During this 20-25 minute pre-recorded lecture, Dr. Alexandros Polydorides discusses the topic of upper GI pathology. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards. CME pre-requiste of live Q & A webinar, 8th Annual Mount Sinai Intensive Board Review in Gastroenterology & Hepatology on Sept 22 Hello this is dr Polidori is I'm a gastrointestinal pathologist and today I'm gonna guide you through A session on upper gastrointestinal pathology review which is going to be in the form of four patient based cases. So let's begin case number one mm. This is a five year old boy with various allergies and who presented with abdominal pain, heartburn and dysplasia. The past medical history did not reveal any pertinent findings and um he has been treated in the past unsuccessfully with medications against reflux. Upper endoscopy shows an esophagus with fema, concentric rings, furrows and white patches or exhibits biopsies were taken in this case from the distance which showed this image here which is esophageal squamous epithelium. And these are squamous cells that are political cells with large nuclei. And through this uh digital squamous epithelium is an infiltrate of inflammatory cells with characteristic um dark nuclear which sometimes can be biloba as you can see here and they contain very bright red pink small Granules in the cytoplasm. This is a presentation of the sofa geo using ophelia. This infiltrate uh in filtering cells and from their cells are your scene unfolds. Mhm. So the question is which of the following statements regarding this diagnostic entity is correct. Upper endoscopy findings such as rings are not characteristic Part uh choice be interpreted. Sniffles 15 or more per hyper field are sufficient for diagnosis part c only Children and young adults are affected party. This entity predominantly involves the distal esophagus or choice E there's significant histological overlap with gases of a jail reflux disease. I'll give you a couple of seconds before I reveal the correct answer, remember which one of these statements is correct and the answer is choice E. Is correct. The others are incorrect and we'll go through them in the senate. So Houston affiliates of had itis which is the diagnosis in this case is a chronic androgen mediated disease which is characterized by two main things is of a jail dysfunction. Clinically and entrepreneurial Houston feels identified in the video square Miss epithelium which our president is to logically. So this is a clinical pathologic entity that requires both clinical and his a pathologic evidence for its diagnosis and the criteria are four. All four of them need to be um satisfied for the diagnosis of E. O. E. Number one is symptoms of esophageal dysfunction. This can be dysplasia, vomiting and food imp action. Those are the ones that are most considered significant for E. A history of concomitant uh entropy or endoscopic findings such as rings and first should actually increase the suspicion for E The second part of the diagnosis. Second critical diagnosis includes the presence of at least 15 years in fields per high power field. That's a peak count meaning of all the uh tissue samples. President of biopsy. The peak count should be at least 15 and he should be president at least one biopsy. This criteria is supposed to be 100% sensitive because it's part of the diagnostic uh Criteria and 96% specific for diagnosis. UE the third part of the diagnosis um postulates that is an affiliate has to be isolated to the esophagus. And the fourth part um suggests that other causes of eastern ophelia should be excluded. Okay, So the incidents of you know, he has been increasing throughout the world in the last couple of decades. The prevalence is supposed to be up to 0.1% of the population in the West. There is a 3-1 um preponderance in men over women. The onset is usually in childhood or midlife. Most patients present when they are younger than 40 years old, but all ages can be affected. Usually the patients have some sort of history of allergy and other a topic disorders and the complications. Long term complications of uh oh include imp action, food, impact in structure and preparation. If that structure is attended to be dilated. Very importantly, diagnosed of uE or the presence of your your business fields and esophagus can be patchy. So multiple biopsies are recommended from at least two different levels in the esophagus, proximal and distal if six bites are obtained from various levels including a proximal middle distal esophagus. The sensitivity of these biopsies start to be increased up to 99%. So multiple biopsies are definitely recommended treatment of yogi such as with diet or even steroids um should um cause the symptoms to remit and importantly, other cause of this video is not feel it should be excluded. These are usually rare but they can include infection through a parasite. A warm allergic vasculitis sometimes can give you cinephiles and even Crohn's disease can do that as well. It's the logically on the left. You see our patients biopsy compared to normal esophageal squamous mucosa which should not have any inflammatory cells infiltrating through it. With the exception of some may be rare lymphocytes. There lymphocytes squeezing their way through the very tight junctions between squamous. Um It's a vaginal epithelial cells and therefore becoming a bit more relegated but notice that there are no other uh inflammatory cells in the vaginal mucosa. In contrast when you have these affiliates of vaginitis, you have multiple By definition at least 15 but frequently more than that you cinephiles percolated through this G. O. Nik Osa. Let's review some of the characteristics that you find usually those your sniffles in the O. R. Distributed more superficially. In other words, the top half of the squamous epithelium tends to have more, you sniffles than the bottom half what you can also see. Sometimes these so called dilated in their cellar spaces. Now these uh squamous epithelial cells have very tight junctions between them. But if there is a Dema or fluid in the cervical epithelium. These tight junctions will be uh delegated will be uh stressed and therefore might present with spaces between this is a vaginal square muscles. Um The sinful because sometimes uh form what are called micro abscesses that these collections of at least five or more your sinful sort of together. Um And that's the term we use to describe that. And also what you can see sometimes is is this the sniffles d granulated or releasing releasing their Granules into the surrounding micro environment and therefore you sometimes can see just the Granules without a nucleus nearby. Finally sometimes you see basil zone hyperplasia of the sort of immature or reactive epithelium in the bottom half the bottom uh 10% of the Mucosa is a little bit expanded up to 30% or more. And if you have a deeper biopsy which this is not you might see lamb inappropriate fibrosis. Now all of these are all of these histological features that we just described are characteristic of eosinophilic uh hepatitis but they're not fun demonic, they might not always be present. Um And some of them might be present in other disorders as well. But if you see a lot of them of course the suspicion of the uh should be raised. Now it used to be that the diagnosis of UE required an intermediate step of the trial with P. P. I. S. In order to exclude gastroesophageal reflux disease as well as this entity called PP. I responsive is a video using ophelia. However most recent evidence suggests that this P. P. I. Responsive is a geo is no ophelia entity which means that basically that the sniffles go away if the patient has to do with PP. I. This entity has histological clinical and endoscopic and even molecular features that are indistinguishable from E. O. E. So for all intents and purposes this entity PPR responsive. So for geo isn ophelia is basically a subset of Joey at the same time. Um there might be a superimposed component of reflux on top of the O. And for all these reasons these the PPE trial is not anymore required for the diagnose. Mhm. Instead the diagnosis vo he now has the criteria that I just mentioned. The four that include clinical presentations suggestive of the OE with uh video uh symptoms, biopsy showing at least 15 sniffles for high power field from at least one biopsy. But multiple biopsies are recommended and the diagnosis, if this is uh is an affiliate is limited to the esophagus and other causes of individualism affiliate have been excluded would then lead to diagnosis. Eosinophilic esophagitis. One of the main problem is that uh esophageal reflux can be um superimposed or difficult to distinguish from you and here are some clinical and endoscopic characteristics that might help distinguish between the two. So going back to our patient, this is a five year old boy with allergies and isf asia the histological section that I sold you from the diesel esophagus showed significant intra pathologist ophelia in a superficial distribution with degranulation and micro cap disease. These findings are characteristic obviously focus of vaginitis. Um However, into epithelial stem fields on histology alone are not sufficient for the diagnosis. So the choice B is incorrect. Um Also is the focus of agendas is most common in patients younger than 40 years old but has been described across the age spectrum. So Joyce C. Is also incorrect. The findings that we see an endoscopy such as rings first et cetera are characteristic. Um but they're not specific but their characteristics. Choice A. Is incorrect as well. Importantly, E we can be patchy generally involves the entire length of the esophagus, whereas reflux tends to involve the district part of the esophagus. So party is actually incorrect as well. So biopsy sampling from both approximately and the distal esophagus is highly recommended for diagnosis of UE. And as we mentioned already there is significant histological overlap with reflux. Um So Choice E. Is the correct answer in this case. Let's move onto the next case. This is a 56 year old overweight caucasian man who presents with reflux heartburn and the cough. The best medical history reveals longstanding alcohol and tobacco use. Upper endoscopy shows that he had a hernia and salmon, colder patches or tongues of mucosa above the G junction pipes. These are taken from these patches above the and show this finding which includes gobble cells. These are the cells that have a large musing vacuum that displays the nucleus to the bottom of the cell, apparently making it look like a goblet cup. So these are called gobble sells this music is characteristically white on a chinese, although sometimes you can see this blue gray coloration to it and that's important for the diagnosis on top of this presence of gobbles. That's here in this biopsy from above the G junction which was taken from a patch of salmon colored mucosa. We can also see nuclear that are very large, very dark and have significant overlap. They crowd over on top of each other. There's a significant metallic activity. There's one here, another one there, another one here, there's tons of my toes is all around this section. But more importantly, these nuclear are very large and there is no uh polarity in the base of the cell that the nuclear start occupying the upper half of the cell in a lot of these um uh in a lot of these cells and start having. Besides, there's lots of polarity they start to crowd um each other and overlap with each other. So the diagnosis here is barrett esophagus with high grade dysplasia. Okay, the question for you is which of the following statements regarding parliament? A pleasure paris, esophagus is correct. A it is associated with an increased risk of squamous cell carcinoma. Be the extent of displeasure is not a risk for adenocarcinoma. See gobble cells on histology are sufficient for the diagnosis. The longstanding reflux is a risk factor and EP 53 mutations do not play a role in carcinogen icis, I'll give you a couple of seconds to identify which of these options are is correct correct choices. Part D. This is the only correct statement. The other statements are incorrect and we'll go through them in a second. So barry esophagus or Parramatta play asia is by definition the replacement of the distal esophageal squamous mucosa with meta plastic Kalantari epithelium. So we're talking about the part of the esophagus above the G junction and this is also a clinical pathologic diagnosis, just like Joey was where at least one centimeter of Colombia Nikos above the G junction needs to be identified and disk optical. This means that it should be in the tubular oesophagus and is usually present with patches of salmon colored pink columnar. Um Technicals has seen above the esophagus. Endoscopic lee. This is to juxtapose from the pearly white esophagus of a jail squares to be feeling that no normally covers the distal esophagus. In addition to this endoscopic criterion, what you also need to find that a biopsy from that patch of pink or salmon colored uh lesion above the G junction should show in testament of pleasure histological E which is identified by the presence of goblet cells. Now the definition of marriage is a little bit different in japan and the UK goblet cells are actually not required there but in the U. S. Definition still requires intestinal dysplasia identified through the presence of global sales for the diagnosis back. Mhm. Barrett has also been increasing incidents. The prevalence in the general population is thought to be between two and 7% and risk factors for the development of Barrett Mucosa include obesity, higher body mass index, age about 50 years old, smoking uh male sex wide race and a family history. Um overall it's considered to be the end result of abnormal and chronic exposure to gastric acid as well as bile acid. Remember that also that always plays a role particularly in the progression to dysplasia and carcinoma. So it doesn't necessarily have to be uh reflex of gastric acid bile acid can also be causing parents. The progression to esophageal adenocarcinoma start to occur at a rate of 0.1 to 0.6 per year. In non this plastic paradise esophagus however, it is as high as 5 to 8% per year in patient with high grade dysplasia. So the degree of dysplasia present if at all is an important um uh method to identify patients at risk and stratify patients at risk for further management and surveillance. The thinking is that burn mucosa progresses through a linear sequence through increasing grades of dysplasia. From Logan to high grade and eventually to adenocarcinoma. So the displays of grade is used for this risk stratification and 53 mutations are actually thought to play a role at least in the later steps of this linear progression. Now it's important to know that there is substantial inter observer variability among pathologists in terms of what constitutes especially low grade dysplasia. There's little bit more agreement in terms of high grade dysplasia and carcinoma. But to identify logo displeasure as opposed to negative. There's a lot of their building among pathologists and it is recommended at least a second. Hopefully expert gi pathologist is going to verify that biopsy diagnosis of dysplasia. So this is a picture, an image from our patient again compared to esophageal um to bear this out because there's some gobble cells here as well. This is taken above the rejection so it should have been squamous epithelium. Instead it's kilometer biathlon with a single row of cells basically located nuclear. And using vacuums um often displacing the nucleus to the bottom in the shape of a goblet cells. So these are all gobbled cells. Um This one is negative for dysplasia because it doesn't have the nuclear and psychological tapia that's present on the left. These are the same magnification. So you can see how much bigger this nuclear are, how much darker there are in the presence of multiple methodic figures and crowding of nuclei with overlap and loss of polarity. These are not so much basically located anymore as they should in uh non this plastic itself because but they reached all the way to the top. So that's high grade dysplasia. Um To review those findings. Again, the goblet cells seen here with his large vacuum of white musing are diagnostic of intestinal ecclesia. And if seen in a biopsy from a um uh irregularly colored of salmon colored patch of mucosa in the tubular suffix above the T junction. They are diagnostic of barrett esophagus, the presence of additional significant nuclear tibia. With methodic figures, large epigrammatic nuclei, presence of obvious nuclear lie reduced maturation to the surface meeting. These nuclei persist to the top and loss of polarity suggests the presence of hybrid mhm. For both local dysplasia and high grade dysplasia, it is highly recommended that the the diagnosis confirmed by a second hopefully experienced job pathologist. In terms of the treatment. Um uh The advice is a little bit different. B. T. Stands for bears endoscopic treatment. But both dystopic treatment and continuous surveillance are considered reasonable options for management of local dysplasia. Whereas for high grade dysplasia, the preferred treatment is endoscopic treatment over subject to me. But a visible lesion which is diagnosed with dysplasia should be um removed if possible. So in terms of going over our patient this is patient is buried with a pleasure or barrett esophagus again diagnosed with the presence of intestinal pleasure meaning gobble cells. President a biopsy from the tubular oesophagus above the g junction that showed and at least one centimeter nikko cell abnormality visible lesion in terms of being a pink colored patch of Colombia mucosa. Above the t junctions. However gobbled cells alone. Nostalgia are not sufficient for the diagnosis, They are required but by themselves are not sufficient since the endoscopic abnormality was also required. So this part, see specimens uh Choice C. Is not correct. Paris is a recognized precursor in the development. Obviously vaginal adenocarcinoma, not square missile carcinomas. Choice A. Is incorrect as well. Risk factors for the development of barrett esophagus as well as adenocarcinoma include longstanding reflux, advanced age older than 50 years, male sex, white race and elevated BME. So Choice D is actually the correct choice. The progression of carcinoma usually occurs through intermediate steps of dysplasia, including low growth and high grade dysplasia. And the extent or length of dysplasia actually correlates with increased Greece of adenocarcinoma. So the longer uh segment of theirs and the more extensive dysplasia that is present, the risk of adenocarcinoma is increased. So, Choice B is incorrect because actually it is a risk for adenocarcinoma and finally try mutations do play a role in christian genesis, particularly in the later steps of haiku dysplasia. And Our 3rd case is a patient who is 35 years old recently immigrated from Mexico presenting for the evaluation of anemia medical history reveals vague symptoms of dyspepsia and an upper endoscopy show diffuse gastric erythema with seminal gender parity and the presence of ulcers in the duodenum. A biopsy was taken from that looks like this. This is the gastric and um because all cells have this light pink muse isn't there is no bright pink parietal cells here that would suggest that we are in the gastric body or fungus instead. All the museums of lithium here proves that this is the gastric enter. There is there are a lot of inflammatory cells here in the lamb inappropriate. That is the soft tissue between the epithelial cells and most of these inflammatory cells are actually plasma cells. With these extent trick nuclei. Um there's some you sniffles as well as well as some neutrophils in some areas with uh more segmented nuclei. Normally the the lamb inappropriate. The gastric anthem should actually not even be visible. So it shouldn't have uh inflammation or an infiltrator of any cells and the gastric mucous glands that are basically juxtaposed next to each other with no intervening tissue. So here the replacement of that um fish you buy an inflammatory infiltrate is what is abnormal. And in fact if you were actually to look under very high magnification in the amusement within these um For viola crips you would find these uh squiggly long organisms living in the amusement which can be confirmed to be positive or black on a game sustain or with enemy. So chemical stain against H. Pylori because this is helicobacter pylori associated. The question for this cases, which statement about gastric carcinoma in the setting of chronic H. Pylori infection is correct. A it always develops through intestinal ecclesia Be, it develops in 1-3% of H. Pylori infected patients. C. H. Pylori. eradication does not reduce cancer risk D it is always intestinal type gastric cat and carcinoma that develops an e virulence factors are not markers of increased risk. So which one of these statements is correct regarding uh regarding gastric carcinoma rising in the setting of chronic h pylori infection. I'll give you a couple of seconds before I reveal the correct answer, which is b is the only correct statement. The other statements are incorrect. So helicobacter pylori is thought. In fact more than 50% of the world's population. Some areas have prevalence rates of 70 to 80% in the U. S. It's not to be around 35%. But less than 20% of these patients are symptomatic and therefore they do not come to clinical attention and do not get treated. Um patients when they are infected with h pylori gastritis may develop a chronic active gastritis at least initially. This gastritis is thought to be Antrim predominant and due to the inflammation G cells in the anteroom um secret gastric leading to increased acid secretion and a hyper claudia again at least initially which leads to an increased risk of ulcers in these patients. Eventually the chronic inflammation um will result in some atrophy particularly of the g cells in the gastric Antrim um reduced levels of acid and hypo chloride ria. In addition with the reduced acid throughout the stomach. The h pylori organisms which like um at least some asset to be present, will now move more approximately to the gastric body or the gastric funders. Where the ph is more appropriate is more appropriate for them as a micro environment. So you have a chapel or develop eventually involving the entire stomach. So a pan gastritis with concomitant hypo chloride ria um and decreased acid throughout which is the risk factor for the development gastric ulcers um intestinal Malaysia as a result of the atrophy and eventually the development of gastric carcinoma. It's not always clear whether these two processes happen sequentially in other words first and two predominant other pan gastritis or whether some H pylori um various variants uh cause of gastritis uh early on but at least it makes sense sort of physiologically that initially the uh infection will be anti predominant with eventually becoming a pan gastritis with the present. Yeah. H. Pylori is considered a class 1% in humans, 1 to 3% of infected patients will develop gastric cancer in their lifetimes. The uh prevalence of H. Pylori within intestinal carcinoma is thought to be around 90% very high, but it can also be seen in diffuse type gastric carcinoma, approximately 30% in those which is the other type of gastric adenocarcinoma. Customization in this setting uh is at least in the intestinal type follows what's what's called the Korea sequence where a chronic pain gastritis leads to atrophy, leading to intestinal pleasure with the presence of goblet cells again and through increasing grades of displeasure to the development of gastric adenocarcinoma. Again, this is considered the linear sequence of events that takes place when intestinal type gastric adenocarcinoma develops. These are not all required, they're not always present, they might not always be identified. In other words, you don't always have to identify every single step in that sequence. Sometimes they progress it will be faster. Sometimes the intermediate steps cannot be seen. So you might have atrophy and carcinoma right next to each other. But the thinking is at least biologically increasing mutations in this sequence or what leads to the lead to the development of carcinoma as a as a risk factor for the development carcinoma. Eradication of H pylori is considered to reduce the risk of cancer and is actually the first line treatment for the other type of neo plasm that these patients get, which is a lymphoma of the mucosa associated lymphoid tissue or malt lymphoma. It's a low grade diesel lymphoma. Um In terms of the outcome and their progression through this sequence, the certain various factors of H pylori is such as the Kagame back a proteins play role as to the genetic um environment of the host. Mhm. Um This is to compare the histological findings of H. Pylori gastritis as I described earlier to the normal gastric mucosa. Were the intervening uh lamb inappropriate between gastric epithelial cells is pretty empty. Um and pretty much a white potential space rather than being infiltrated by tons of inflammatory cells. Again, particularly plasma cells. As seen with these darker eccentric nuclei here. Mhm. So to review what we find histological in H. Pylori gastritis is a very prominent tensile in football specific infiltrate, particularly in the upper half of the lemon. Appropriate. Remember the organisms are actually sitting in the museum here in the lumen of the stomach. So the inflammatory infiltrate is responding to these organisms here. Sometimes you might find neutrophils. So an active gastritis and sometimes these uh limpopo inside uh lymphocytic infiltrates. Um conform actual mature lymphoid follicles. Um you might you'll be able to find these slender, curved rods in the epithelial surface or a little bit deeper within this musing gland crips but they like to live in the music that gets secreted um gastric cancer. So, since the H. Pylori infection is the most consistent risk factor for gastric cancer, it's elimination is a promising strategy to reduce the incidence of castor cancer. And this is the classic sequence the Korea sequence that I mentioned with sequential mutations, 53 is also thought to play a role here, especially at later stages. But remember not every single step in this sequence is identifiable or present. Yes. So the diagnosis here is helicobacter pylori gastritis which infects more than 50% of the world's population, but only 1 to 3% of these patients infected will consequently developed gastric adenocarcinoma. So choice B is the correct one. Eradication of H. Pylori therefore is a strategy to reduce gastric cancer risk at least in high risk populations. So Choice C. Is incorrect. The clinical outcome of the infection depends on various various factors including um as well as host genetic predisposition. So Choice E. Is incorrect. And even though H. Pylori infection is strongly associated with intestinal type carcinoma, gastric carcinoma, what is presumed to follow the sequence that we described through a traffic gastritis, intestinal pleasure dysplasia and carcinoma. It is also actually associated with diffuse type um carcinoma. So both choices A. And D. Are incorrect. Let's move to the last case which is a 40 year old man presented with abdominal pain, diarrhea and foul smelling stool review system revealed some weight loss and fatigue. And lab results show our deficiency anemia. Upper endoscopy shows diffuse scalloping and loss of folds in the duodenum and biopsy show this image here with a relatively flattening or atrophy of the surface epithelium. Normally this uh epithelial cells in the duodenum should form a nice long slender villa at the very top of the mucosa. These are not present here. They're very blunted. Uh In addition, if you were to look at higher magnification in the epithelium. You will see many of these darker round uh nuclear. These are the nuclear of lymphocytes and the in between cells are the enter sites. The ratio here of lymphocytes to enter site is almost 1-1 for everyone intersect. You can almost identify and lymphocyte normally the ratio is about 20 at most 20 lymphocytes for 100 enter sides meaning approximately one in 41 in five is the upper limit of normal. So this is highly increased in terms of these inter epithelial lymphocytes um present in the duodenum. So this is uh suggestive of syriac disease. And here's your question regarding this patient. Which of the following statements regarding markers and features of celiac disease is correct choice A and that tissue tropical dampness IgG antibodies are always elevated. Be happy types other than the Q two and Q eight are present. See entrepreneurial lymphocytes are B cells CD 20 positive. D interpreted lymphocytes are T cells CD three positive and E. Villus atrophy and histology is always present. So which one of these statements is correct regarding the diagnosis of celiac disease? The correct statement is D interpersonal emphasize our T cells that are city three positive and will go through the other choices. Okay, so celiac disease or celiac spruce also known as good and sensitive and neuropathy um has a pretty high prevalence. The average preferences about around wanted to present worldwide. It is higher in Scandinavian countries or other countries in the northern hemisphere and there are autoimmune and familiar associations. Almost all patients have an H L A G Q two or Q eight Haplotype. So the negative predictive value is practically 100% of these cases, antibodies Including uh calamities but others as well are overall more than 90% sensitive and specific. However they may not always have a tissue transport amnesty positive antibody test panel including more than one antibodies is usually recommended and beware of a coexisting aiga deficiency. So if one of the antibodies you're testing is an iG antibody this might not be present. If the patient has an idea deficiency and up to 2 to 3% of celiac disease patients have a coexisting uh G. A. Deficiency. So it's important to make sure that that's not the long term complications and risks that develop in the setting of celiac disease include refractory celiac disease. Um The so called alt generally itis at peace a lymphoma that is called neuropathy associated T cell lymphoma. A non hodgkin's. B. Cell lymphoma. Um In addition to small intestinal carcinoma as well as head and neck squamous cell carcinomas and the development of collage Nelspruit. Mhm. Compared to the normal giardino mucosa seen here on the right that has long, slender or thin intestinal villi with uh epithelium that contains enter sites and sparsely spaced lymphocytes. As you can see here. What happens in spruce is the flattening of those villains. So the surface looks much more flat rather than having these um tall villa and the film as we saw already has many many lymphocytes much more than the upper limit of normal which is around 20 per 100 sites. So again villus atrophy or blunting this can actually be graded as being mild, moderate or severe in terms of the extent of the atrophy of the villain and increasing the potential lymphocytes or I. L. S. As they're known for short these are city three positive T cells and by definition should be more than 25 or 100 enter sites. You might also see increased lamb inappropriate plasma cells are seen here. But the interpretation lymphocytes are diagnostically important. So the cut off for interpreting will emphasize uh in terms of diagnosing celiac disease um is 40 per 100 according to the original Marsh classification. But more recently the Karadzic classification has used an upper limit of 25. And in fact most pathologies used 25 lymphocytes or one in four. Um As the cut of for diagnosing increased interpreted will emphasize now the diagnosis not always prove there are other things that can cause that. And let's go through the classification according to the marsh system. Um when you have less than 40 but more importantly, less than 25 interpreted lymphocytes per 100 exercise no create have a pleasure and all those atrophy. That's basically describing the normal duty. No mucosa. Uh if you have just increasing capital lymphocytes but no atrophy is what's referred to as Marshall one March two is very rare. You have increasing the potential for sites and crypt hyperplasia only. But no villus atrophy. Once you start having villas entropy. You can actually grade that as mild, moderate or severe and that is consistent with gluten sensitive and dry apathy or celiac disease more than 25 interpreting emphasis per 100 enter sites as well as uh different grades of uh villus atrophy. And finally eventually you get complete atrophy um of the epithelium and the lymphocytes sort of um is more like a burnt out kind of uh situation must grade three. Uh That's also very rare. Um So what we're talking about celiac disease, we're talking about a March, grade 33. And then the sub classification A. B. Or C. Depending on whether the atrophy is mild, moderate or severe. The point is what to do when you have interpreted lymphocytes but no atrophy. This can still be celiac disease, particularly if it's early on or if it's a mild case. But the financial diagnosed in this case also includes bacterial overgrowth. Um Drug use particularly insets obesity, peptic damage, a concomitant H pylori infection in the stomach. That's why it's important to take a biopsy of the stomach. Tropical screw or other immune disorders about sometimes a biopsy of the lower GI tract might help as well as would help with Crohn's disease, infectious enteritis can also do it in some food sensitivities as well. So go back to your question. This patient has celiac disease which almost always presents in patients who carry which one of two habit tights DK two or DK eight. So statement B. Is incorrect. They may also have antibodies other than anti tissue transport Minister. Choice A is incorrect as well. That's why a panel of antibodies is usually recommended. The main histological optimistic of cilic disease is infiltration of the small intestinal epithelium, particularly the duodenum by lymphocytes more than 25 or 100 exercise. And the vast majority of those R. B cells I'm sorry. T cells T cells which would be city three positive. Therefore Choice D. Is correct and Choice C. Is incorrect. So um violence atrophy may eventually develop. It is not always present. So choice is incorrect. But when it's not present, when philanthropy is not present and you only have the entrepreneur lymphocytes. Um The differential includes mild disease as well as a whole other list um Of other entities that would be referred to as modified Marsh Grade one. So I hope this was helpful. Um There will be a panel as well for any of your questions. Um And I'm looking forward to that. Thank you very much.