The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury

The esophagus, a straight tube that connects the pharynx to the stomach, has the complex architecture common to the rest of the gastrointestinal tract with special differences that relate to its function as a conduit of ingested substances. For instance, it has submucosal glands that are unique and have a specific protective function. It has a squamous lining that exists nowhere else in the gut except the anus and it has a different submucosal nerve plexus when compared to the stomach and intestines. All of the layers of the esophageal wall and the specialized structures including blood and lymphatic vessels and nerves have specific responses to injury. The esophagus also has unique features such as patches of gastric mucosa called inlet patches at the very proximal part and it has a special sphincter mechanism at the most distal aspect. This review covers the normal microscopic anatomy of the esophagus and the patterns of reaction to stress and injury of each layer and each special structure.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147079/1/nyas13705_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147079/2/nyas13705.pd

Large Cancer Pedigree Involving Multiple Cancer Genes including Likely Digenic MSH2 and MSH6 Lynch Syndrome (LS) and an Instance of Recombinational Rescue from LS

Funding Information: This research was funded in part by a Cedars-Sinai Medical Center Precision Health Initiative Award to Megan P. Hitchins and Andrew Hendifar. Publisher Copyright: © 2022 by the authors.Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in which multiple LS branches carry the MSH2 pathogenic variant c.2006G>T (p.Gly669Val), one branch has this and an additional novel MSH6 variant c.3936_4001+8dup (intronic), and other non-LS branches carry variants within other cancer-relevant genes (NBN, MC1R, PTPRJ). Both MSH2 c.2006G>T and MSH6 c.3936_4001+8dup caused aberrant RNA splicing in carriers, including out-of-frame exon-skipping, providing functional evidence of their pathogenicity. MSH2 and MSH6 are co-located on Chr2p21, but the two variants segregated independently (mapped in trans) within the digenic branch, with carriers of either or both variants. Thus, MSH2 c.2006G>T and MSH6 c.3936_4001+8dup independently confer LS with differing cancer risks among family members in the same branch. Carriers of both variants have near 100% risk of transmitting either one to offspring. Nevertheless, a female carrier of both variants did not transmit either to one son, due to a germline recombination within the intervening region. Genetic diagnosis, risk stratification, and counseling for cancer and inheritance were highly individualized in this family. The finding of multiple cancer-associated variants in this pedigree illustrates a need to consider offering multicancer gene panel testing, as opposed to targeted cascade testing, as additional cancer variants may be uncovered in relatives.Peer reviewe

Consensus Recommendations for Histological Criteria of Autoimmune Hepatitis from the International AIH Pathology Group

Background & Aims Diagnostic histological criteria for autoimmune hepatitis (AIH) have not been clearly established. Previously published criteria focused mainly on chronic AIH, in which inflammatory changes mainly occur in portal/periportal regions and may not be applicable to acute presentation of AIH, in which inflammatory changes are typically predominantly lobular in location. International consensus criteria for the diagnosis and assessment of disease severity in both acute and chronic AIH are thus urgently needed. Methods Seventeen expert liver pathologists convened at an international workshop and subsequently used a modified Delphi panel approach to establish consensus criteria for the histopathological diagnosis of AIH. Results The consensus view is that liver biopsy should remain standard for diagnosing AIH. AIH is considered likely, if there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis in the absence of histological features suggestive of another liver disease. AIH is also considered likely if there is predominantly lobular hepatitis with or without centrilobular necroinflammation and at least one of the following features: portal lymphoplasmacytic hepatitis, interface hepatitis or portal-based fibrosis, in the absence of histological features suggestive of another liver disease. Emperipolesis and hepatocellular rosettes are not regarded as being specific for AIH. Conclusions The criteria proposed in this consensus statement provide a uniform approach to the histological diagnosis of AIH, which is relevant for patients with an acute as well as a chronic presentation and to more accurately reflect the current understanding of liver pathology in AIH

Metastatic Periampullary Tumor from Hepatocellular Carcinoma Presenting as Gastrointestinal Bleeding

Periampullary tumors constitute a number of diverse neoplastic lesions located within 2 cm of the major duodenal papilla; among these, metastatic lesions account for only a small proportion of the periampullary tumors. To our knowledge, a metastatic periampullary tumor from hepatocellular carcinoma has never been reported. A 62-year-old male reported to our institute for fatigue and low hemoglobin. His medical history was remarkable for multifocal hepatocellular carcinoma (HCC) treated with selective transcatheter arterial chemoembolization (TACE). An esophagogastroduodenoscopy (EGD) was performed which revealed a periampullary mass. Histopathology was consistent with metastatic moderately differentiated HCC. Two endoloops were deployed around the base of the mass one month apart. The mass eventually sloughed off and patient’s hemoglobin level stabilized. We postulated that periampullary metastasis in this patient was the result of tumor fragments migration through the biliary tracts and that TACE which increases tumor fragments burden might have played a contributory role. Metastasis of HCC to the gastrointestinal (GI) tract should be considered as a cause of GI bleeding

Non-alcoholic fatty liver disease is associated with lower hepatic and erythrocyte ratios of phosphatidylcholine to phosphatidylethanolamine

Non-alcoholic fatty liver disease (NAFLD) is associated with altered hepatic lipid composition. Animal studies suggest that the hepatic ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) contributes to steatogenesis and inflammation. This ratio may be influenced by dysregulation of PE N-methyltransferase (PEMT) pathway or low choline diet. Alterations in the liver may also influence lipid composition in circulation such as in erythrocytes, which therefore may have utility as a biomarker of hepatic disease. Currently, no study has assessed both liver and erythrocyte PC/PE ratios in NAFLD. Aim was to compare PC/PE ratio in liver and erythrocytes of patients with simple steatosis (SS) or steatohepatitis (NASH) to healthy controls. PC and PE were measured by mass spectrometry in 28 patients with biopsy proven NAFLD (14 SS, 14 NASH) and 9 healthy living liver donors as controls. The hepatic PC/PE ratio was lower in SS (median [range]) (1.23 [0.27-3.40]) and NASH (1.29 [0.77-3.22]) compared to controls (3.14 [2.20-3.73]); both P<0.001), but it was not different between SS and NASH. PC was lower and PE higher in the liver of SS patients compared to controls, whereas in NASH only PE was higher. The PC/PE ratio in erythrocytes was also lower in SS and NASH compared to controls, due to lower PC in both patient groups. PE in erythrocytes was not different among the groups. In conclusion, NAFLD patients have lower PC/PE ratio in liver and erythrocytes than healthy controls, which may play a role in the pathogenesis. Underlying mechanisms require further investigation.Canadian Institutes of Health Research (CIHR, operating grants NMD-86922, MOP-89705); American College of Gastroenterology (ACG) Clinical Research Award; summer studentship from Canadian Association of Gastroenterology / Crohns' and Colitis Foundation of Canada / CIH