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Histopathological assessment of esophageal biopsies is a key part in the management of patients with Barrett esophagus (BE) but prone to observer variability and reliable diagnostic methods are needed. Artificial intelligence (AI) is emerging as a powerful tool for aided diagnosis but often relies on abstract test and validation sets while real-world behavior is unknown. In this study, we developed a 2-stage AI system for histopathological assessment of BE-related dysplasia using deep learning to enhance the efficiency and accuracy of the pathology workflow. The AI system was developed and trained on 290 whole-slide images (WSIs) that were annotated at glandular and tissue levels. The system was designed to identify individual glands, grade dysplasia, and assign a WSI-level diagnosis. The proposed method was evaluated by comparing the performance of our AI system with that of a large international and heterogeneous group of 55 gastrointestinal pathologists assessing 55 digitized biopsies spanning the complete spectrum of BE-related dysplasia. The AI system correctly graded 76.4% of the WSIs, surpassing the performance of 53 out of the 55 participating pathologists. Furthermore, the receiver-operating characteristic analysis showed that the system's ability to predict the absence (nondysplastic BE) versus the presence of any dysplasia was with an area under the curve of 0.94 and a sensitivity of 0.92 at a specificity of 0.94. These findings demonstrate that this AI system has the potential to assist pathologists in assessment of BE-related dysplasia. The system's outputs could provide a reliable and consistent secondary diagnosis in challenging cases or be used for triaging low-risk nondysplastic biopsies, thereby reducing the workload of pathologists and increasing throughput., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background:  This study evaluated the proportion of patients with residual neoplasia after endoscopic resection (ER) for Barrett's neoplasia with confirmed tumor-positive vertical resection margin (R1v)., Methods:  This retrospective cohort study included patients undergoing ER for Barrett's neoplasia with histologically documented R1v since 2008 in the Dutch Barrett Expert Centers. We defined R1v as cancer cells touching vertical resection margins and Rx as nonassessable margins. Reassessment of R1v specimens was performed by experienced pathologists until consensus was reached regarding vertical margins., Results:  101/110 included patients had macroscopically complete resections (17 T1a, 84 T1b), and 99/101 (98%) ER specimens were histologically reassessed, with R1v confirmed in 74 patients (75%), Rx in 16%, and R0 in 9%. Presence/absence of residual neoplasia could be assessed in 66/74 patients during endoscopic reassessment (52) and/or in the surgical resection specimen (14), and 33/66 (50%) had residual neoplasia. Residual neoplasia detected during endoscopy was always endoscopically visible and biopsies from a normal-appearing ER scar did not detect additional neoplasia. Of 25 patients who underwent endoscopic follow-up (median 37 months [interquartile range 12-50]), 4 developed local recurrence (16.0%), all detected as visible abnormalities., Conclusions:  After ER with R1v, 50% of patients had no residual neoplasia. Histological evaluation of ER margins appears challenging, as in this study 75% of documented R1v cases were confirmed during reassessment. Endoscopic reassessment 8-12 weeks after ER seems to accurately detect residual neoplasia and can help to determine the most appropriate strategy for patients with R1v., Competing Interests: B.L.A.M. Weusten has received financial research support from Pentax Medical and Aqua Medical, and has received lecture fees from and is a consultant for Pentax Medical. J.J.G.H.M. Bergman has received financial support for institutional review board-approved research from C2Therapeutics/Pentax Medical, Medtronic, and Aqua Medical. R.E Pouw is a consultant for Medtronic BV and MicroTech Europe, and has received speaker fees from Pentax. L. van Tilburg, E.P.D. Verheij, S.E.M. van de Ven, S.N. van Munster, L. Alvarez Herrero, W.B. Nagengast, E.J. Schoon, A. Alkhalaf, L. Oudijk, S.L. Meijer, M. Jansen, M. Doukas, and A.D. Koch declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

MR1 : ESGE recommends the following standards for Barrett esophagus (BE) surveillance:- a minimum of 1-minute inspection time per cm of BE length during a surveillance endoscopy- photodocumentation of landmarks, the BE segment including one picture per cm of BE length, and the esophagogastric junction in retroflexed position, and any visible lesions- use of the Prague and (for visible lesions) Paris classification- collection of biopsies from all visible abnormalities (if present), followed by random four-quadrant biopsies for every 2-cm BE length.Strong recommendation, weak quality of evidence. MR2:  ESGE suggests varying surveillance intervals for different BE lengths. For BE with a maximum extent of ≥ 1 cm and < 3 cm, BE surveillance should be repeated every 5 years. For BE with a maximum extent of ≥ 3 cm and < 10 cm, the interval for endoscopic surveillance should be 3 years. Patients with BE with a maximum extent of ≥ 10 cm should be referred to a BE expert center for surveillance endoscopies. For patients with an irregular Z-line/columnar-lined esophagus of < 1 cm, no routine biopsies or endoscopic surveillance are advised.Weak recommendation, low quality of evidence. MR3:  ESGE suggests that, if a patient has reached 75 years of age at the time of the last surveillance endoscopy and/or the patient's life expectancy is less than 5 years, the discontinuation of further surveillance endoscopies can be considered. Weak recommendation, very low quality of evidence. MR4:  ESGE recommends offering endoscopic eradication therapy using ablation to patients with BE and low grade dysplasia (LGD) on at least two separate endoscopies, both confirmed by a second experienced pathologist.Strong recommendation, high level of evidence. MR5:  ESGE recommends endoscopic ablation treatment for BE with confirmed high grade dysplasia (HGD) without visible lesions, to prevent progression to invasive cancer.Strong recommendation, high level of evidence. MR6:  ESGE recommends offering complete eradication of all remaining Barrett epithelium by ablation after endoscopic resection of visible abnormalities containing any degree of dysplasia or esophageal adenocarcinoma (EAC).Strong recommendation, moderate quality of evidence. MR7:  ESGE recommends endoscopic resection as curative treatment for T1a Barrett's cancer with well/moderate differentiation and no signs of lymphovascular invasion.Strong recommendation, high level of evidence. MR8:  ESGE suggests that low risk submucosal (T1b) EAC (i. e. submucosal invasion depth ≤ 500 µm AND no [lympho]vascular invasion AND no poor tumor differentiation) can be treated by endoscopic resection, provided that adequate follow-up with gastroscopy, endoscopic ultrasound (EUS), and computed tomography (CT)/positrion emission tomography-computed tomography (PET-CT) is performed in expert centers.Weak recommendation, low quality of evidence. MR9:  ESGE suggests that submucosal (T1b) esophageal adenocarcinoma with deep submucosal invasion (tumor invasion > 500 µm into the submucosa), and/or (lympho)vascular invasion, and/or a poor tumor differentiation should be considered high risk. Complete staging and consideration of additional treatments (chemotherapy and/or radiotherapy and/or surgery) or strict endoscopic follow-up should be undertaken on an individual basis in a multidisciplinary discussion.Strong recommendation, low quality of evidence. MR10 A: ESGE recommends that the first endoscopic follow-up after successful endoscopic eradication therapy (EET) of BE is performed in an expert center.Strong recommendation, very low quality of evidence. B:  ESGE recommends careful inspection of the neo-squamocolumnar junction and neo-squamous epithelium with high definition white-light endoscopy and virtual chromoendoscopy during post-EET surveillance, to detect recurrent dysplasia.Strong recommendation, very low level of evidence. C:  ESGE recommends against routine four-quadrant biopsies of neo-squamous epithelium after successful EET of BE.Strong recommendation, low level of evidence. D:  ESGE suggests, after successful EET, obtaining four-quadrant random biopsies just distal to a normal-appearing neo-squamocolumnar junction to detect dysplasia in the absence of visible lesions.Weak recommendation, low level of evidence. E:  ESGE recommends targeted biopsies are obtained where there is a suspicion of recurrent BE in the tubular esophagus, or where there are visible lesions suspicious for dysplasia.Strong recommendation, very low level of evidence. MR11:  After successful EET, ESGE recommends the following surveillance intervals:- For patients with a baseline diagnosis of HGD or EAC:at 1, 2, 3, 4, 5, 7, and 10 years after last treatment, after which surveillance may be stopped.- For patients with a baseline diagnosis of LGD:at 1, 3, and 5 years after last treatment, after which surveillance may be stopped.Strong recommendation, low quality of evidence., Competing Interests: M. Barret has received consultancy fees from Medtronic (2019 to 2023) and Fujifilm (2023), consultancy and research funding from Pentax (2021 to 2022), and fees for training programs from Olympus (2022 to 2023). M. di Pietro has received consultancy fees from Medtronic (2018 to date); the Cytosponge was developed by his institution but he does not have a share in the patent. M. Dinis-Ribeiro has received consultancy fees from Medtronic (2021) and Roche (2022), and a research grant from Fujifilm (2021 to 2022); he is Co-Editor-in-Chief of Endoscopy. G. Fernández-Esparrach has received speaker’s fees from Medtronic (2023). R. Fitzgerald is a co-founder and shareholder (< 3 %) in Cyted Ltd, but is not an employee and does not receive funding or consultancy fees. She is a trustee of the charity Heartburn Cancer UK (HCUK) who have provided patient input and funded mobile units for delivery of heartburn check clinics as part of a research programme called DELTA; her research was funded by The UK Medical Research Council (MRC) who have licensed Cytosponge technology and assays to Medtronic in 2014. M. Jansen has received speaker’s fees from Medtronic (2018 to date). O. Pech has received speaker’s fees from Fujifilm (2012 to 2022), Boston Scientific (2012 to date), and Medtronic (2015 to date). R.E. Pouw has received speaker’s fees from Pentax Medical (2022, 2023) and consultancy fees from Medtronic and MicroTech Europe (both ongoing). M.C.W. Spaander has received research support from Lucid (Esocheck) (2020 to 2023) and Capsulomics (2022 to 2023). B.L.A.M. Weusten has received financial research support, and consultancy and lecture fees from Pentax Medical (2019 to date), and financial research support from Aqua Medical Inc. (2020 to 2022).R. Bisschops, F. Baldaque-Silva, E. Coron, M. Jovani, I. Marques-de-Sa, A. Rattan, W.K. Tan, K. Triantafyllou, E.P.D. Verheij, and P.A. Zellenrath declare that they have no conflict of interest., (European Society of Gastrointestinal Endoscopy. All rights reserved.)

Background & Aims: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression., Methods: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome., Results: We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time., Conclusions: We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic acid-biliary reflux and Helicobacter pylori infection are instrumental environmental drivers of cancer initiation and progression in the upper gastrointestinal tract. Remarkably, although these environmental carcinogens are quite dissimilar, the tumour progression cascade these carcinogens engender is highly comparable. For this reason, studies of malignant progression occurring at the anatomic borderland between the oesophagus and the stomach have traditionally lumped junctional adenocarcinomas with either oesophageal adenocarcinoma or gastric adenocarcinoma. Whilst studies have revealed remarkable epidemiological and genetic similarities of these cancers and their associated premalignant conditions, these works have also revealed some key differences. This highlights that further scientific effort demands a dedicated focus on the understanding of the cell-cell interaction between the epithelium and the local microenvironment in this anatomic region. We here review available evidence with regards to tumour progression occurring at the gastro-oesophageal junction and contrast it with available data on cancer evolution in the metaplastic oesophagus and distal stomach., Competing Interests: Declaration of competing interest None of the authors have any financial or other conflict of interest to disclose with regards to the content of this manuscript., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Guidelines mandate expert pathology review of Barrett's oesophagus (BO) biopsies that reveal dysplasia, but there are no evidence-based standards to corroborate expert reviewer status. We investigated BO concordance rates and pathologist features predictive of diagnostic discordance., Design: Pathologists (n=51) from over 20 countries assessed 55 digitised BO biopsies from across the diagnostic spectrum, before and after viewing matched p53 labelling. Extensive demographic and clinical experience data were obtained via online questionnaire. Reference diagnoses were obtained from a review panel (n=4) of experienced Barrett's pathologists., Results: We recorded over 6000 case diagnoses with matched demographic data. Of 2805 H&E diagnoses, we found excellent concordance (>70%) for non-dysplastic BO and high-grade dysplasia, and intermediate concordance for low-grade dysplasia (42%) and indefinite for dysplasia (23%). Major diagnostic errors were found in 248 diagnoses (8.8%), which reduced to 232 (8.3%) after viewing p53 labelled slides. Demographic variables correlating with diagnostic proficiency were analysed in multivariate analysis, which revealed that at least 5 years of professional experience was protective against major diagnostic error for H&E slide review (OR 0.48, 95% CI 0.31 to 0.74). Working in a non-teaching hospital was associated with increased odds of major diagnostic error (OR 1.76, 95% CI 1.15 to 2.69); however, this was neutralised when pathologists viewed p53 labelled slides. Notably, neither case volume nor self-identifying as an expert predicted diagnostic proficiency. Extrapolating our data to real-world case prevalence suggests that 92.3% of major diagnostic errors are due to overinterpreting non-dysplastic BO., Conclusion: Our data provide evidence-based criteria for diagnostic proficiency in Barrett's histopathology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Esophageal adenocarcinoma carries a poor prognosis and therefore treatment of early neoplasia arising in the precursor condition Barrett's esophagus (BE) is desirable. Visible lesions arising in BE need endoscopic mucosal resection for accurate staging and removal. Resection modalities include a cap-based system with snare and custom-made multiband mucosectomy (MBM) devices (Duette, Cook Medical Ltd). A new MBM device has recently become available (Captivator, Boston Scientific Ltd)., Objectives: A retrospective pilot study to compare the efficacy, safety, specimen size and histology of endoscopic mucosal resection (EMR) specimens resected with two MBM devices (Cook Duette and Boston Captivator) in treatment naive patients undergoing endoscopic therapy for BE neoplasia., Methods: Consecutive EMR procedures carried out by a single experienced endoscopist were analysed. All visible lesions were marked and resected using one of the two MBM devices. All resected specimens were analysed by the same two experienced pathologists. The resected specimens in both groups were analysed for maximum diameter, minimum diameter, surface area and depth., Results: Twenty consecutive patients were analysed (18M + 2F; mean age 74) in the Duette group and 20 (17M + 3F; mean age 72) in the Captivator group. A total of 58 specimens were resected in the Duette and 63 in the Captivator group. Min diameter, max diameter, surface area and depth of the ER specimens resected by the Captivator device were significantly larger than that by the Duette device [min diameter 9.89 mm vs 9.07 mm (p = 0.019); max diameter: 13.54 mm vs 12.38 mm (p = 0.024); surface area: 135.40 mm 2 vs 113.89 mm 2 (p = 0.005); depth 3.71 mm vs 2.89 (p = 0.001)]., Conclusions: These two MBM devices showed equivalent efficacy and safety outcomes, but the EMR Captivator device resected specimens with a larger area in the esophagus when compared with the Duette device. A possible advantage of this is in situations where en bloc resections with fewer EMRs are desirable for larger lesions.

Barrett's oesophagus surveillance biopsies represent a significant share of the daily workload for a busy histopathology department. Given the emphasis on endoscopic detection and dysplasia grading, it is easy to forget that the benefits of these screening programs remain unproven. The majority of patients are at low risk of progression to oesophageal adenocarcinoma, and periodic surveillance of these patients is burdensome and costly. Here, we investigate the parallels in the development of Barrett's oesophagus and other scenarios of wound healing in the intestine. There is now increased recognition of the full range of glandular phenotypes that can be found in patients' surveillance biopsies, and emerging evidence suggests parallel pathways to oesophageal adenocarcinoma. Greater understanding of the conditions that favour progression to cancer in the distal oesophagus will allow us to focus resources on patients at increased risk.

Although researchers have identified genetic alterations that contribute to development of esophageal adenocarcinoma, we know little about features of patients or environmental factors that mediate progression of chronic acid biliary reflux to Barrett's esophagus and cancer. Increasing our understanding of the mechanisms by which normal squamous epithelium progresses to early-stage invasive cancer will help formulate rational surveillance guidelines and allow us to divest resources away from patients at low risk of malignancy. We review the cellular and genetic alterations that occur during progression of Barrett's esophagus, based on findings from clinical studies and mouse models of disease. We review the features of the luminal and mucosal microenvironment of Barrett's esophagus that promote, in a small proportion of patients, development of esophageal adenocarcinoma. Markers of clonal evolution can be used to determine patient risk for cancer and set surveillance intervals., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Barrett's oesophagus commonly presents as a patchwork of columnar metaplasia with and without goblet cells in the distal oesophagus. The presence of metaplastic columnar epithelium with goblet cells on oesophageal biopsy is a marker of cancer progression risk, but it is unclear whether clonal expansion and progression in Barrett's oesophagus is exclusive to columnar epithelium with goblet cells., Design: We developed a novel method to trace the clonal ancestry of an oesophageal adenocarcinoma across an entire Barrett's segment. Clonal expansions in Barrett's mucosa were identified using cytochrome c oxidase enzyme histochemistry. Somatic mutations were identified through mitochondrial DNA sequencing and single gland whole exome sequencing., Results: By tracing the clonal origin of an oesophageal adenocarcinoma across an entire Barrett's segment through a combination of histopathological spatial mapping and clonal ordering, we find that this cancer developed from a premalignant clonal expansion in non-dysplastic ('cardia-type') columnar metaplasia without goblet cells., Conclusion: Our data demonstrate the premalignant potential of metaplastic columnar epithelium without goblet cells in the context of Barrett's oesophagus., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Clonal evolution to esophageal adenocarcinoma in Barrett's esophagus (BO) is characterized by relentless clonal competition. Developing markers that capture the dynamics of clonal competition in BO patients for risk stratification purposes is a key goal of translational research. Dysplastic epithelial changes in patients who progress to neoplasia can be viewed as a proxy marker of the clonal dynamics in BO progression. However, this marker is relatively insensitive because it does not pick up on clonal expansions that are not accompanied by morphologic changes. Moreover, interobserver variability between histopathologists hampers the specificity of this marker in predicting disease progression. International guidelines now stipulate that dysplasia should be confirmed by a second gastrointestinal histopathologist. This recommendation emphasizes the importance of special expertise in Barrett's histopathology. Currently, though there are no criteria that lay down "what makes an expert Barrett's histopathologist?" Here we review the histopathology of Barrett's dysplasia with an emphasis on the collaborative role of the histopathologist in the management of BO patients who progress to dysplasia, while the accompanying paper by Shepherd and colleagues discusses the histopathology of nondysplastic BO. We evaluate factors that may contribute to interobserver variability and provide details on adjunct tests (such as p53 immunohistochemistry) and standardized handling and reporting of risk factors in endoscopic resection specimens. Strict application of diagnostic criteria fosters diagnostic uniformity and facilitates tailored care of patients with early stage esophageal adenocarcinoma and its precursor lesions.

Objective: Barrett's oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands., Methods: Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry., Results: Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell., Conclusions: Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)