and progresses through distinct precursor intermediate lesions, beginning with non-atrophic gastritis, followed by gastric atrophy, intestinal metoplasia of varying degrees of both topographic as well as histologic severity, which we'll discuss later, dysplasia, and finally, cancer. Worldwide, the most common cause of intestinal metoplasia is helicobacter pylori infection. And that is the case in the United States as well. However, in the U.S., we also have a fairly high prevalence of autoimmune gastritis, which is an alternative form of inflammatory insult. So briefly, how do we distinguish H. pylori versus autoimmune gastritis? Well, they have very distinct both topographic and hormonal profiles. When we think of H. pylori-induced gastritis, we usually think of a gastritis that starts low in the stomach, in the antrum or the incisor region. And over time, usually over the course of a lifespan, many decades, this inflammation proceeds upward into the corpus, first along the lesser curvature, and in very advanced cases, wrapping around into the greater curvature. The pattern you'll see from precursor lesions, atrophy, and intestinal metoplasia will follow this pattern of infection. By contrast, autoimmune gastritis is nearly the total opposite. Autoimmune gastritis begins predominantly in the body of the stomach and very rarely involves the antrum. And as a result of this, a distinct hormonal profile emerges from the relative hypochlorhydria, which results from this pattern of inflammation. Compensatory and appropriate hypergastronemia drives enterochromaffin cell-like hyperplasia and the development of neuroendocrine tumors. So through a combination of both understanding the topographic extent of inflammation as well as the hormonal profiling, one can distinguish between H. pylori versus autoimmune gastritis. The estimated prevalence of GIM in the U.S. population is about 5%. This figure is from the technical review, which accompanied the 2020 AGA guidelines, which we'll discuss at length later. This 5% figure, I will note, was primarily driven by one large national database study, national pathology database study, the Sonnenberg et al. study. There was substantial, however, heterogeneity in this estimate. What are the risk factors for GIM? The risk factors for GIM are very similar to the risk factors for gastric cancer. So non-modifiable risk factors include Asian, Black, American Indian, and Alaskan Native race, Hispanic ethnicity, male sex, a family history in either first or secondary relative of gastric cancer, increasing age, and older birth year, cohort effect. And this is coincident with the secular trend toward decreasing helicobacter pylori prevalence worldwide. Modifiable risk factors include either a current or historical infection by helicobacter pylori, current or prior smoking, and residence in a region of the world with high HP or high gastric cancer incidence. So what are some endoscopic and histologic considerations when diagnosing and stratifying intestinal metaplasia? So first, we should be performing high-quality endoscopic exams. That is to say, adequate time should be allowed for a careful mucosal cleaning and gas insufflation of the stomach. It has been suggested that seven-minute exam time, that is the time from when the scope enters to when the scope leaves the body, improves the detection of gastric cancer, dysplasia, and metaplasia relative to exam times under seven minutes. Adequate photodocumentation of all examined areas of the stomach should be performed. This is particularly salient in nations of East Asia, such as Japan and South Korea, where protocolized versions of photodocumentation have been adopted. Finally, the use of narrowband imaging and the use of high-quality latest generation endoscopes is essential, just as it is for Barrett's esophagus. So briefly, the importance of NBI imaging and GIM. GIM has certain distinct features on NBI. So these, the four figures on the left, taken from manuscripts by Pimentel-Nunez et al, show normal antrum and normal body on top. And antrum and body involved by GIM shown below. So there are certain patterns that we see. We see ridge-like mucosa. We see distinct foci of tubulovilous-like mucosa. And we also see the light blue crest sign. The importance of NBI exam in improving the diagnostic yield of GIM can be seen in a prospective repeated measures design study of 112 patients. In this study, high-definition white light endoscopy by one endoscopist was immediately followed by NBI exam by a second endoscopist. And lesions, visible lesions, were then marked for later biopsy. Following HD, following high-definition white light and NBI exam, mapping biopsies were then performed and the diagnostic yield of each method was compared. Both at the level of the patient and at the level of the site, NBI exam nearly doubled the diagnostic yield for GIM compared to high-definition white light. Here's just another picture of the importance of performing a high-quality NBI exam. This is from an endoscopy I did last week on a 50-year-old gentleman with dyspepsia. On the high-definition white light exam, you'll see that at the 3 o'clock position, there's a subtle area of erythema. And just using white light, you can see how even an experienced endoscopist might not think much of this, might not biopsy it. But when you apply the NBI filter clearly, you can see an area of ridge-like mucosa with a light blue crest sign, which biopsies confirmed to be GIM. So we should be using high-definition white light and the NBI exam to find visible lesions to target for biopsies. But after this, we should also be following a protocolized biopsy protocol, so-called mapping biopsies per the SIDNEY system. So in Barrett's, they have the SEATO protocol. In the NAMIC, we have the SIDNEY protocol, which was based on a consensus conference of GI pathologists that met 25 years ago in Sydney, Australia. And so in the SIDNEY protocol, we take two pieces from the antrum lesser and greater curvature, a piece from the incisora, and two pieces from the corpus along the lesser and greater curvature as well. These pieces should be submitted to a GI pathologist with some degree of experience and interest in gastric pathology and should be scored according to a severity system ranging from none, mild, moderate, or severe based on the percentage of glandular involvement. Using both the topographic information as well as the histologic severity information, an aggregate summary score called the operative link on GIM or old game score can be calculated. And this ranges from stage zero, no intestinal metaplasia, all the way to stage four, or very high-risk metaplasia, which we'll see later. Finally, a brief word on incomplete versus complete GIM. Most GIM is complete metaplasia. In complete metaplasia, the mucosa represents small intestine with evenly spaced mucin deposits within goblet cells in the presence of a clear brush border, as can be seen in the figure on the left. Incomplete, or in older literature what was called colonic metaplasia, demonstrates the loss of this brush border as well as mucin deposits of variable size. As you can see from the figure on the right, the mucin deposits are irregularly shaped and sized, and you can see how this looks more disorganized than the complete type of metaplasia. In a previous generation, incomplete versus complete could be distinguished through mucin staining. So complete type metaplasia expresses mostly sialomucins, whereas incomplete metaplasia expresses mostly sulfamucins. However, this is no longer used either for research or clinical practice due to the toxicity of the stains. So using the knowledge that we have about the topographic extent, the histologic severity, and the patient-level features, how can we use these data to come up with a logical, reasonable way to risk stratify and manage our patients? So first and foremost, the key here is eradication of H. pylori, the environmental insult. Unlike colonoscopy, where we can remove precancerous lesions, or unlike Barrett's, where we can ablate, we don't have any way to ablate a gastric intestinal metaplasia, so arresting the main etiologic agent is key. Notably, all of our professional societies, as well as all of the infectious disease professional societies, recommend treatment of H. pylori detected for any reason. Therefore, it goes without saying that if a patient has GIM, H. pylori must be eradicated, and eradication should be confirmed. We know from well-conducted randomized clinical trials that H. pylori eradication decreases the risk of both cancer incidence as well as cancer mortality in the general population. We believe that H. pylori eradication should decrease cancer incidence and mortality in the population with GIM, but we don't have RCT data yet to support that. However, patients with GIM are at elevated risk for subsequent cancer compared to those without GIM even after H. pylori eradication. The importance of H. pylori eradication in inducing histologic regression, or at least preventing histologic progression, has been observed in numerous trials. In this study of 800 Colombian adults with gastric precancerous lesions ranging across the spectrum from normal, atrophic gastritis, and testo-menopausal dysplasia all the way to cancer, these 800 subjects were randomized to either receive anti-H. pylori treatment or placebo at baseline, and repeat biopsies were taken at 3, 6, 12, and 16 years. As can be seen on the figure on the right, those who were successfully eradicated, meaning they were H. pylori negative at 12 and 16 years, had clear, statistically significant histologic regression, whereas those who had persistent H. pylori, the far right bar, those had very clear histologic progression. Here's just another piece of data suggesting the importance of H. pylori eradication in very high-risk populations. So this is published in New England Journal in 2018, a randomized controlled trial of 400 individuals from South Korea who had endoscopic submucosal dissection for an early gastric cancer. So obviously these are very high-risk patients because they've already had cancer at South Korea. Presumably the majority of these patients had intestinal menopausia. And these patients were randomized after their ESD to one of two arms, either received a placebo or H. pylori treatment. At the time of this study, this could be conducted with some degree of clinical equipoise as there wasn't, at that time, definitive evidence that H. pylori treatment prevented cancer. And as you can see, both in the intention to treat analysis on the left, the H. pylori eradication was associated with a 50% reduction in risk for metacronis gastric cancer. And even more impressively, in the successful eradication group, this decrease in risk was 68%. So you heard just now that the estimated rate of progression from Barrett's esophagus to esophageal adenocarcinoma to be somewhere in the range of 0.1 to 0.3%. We also estimate that the incidence of gastric cancer from gastric intestinal menopausia to be about 0.1 to 0.2%. This is from the AGA technical review, which accompanied the 2020 guidelines. And a pooled estimate of about 0.12% was found. But of course, this is all comers with GIM. Can we do better? Can we use patient-level factors and tissue-level factors to further risk stratify this population? So first, at the patient level, one thing to look at is the family history. There have been a limited number of studies published on this topic, but this limited data suggests that GIM patients with a first-degree relative with gastric cancer are at significantly increased risk, three- to four-fold increased risk for progression to gastric cancer. But also tissue-level factors are very important in risk stratification as well. Extensive GIM, that is GIM which involves both the antrum and the corpus, is approximately two-fold or more increased risk for progression compared to GIM limited to antrum. Using Olgham scores, there have been a number of case-control studies that have been published using Olgham score, and it suggests that the odds ratio for progression onto cancer is about four-fold. And finally, last year, there was a single cohort study published from Singapore based on the gastric cancer epidemiology program. This is a cohort of 3,000 Chinese Singaporeans at elevated risk for cancer who have had biennial surveillance for the last 15 years. And so they used the Olgham score of the patients at baseline to determine the incidence of gastric cancer. And so in the no-IM group, the incidence was about 12 per 100,000. In the Olgham-1 group, this went up to about 22 per 100,000. In the Olgham-2 group, this was about 110. And in the Olgham-3 and 4 group, a shocking 540 per 100,000. That is to say that in high-Olgham groups, Olgham-3 and 4, your rate for progression onto cancer is greater than 25-fold compared to low-Olgham groups. I'm finally using our phenotyping of incomplete versus complete metaplegia. Of course, there's some variability in the way pathologists interpret incomplete versus complete, but we think that incomplete is associated with a significant, somewhere around three- to four-fold risk of progression compared to complete metaplegia. Okay, so using all of the data, both patient-level and tissue-level data, that's now turned to the 2020 AGA guidelines. So I'm just gonna read part of the recommendation. In patients with GIM, the AGA suggests against routine use of endoscopic surveillance, conditional recommendation, very low-quality evidence. So in the initial version of the guidelines, which was released for public commentary, that was it, just that first single sentence in the box. There was nothing else in the box. So after a period of public commentary, a vigorous social media campaign was launched to try to qualify these guidelines, and I'm very happy that the Guidelines Writing Committee then added this extensive commentary after in the final version, and I'm just gonna read in pertinent part. Patients with GIM at higher risk for gastric cancer who put a high value on potential but uncertain reduction of mortality and who put a low value on potential risks of surveillance endoscopy may reasonably elect for surveillance. These patients include those with incomplete IM, extensive IM, a family history of gastric cancer, and patients at overall increased risk for gastric cancer, including racial and ethnic minorities and immigrants for high incidence regions. Now while a precise surveillance interval was not specified in the AGA guidelines, it is stated that upper endoscopy every three to five years with careful visualization and biopsies of antrum, body, and any concerning lesions can be considered if shared decision making favors surveillance. So I wanted to take these AGA guidelines, and I would also like to comment that the ASGE in the Standards of Practice document in 2015 in the text of the document also mentioned that endoscopic surveillance for IM should be performed in patients at increased risk of gastric cancer because of race, ethnicity, family history, or topographic extent of disease. So those are the two existing American guidelines on the left, and I wanted to compare with the European guidelines on the right. So first the ESGE published the MAPS II guideline in 2019. So for mild IM or IM limited to antrum, no surveillance is recommended. For IM which is limited but where there is a family history or where there is any kind of incomplete phenotype or where H. pylori eradication cannot be achieved, three-year surveillance is recommended. With advanced IM or histologically severe IM, three-year surveillance is recommended. And when there is advanced IM, histologically severe IM, and a family history, one or two-year surveillance is recommended. For autoimmune gastritis, three to five-year surveillance is recommended. The British guidelines are pretty much in line with this. For extensive IM, three-year recommendation is recommended. And for limited IM but where there is a family history or where H. pylori eradication cannot be achieved, three-year surveillance is recommended. Finally, the Italian guidelines for advanced IM or histologically severe IM, three-year recommendation, and for atrophic gastritis, three to five-year recommendation. So overall, the European guidelines seem to be fairly concordant with each other and tend to be more structured than the American guidelines shown on the left. Briefly, I also wanted to mention the screening practices in East Asia, specifically South Korea and Japan. Now, these are screening guidelines, so this applies to the general population, not individuals with intestinal metaplasia. And the Korean screening guidelines recommend bi-annual endoscopy, so every two-year endoscopy for men and women from the ages of 40 to 75. From 75 to 84, no recommendation. And from 85 and above, recommend against endoscopy. The Japanese guidelines recommend equal-weight recommendation for either endoscopy or radiography every two years beginning at the age of 50. So how do we make sense of guidelines? We have these North American guidelines, which are loquacious, and with a lot of different risk groups mentioned. We have the European guidelines, which are a little bit more structured. We have the screening guidelines from Japan and South Korea. Given the heterogeneity of the guidelines and given the multiple ways one could interpret the AGA guidelines, I think basically you can do anything that's reasonable, but the key here is discuss it with your patients and practice shared decision-making. I think we should discuss the risks of endoscopy, the uncertain benefit of mortality reduction with our patients, and also note that as patients get older and their comorbidity profile changes, that risk-benefit calculation can change as well. Sydney protocol biopsies should be used to biopsy the stomach and topographically map the extent of the disease, and a GI pathologist with experience and interest in interpretation of gastric biopsies should be used to interpret both for histologic severity and incomplete phenotyping. So the general takeaways from this talk are GIM is a key precursor lesion along Correa's cascade, and once GIM has developed, this patient is at elevated cancer risk even after H. pylori eradication has been achieved. The prevalence of GIM is estimated to be about 5 to 10% of the U.S. population, and risk factors for GIM are similar to risk factors for gastric cancer. GIM should be examined via both white light and NBI exam. Sydney protocol biopsies should be used, and a GI pathologist with experience should be used to interpret the biopsies. GIM, which is topographically extensive, histologically severe, and or histologically incomplete, is at increased risk for cancer progression. And finally, various guidelines exist for GIM surveillance. The underlying principle should be to educate patients about risks and benefits and allow them to make the informed decision regarding surveillance. And with that, I'm going to end my talk, and thank you for your kind attention. Thank you.

gastric intestinal metaplasia

Correa's cascade

gastric cancer

Helicobacter pylori eradication

endoscopic exams

Sydney protocol biopsies