Global variations in diagnostic guidelines for Barrett's esophagus.

Endoscopic diagnosis of gastroesophageal junction and Barrett's esophagus is essential for surveillance and early detection of esophageal adenocarcinoma and esophagogastric junction cancer. Despite its small size, the gastroesophageal junction has many inherent problems, including marked differences in diagnostic methods for Barrett's esophagus in international guidelines. To define Barrett's esophagus, gastroesophageal junction location should be clarified. Although gastric folds and palisade vessels are landmarks for identifying this junction, they are sometimes difficult to observe due to air entry or reflux esophagitis. The possibility of diagnosing a malignancy associated with Barrett's esophagus <1 cm, identified using palisade vessels, should be re-examined. Nontargeted biopsies of Barrett's esophagus are commonly used to detect intestinal metaplasia, dysplasia, and cancer as described in the Seattle protocol. Barrett's esophagus with intestinal metaplasia has a high risk of becoming cancerous. Furthermore, the frequency of cancer in patients with Barrett's esophagus without intestinal metaplasia is high, and the guidelines differ on whether to include the presence of intestinal metaplasia in the diagnosis of Barrett's esophagus. Use of advanced imaging technologies, including narrow-band imaging with magnifying endoscopy and linked color imaging, is reportedly valid for diagnosing Barrett's esophagus. Furthermore, artificial intelligence has facilitated the diagnosis of Barrett's esophagus through its deep learning and image recognition capabilities. However, it is necessary to first use the endoscopic definition of the gastroesophageal junction, which is common in all countries, and then elucidate the characteristics of Barrett's esophagus in each region, for example, length differences in the risk of carcinogenesis with and without intestinal metaplasia.

Evaluation and reporting of biopsies from the columnar-lined esophagus and gastro-esophageal junction (GEJ).

This review is part of a collaboration between the American Registry of Pathology (the publisher of the Armed Forces Institute of Pathology Fascicles) and Annals of Diagnostic Pathology. It is in a series of expert recommendations on topics encountered in daily practice. The authors, two pathologists and a gastroenterologist, met on 19 January 2019 tasked with developing expert recommendations on reporting biopsies from the columnar lined esophagus and gastroesophageal junction. Our opinions for reporting revolve around noting the presence and absence of goblet cells and clues for confirming whether a sample is from the tubular esophagus. We also illustrate congeners of goblet cell. We present the information in the form of questions and answers.

Challenges to diagnostic standardization of Barrett's esophagus in Asia.

Barrett's esophagus (BE), a premalignant condition of the lower esophagus, is increasingly prevalent in Asia. However, endoscopic and histopathological criteria vary widely between studies across Asia, making it challenging to assess comparability between geographical regions. Furthermore, guidelines from various societies worldwide provide differing viewpoints and definitions, leading to diagnostic challenges that affect prognostication of the condition. In this review, the authors discuss the controversies surrounding the diagnosis of BE, particularly in Asia. Differences between guidelines worldwide are summarized with further discussion regarding various classifications of BE used, different definitions of gastroesophageal junction used across geographical regions and the clinical implications of intestinal metaplasia in the setting of BE. Although many guidelines recommend the Seattle protocol as the preferred approach regarding dysplasia surveillance in BE, some limitations exist, leading to poor adherence. Newer technologies, such as acetic acid-enhanced magnification endoscopy, narrow band imaging, Raman spectroscopy, molecular approaches and the use of artificial intelligence appear promising in addressing these problems, but further studies are required before implementation into routine clinical practice. The Asian Barrett's Consortium also outlines its ongoing plans to tackle the challenge of standardizing the diagnosis of BE in Asia.

Histology of Barrett's Metaplasia: Do Goblet Cells Matter?

This review has provided a summary of the biology of goblet cell metaplasia in CLE as it pertains to BE. Goblet cells are terminally differentiated nonproliferative cells that have many overlapping histochemical characteristics with mucinous columnar cells and pseudogoblet cells. There is an abundance of evidence that suggests that use of goblet cells as a biomarker of BE, and its progression to malignancy, is problematic. Some of these limitations include the fact that the background non-goblet epithelium in most patients with CLE is biologically intestinalized and contains molecular abnormalities similar to goblet cell CLE, goblet cells fluctuate with time and decrease in number with progression of neoplasia, and pathologists have problems with interpretation, and distinction, of goblet cells from other types of cells in the esophagus. Sampling error results in sensitivity and specificity issues that limit its positive predictive value. Goblet cells are fewest in number in the same population of patients with CLE that are hardest to detect endoscopically (i.e., those with short or ultrashort CLE). Nevertheless, the risk of cancer in patients with short-segment BE, a condition difficult to distinguish from the stomach, is very low regardless of the presence or absence of goblet cells so it is unclear what the role of goblet cells is in these patients as a biomarker. Nevertheless, if the answer to the following question, "Would you as a gastroenterologist recommend surveillance for a patient with clear endoscopic evidence of CLE, particularly if it is ≥ 3 cm in length, but in which goblet cells were not reported to be present by the pathologist," is yes, then the US requirement for goblet cells as part of the criteria for "BE" is superfluous.

A New Pathologic Assessment of Gastroesophageal Reflux Disease: The Squamo-Oxyntic Gap.

Diagnosis of gastroesophageal reflux disease (GORD) is delayed by the lack of uniform histopathologic criteria for diagnosis. The only practical value of pathology is the assessment of columnar lined esophagus (CLO). As a result, GORD is treated with acid suppressive drug therapy until there is a failure to control symptoms and/or advanced adenocarcinoma develops. The reasons why there is a failure of pathologic diagnosis are two false dogmas that result in two widely believed fundamental errors. These are the belief that cardiac epithelium normally lines the proximal stomach (1) and that the gastroesophageal junction (GOJ) is defined by the proximal limit of rugal folds (2). When these false dogmas are eradicated by existing powerful evidence, the pathology of GERD falls into the following stages, all defined by histology: (a) The normal state where the esophageal squamous epithelium transitions at the GOJ to gastric oxyntic epithelium with no intervening cardiac epithelium; (b) cardiac metaplasia of the squamous epithelium due to exposure to gastric juice results in cephalad movement of the squamo-columnar junction (SCJ). This creates the squamo-oxyntic gap and the dilated distal esophagus, which is distal to the endoscopic GOJ. The length of the squamo-oxyntic gap in the dilated distal esophagus is concordant with the shortening of the abdominal segment of the lower esophageal sphincter (LOS); (c) in the early stages, the gap is <5 mm and the LOS retains its competence. Reflux is uncommon and patients are asymptomatic; (d) the squamo-oxyntic gap increases in length, concordant with the amount of shortening of the LOS, which becomes increasingly incompetent. At a gap length of 5-15 mm, reflux is sufficient to cause symptoms, but in most patients, symptoms are controllable and the patients are normal at endoscopy. The gap is entirely within the dilated distal esophagus, which is mistaken by present criteria for proximal stomach. (e) The last stage of GORD is when the squamo-oxyntic gap is >15 mm. In these patients, reflux is severe with increasingly uncontrollable symptoms and columnar lined esophagus, both irreversible states.Understanding this pathophysiology of GORD by these new histologic criteria will allow diagnosis at the earliest and eminently reversible stages of the disease. This can open the door to new methods of treatment that will have the potential to prevent progression to the irreversible phase of GORD, including columnar lined esophagus. If successful, this will effectively prevent progression to adenocarcinoma.

Presence or absence of intestinal metaplasia but not its burden is associated with prevalent high-grade dysplasia and cancer in Barrett's esophagus.

Universal agreement on the inclusion of intestinal metaplasia to diagnose Barrett's esophagus (BE) is lacking. Our aim was to determine the association of intestinal metaplasia and its density with the prevalence of dysplasia/cancer in columnar lined esophagus (CLE). Patients with CLE but no intestinal metaplasia (CLE-no IM) were identified by querying the clinical pathology database using SNOMED codes for distal esophageal biopsies. CLE-IM patients were identified from a prospectively maintained database of BE patients. Subsequently, relative risks for prevalent dysplasia and cancer were calculated. Since patients with CLE-no IM are not usually enrolled in surveillance, only prevalent dysplasia/cancer on index endoscopy was analyzed. Goblet cell density and percent intestinal metaplasia were estimated. All biopsy slides were reviewed for dysplasia by two experienced gastrointestinal pathologists. Two hundred sixty-two CLE-IM and 260 CLE-no IM patients were included (age 64±12 vs. 60±11 years, P=0.001; whites 92% vs. 82%, P=0.001; males 99.7% vs. 99.3%, P=NS; CLE length 3.4±3.2 vears 1.4±0.4 cm, P=0.001 and hiatus hernia 64% vs. 56%, P=0.013). The odds of finding low-grade dysplasia and of high-grade dysplasia (HGD)/cancer were 12.5-fold (2.9-53.8, P=0.007) and 4.2-fold (95% CI 1.4-13, P=0.01) higher, respectively, in the CLE-IM group. Reanalysis after controlling for important variables of age, race, and length did not significantly alter the overall results. In CLE-IM group, when patients with high (>50/LPF) versus low goblet cell density (<50/LPF) and <10% versus >10% intestinal metaplasia were compared, the odds of HGD/cancer, OR 1.5 (0.5-4.9, P=0.5) and 1.97 (0.54-7.22), respectively, were not significantly higher. Demonstration of intestinal metaplasia continues to be an essential element in the definition of BE, but its quantification may not be useful for risk stratification of HGD/cancer in BE.

Histopathological diagnosis of adenocarcinoma in Barrett's esophagus.

The present review describes the histological markers of Barrett's esophagus (BE) that make it possible to distinguish between Barrett's carcinoma (BC) and gastric carcinoma. With regard to high-grade dysplasia, the indications for endoscopic resection (ER) or major surgery for management of BC cannot be decided on the basis of biopsy histology, and the choice between them should be made according to BC invasion depth. Therefore, we recommend that the term 'well-differentiated tubular adenocarcinoma' be used rather than 'high-grade dysplasia' (intraepithelial neoplasia). High-grade dysplasia is regarded as BC in Japan and other countries such as Germany. Such lesions should not be treated by endoscopic ablation but by ER, because components of invasive carcinoma are frequently present in the mucosa and submucosa, and knowledge obtained from ER samples is needed for additional therapy. Further studies on the relationship between the incidence of nodal metastasis and mucosal depth in mucosal BC are needed to decide the indications for ER. Suchstudies should involve subserial microscopic examination of slices 2-3 mm thick. To resolve the issue of regression of high-grade dysplasia, international experts in gastroenterological pathology need to conduct histopathological reviews of the first and last samples taken from such cases, as there are large differences between North American, European, and Japanese pathologists in the criteria used for histological diagnosis of dysplasia and adenocarcinoma without clear invasion, and both interobserver and intraobserver variations have been reported. Future studies will need to focus on which carcinomas are curable by ER.

Understanding the Columnar Lined Esophagus and Its Variations in Length With Age: A Cadaveric Study.

Introduction Columnar lined epithelium (CLE) of the esophagus holds particular importance in diagnosing Barrett's esophagus (BE). In Asia, the prevalence of BE ranges from 0.06% to 6.2%. In India, prevalence estimates vary from 2.6% to 23%. The frequency of esophageal adenocarcinoma has also been observed to be increasing alarmingly over the past few decades. The length of CLE as a criterion for diagnosing BE is the subject of considerable debate. Changes in CLE length among different age groups may exist. Our study aims to measure the length of CLE, or the distance between the angle of His and the Z Line (AZ distance), in normal individuals from Northeast India, and to analyze its variation across different age groups. Materials and methods The study was conducted in the Department of Anatomy and the Department of Forensic Medicine and Toxicology at Gauhati Medical College, Guwahati, Assam, India, during the period 2017-2019. Once opened, each specimen was laid flat on a board. The distance between the A and Z lines was measured using a pair of vernier calipers. This distance was recorded as the AZ distance in millimeters (mm). Results The mean AZ Distance was found to be 12.4 ± 5.3 mm. A significant correlation between age and AZ distance was observed. Conclusion Our present study suggests that the length of the CLE increases with age. This observation offers an opportunity to revisit or revise the diagnostic criteria based on CLE length, taking into account the age of the individual.

Gastrointestinal pathologists' perspective on managing risk in the distal esophagus: convergence on a pragmatic approach.

Here, we discuss recent updates and a continuing controversy in the diagnosis and management of Barrett's esophagus, specifically the recommendation that the irregular Z-line not be biopsied, the diminished status of ultrashort-segment Barrett's esophagus, the evidence basis for excluding and including the requirement of goblet cells for the diagnosis of Barrett's esophagus, and the conclusion that histologically confirmed low-grade dysplasia is best managed with endoscopic ablation rather than surveillance. We reference the American Gastroenterological Association and College of Gastroenterology and the British Society of Gastroenterology guidelines throughout, with the thesis that the field is converging on the concept of applying scarce medical resources to the diagnosis, surveillance, and therapy of patients most likely to derive benefit.

Presence of columnar-lined esophagus is negatively associated with the presence of esophageal varices in Japanese alcoholic men.

AIM: To determine whether the presence of columnar-lined esophagus (CLE) is associated with the presence of esophageal varices (EVs) in male Japanese alcoholics. METHODS: The subjects were 1614 Japanese alcohol-dependent men (≥ 40 years of age) who had undergone upper gastrointestinal endoscopic screening. Digitalized records of high-quality endoscopic images that included the squamocolumnar junction and esophagogastric junction were retrospectively jointly reviewed by four expert endoscopists for the purpose of diagnosing CLE. The authors investigated whether and to what extent there were associations between the presence of CLE and the presence of EVs, especially in the group with liver cirrhosis (LC). RESULTS: CLE ≥ 5 mm in length was found in 355 subjects (≥ 30 mm in 6 of them), LC without EVs in 152 subjects, LC with EVs in 174 subjects, and EVs without LC in 6 subjects. Advanced EVs, i.e., nodular, large or coiled forms, red color sign, or post-treatment, were found in 88 subjects. The incidence of CLE ≥ 5 mm decreased in the following order (P < 0.0001): 23.3% in the group without EVs, 17.4% in the group with small and straight EVs, and 5.7% in the group with advanced EVs. The multivariate ORs (95%CI) for EVs and advanced EVs in the group with LC were lower when CLE ≥ 5mm was present [0.46 (0.23-0.93) and 0.24 (0.08-0.74), respectively, vs 0-4 mm CLE]. CONCLUSION: The presence of CLE in male Japanese alcoholics was negatively associated with the presence of EVs.

Analysis of tissue and circulating microRNA expression during metaplastic transformation of the esophagus.

Genetic changes involved in the metaplastic progression from squamous esophageal mucosa toward Barrett's metaplasia and adenocarcinoma are almost unknown. Several evidences suggest that some miRNAs are differentially expressed in Barrett's esophagus (BE) and esophageal adenocarcinoma. Among these, miR-143, miR-145, miR-194, miR-203, miR-205, miR-215 appear to have a key role in metaplasia and neoplastic progression. The aim of this study was to analyze deregulated miRNAs in serum and esophageal mucosal tissue biopsies to identify new biomarkers that could be associated with different stages of esophageal disease. Esophageal mucosal tissue biopsies and blood samples were collected and analyzed for BE diagnosis. Quantitative Real-time PCR was used to compare miRNA expression levels in serum and 60 disease/normal-paired tissues from 30 patients diagnosed with esophagitis, columnar-lined esophagus (CLO) or BE. MiRNA expression analysis showed that miR-143, miR-145, miR-194 and miR-215 levels were significantly higher, while miR-203 and miR-205 were lower in BE tissues compared with their corresponding normal tissues. Esophageal mucosa analysis of patients with CLO and esophagitis showed that these miRNAs were similarly deregulated but to a lesser extent keeping the same trend and CLO appeared as intermediate step between esophagitis and BE. Analysis on circulating miRNA levels confirmed that miR-194 and miR-215 were significantly upregulated in both BE and CLO compared to esophagitis, while miR-143 was significantly upregulated only in the Barrett group. These findings suggest that miRNAs may be involved in neoplastic/metaplastic progression and miRNA analysis might be useful for progression risk prediction as well as for monitoring of BE/CLO patients.

Interobserver reproducibility in pathologist interpretation of columnar-lined esophagus.

Confirmation of endoscopically suspected esophageal metaplasia (ESEM) requires histology, but confusion in the histological definition of columnar-lined esophagus (CLE) is a longstanding problem. The aim of this study is to evaluate interpathologist variability in the interpretation of CLE. Thirty pathologists were invited to review three ten-case sets of CLE biopsies. In the first set, the cases were provided with descriptive endoscopy only; in the second and the third sets, ESEM extent using Prague criteria was provided. Moreover, participants were required to refer to a diagnostic chart for evaluation of the third set. Agreement was statistically assessed using Randolph's free-marginal multirater kappa. While substantial agreement in recognizing columnar epithelium (K = 0.76) was recorded, the overall concordance in clinico-pathological diagnosis was low (K = 0.38). The overall concordance rate improved from the first (K = 0.27) to the second (K = 0.40) and third step (K = 0.46). Agreement was substantial when diagnosing Barrett's esophagus (BE) with intestinal metaplasia or inlet patch (K = 0.65 and K = 0.89), respectively, in the third step, while major problems in interpretation of CLE were observed when only cardia/cardia-oxyntic atrophic-type epithelium was present (K = 0.05-0.29). In conclusion, precise endoscopic description and the use of a diagnostic chart increased consistency in CLE interpretation of esophageal biopsies. Agreement was substantial for some diagnostic categories (BE with intestinal metaplasia and inlet patch) with a well-defined clinical profile. Interpretation of cases with cardia/cardia-oxyntic atrophic-type epithelium, with or without ESEM, was least consistent, which reflects lack of clarity of definition and results in variable management of this entity.

Application of the Prague C and M criteria for endoscopic description of columnar-lined esophagus in South Korea.

AIM: To ascertain whether the Prague circumferential (C) length and maximal (M) length criteria for grading the extent of Barrett's esophagus can be applied prior to its widespread application in South Korea. METHODS: Two hundred and thirteen consecutive cases with endoscopic columnar-lined esophagus (CLE) were included and classified according to the Prague C and M criteria. RESULTS: Of 213 cases with CLE, the distribution of maximum CLE lengths was: 0.5-0.9 cm in 99 cases (46.5%); 1.0-1.4 cm in 63 cases (29.6%); 1.5-1.9 cm in 15 cases (7.0%); 2.0-2.4 cm in 14 cases (6.6%); 2.5-2.9 cm in 1 case (0.5%); and 7.0 cm in 1 case (0.5%). Twenty cases (9.4%) had columnar islands alone. Two hundred and eight cases (97.7%) lacked the circumferential CLE component (C0Mx). Columnar islands were found in 70 cases (32.9%), of which 20 cases (9.4%) had columnar islands alone. CONCLUSION: In regions where most CLE patients display short or ultrashort tongue-like appearance, more detailed descriptions of CLE's in < 1.0 cm lengths and columnar islands, as well as avoidance of repeating the prefix "C0" need to be considered in parallel with the widespread application of the Prague system in South Korea.

Elevated Z line: a new sign of Barrett's esophagus on double-contrast barium esophagograms.

We describe an elevated Z line as a new radiographic sign of Barrett's esophagus characterized by a transversely oriented, zigzagging, barium-etched line extending completely across the circumference of the midesophagus. An elevated Z line is rarely seen in other patients, so this finding should be highly suggestive of Barrett's esophagus on double-contrast barium esophagograms. If the patient is a potential candidate for surveillance, endoscopy and biopsy should be performed to confirm the presence of Barrett's esophagus.

Natural history of Barrett's esophagus.

The natural history of Barrett's esophagus (BE) is difficult to quantify because, by definition, it should describe the course of the condition if left untreated. Pragmatically, we assume that patients with BE will receive symptomatic treatment with acid suppression, usually a proton pump inhibitor, to treat their heartburn. This paper describes the development of complications of stricture, ulcer, dysplasia and adenocarcinoma from this standpoint. Controversies over the definition of BE and its implications in clinical practice are presented. The presence of intestinal metaplasia and its relevance to cancer risk is discussed, and the need to measure the extent of the Barrett's epithelium (long and short segments) using the Prague guidelines is emphasized. Guidelines and international consensus over the diagnosis and management of BE are being regularly updated. The need for expert consensus is important due to the lack of randomized trials in this area. After searching the literature, we have tried to collate the important studies regarding progression of Barrett's to dysplasia and adenocarcinoma. No therapeutic studies yet reported show a clear reduction in the development of cancer in BE. The effect of pharmacological and surgical intervention on the natural history of Barrett's is a subject of ongoing research, including the Barrett's Oesophagus Surveillance Study and the aspirin and esomeprazole cancer chemoprevention trial with interesting results. The geographical variation and the wide range of outcomes highlight the difficulty of providing an individualized risk profile to patients with BE. Future studies on the interaction of genome wide abnormalities in Barrett's and their interaction with environmental factors may allow individualization of the risk of cancer developing in BE.

Short segment hiatal hernia: is it a clinically significant entity?

INTRODUCTION: Hiatal hernia (HH) is a well-known contributory factor of gastroesophageal reflux disease (GERD). However, studies on the clinical significance of simple small HH are lacking. We conducted a study to clarify the clinical significance of short segment HH (SSHH) in relation to GERD. METHODS: 4,592 consecutive cases (male/female: 2,076/2,516, median age: 49 years) examined with diagnostic esophagogastroduodenoscopy for the first time were enrolled. During the insertion of endoscope, presence of HH was determined and the length was measured, if present. The relationships between gender, age, presence of erosive esophagitis, and columnar-lined esophagus (CLE) and the lengths of HH were analyzed. RESULTS: Among 4,592 cases, HH was present in 428 cases (9.3%); SSHH was found in 255 cases (5.6%) and long segment HH (LSHH) in 173 cases (3.8%). HH was more frequent among males and patients with LSHH tended to be older. Erosive esophagitis was observed in 4.8%, 22.0%, and 37.0% of no HH, SSHH, and LSHH group, respectively (p <0.05). CLE was observed in 14.4%, 36.5%, and 24.3% of no HH, SSHH, and LSHH group, respectively (p <0.05). CONCLUSIONS: SSHH is not a clinically silent and "innocent entity," but rather a condition with a significant pathologic significance similar to LSHH in regard to GERD.