Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

Abstract

Esophageal adenocarcinoma (EAC) is a lethal cancer with increasing incidence and mortality rates over the last several decades, with a rising incidence of 7-fold in the United States from 1975 to 2016.1Kolb J.M. Han S. Scott F.I. et al.Early-onset esophageal adenocarcinoma presents with advanced-stage disease but has improved survival compared with older individuals.Gastroenterology. 2020; 159: 2238-2240Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar As many as 40% of patients with Barrett’s esophagus (BE)-associated EACs present with advanced disease with a dismal 5-year survival rate. Several factors contribute to identification at an advanced stage, including the limited effectiveness of current screening and surveillance strategies.2Wani S. Gyawali C.P. Katzka D.A. AGA clinical practice update on reducing rates of post-endoscopy esophageal adenocarcinoma: commentary.Gastroenterology. 2020; 159: 1533-1537Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Similar to post-colonoscopy colorectal cancer,3Rutter M.D. Beintaris I. Valori R. et al.World Endoscopy Organization consensus statements on post-colonoscopy and post-imaging colorectal cancer.Gastroenterology. 2018; 155: 909-925Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar BE-associated high-grade dysplasia (HGD) and EAC can be diagnosed before the next recommended endoscopic evaluation after prior endoscopy that was negative for HGD or EAC.2Wani S. Gyawali C.P. Katzka D.A. AGA clinical practice update on reducing rates of post-endoscopy esophageal adenocarcinoma: commentary.Gastroenterology. 2020; 159: 1533-1537Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Meta-analyses and cohort studies suggest that a high proportion of HGD or EAC are missed within the first year after the index endoscopy that diagnosed BE.4Sawas T, Majzoub AM, Haddad J, et al. Magnitude and time-trend analysis of post-endoscopy esophageal adenocarcinoma: a systematic review and meta-analysis [published online ahead of print April 23, 2021]. Clin Gastroenterol Hepatol https://doi.org/10.1016/j.cgh.2021.04.032.Google Scholar Several factors may contribute to missed lesions, including lack of compliance with the Seattle biopsy protocol, missed dysplasia due to limited mucosal sampling with standard biopsies, inadequate BE segment inspection time (similar to colorectal cancer screening), inability to recognize subtle findings of early neoplasia, and reliance on observer-dependent histologic classification of dysplasia.5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,6Wani S. Williams J.L. Komanduri S. et al.Endoscopists systematically undersample patients with long-segment Barrett's esophagus: an analysis of biopsy sampling practices from a quality improvement registry.Gastrointest Endosc. 2019; 90: 732-741Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar These shortcomings highlight the importance of optimizing endoscopy quality to reduce the incidence and mortality associated with EAC. An American Gastroenterological Association Clinical Practice Update on post-endoscopy EAC (PEEC) identified several knowledge gaps, including the need for consensus standardization of PEEC terminology and calculation.2Wani S. Gyawali C.P. Katzka D.A. AGA clinical practice update on reducing rates of post-endoscopy esophageal adenocarcinoma: commentary.Gastroenterology. 2020; 159: 1533-1537Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar To address these gaps, an international working group (28% women; mean years in clinical practice, 17.7 [SD, 17.1]) on post-endoscopy HGD and EAC was established to achieve the following aims using the RAND/University of California, Los Angeles Appropriateness Methodology: standardize terminology and definitions, identify and assess potential explanations, establish a conceptual framework for future research, introduce post-endoscopy HGD and EAC as performance measures to facilitate benchmarking and comparisons between healthcare settings, and provide best practice advice on reducing the rate of PEEC and HGD in clinical practice. Detailed methodology is reported in Figure 1, Supplementary Methods, and Appendices 1–4. The final statements that met the appropriateness criteria are listed in Table 1.Table 1Appropriate Statements Determined Using the RAND/University of California, Los Angeles Appropriateness Methodology With Median Score and Number of Experts in Each Category RangeConsensus statementsMedian scoreNo. of experts 1–3 range (inappropriate)No. of experts 4–6 range (uncertain)No. of experts 7–9 range (appropriate)MAD-M scoreTerminology and definitions1. PEEN is the preferred term for HGD or EAC detected before the next recommended surveillance endoscopy in a patient with nondysplastic BE81 (4)2 (8)22 (88)1.12. PEEC is the preferred term for EAC detected before the next recommended surveillance endoscopy in a patient with nondysplastic BE83 (12)2 (8)20 (80)1.33. The time interval for which the occurrence of PEEN/PEEC applies is between 6 months and 3 years after screening or surveillance endoscopy71 (4)7 (28)17 (68)1.2Potential explanations4. The potential explanations for PEEN/PEEC include missed HGD/EAC and rapidly progressive EAC81 (4)2 (8)22 (88)0.9Quality review of PEEN/PEEC cases5. Endoscopy practices can consider reviewing PEEN/PEEC cases to understand contributing factors and areas of improvement80 (0)2 (8)23 (92)16. To facilitate the use of a common language when categorizing PEEN/PEEC cases according to their most plausible explanations, we suggest the following categories be used: a. Possible missed visible lesion, prior examination adequateb. Possible missed visible lesion, prior examination inadequatec. Detected visible lesion, no or inadequate sampling with targeted biopsiesd. Detected visible lesion, incomplete resection of previously identified lesione. Prior examination adequate and clinically indicated follow-up not recommendedf. Prior examination inadequate and clinically indicated follow-up not recommendedg. Prior examination adequate and failure of patient to follow-up on a recommended surveillance endoscopy interval.71 (4)3 (12)21 (84)1Best practice advice to reduce PEEN/PEEC7. Endoscopists should define the extent of BE using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and characteristics of visible lesions, when present80 (0)1 (4)24 (96)0.68. Screening and surveillance endoscopy for BE should be performed using high-definition white-light endoscopy and chromoendoscopy (traditional or virtual)80 (0)2 (8)23 (92)0.79. Endoscopists should spend adequate time inspecting the BE segment90 (0)0 (0)25 (100)0.410. In patients undergoing screening or surveillance endoscopy for BE, endoscopists should obtain biopsies using the Seattle biopsy protocol (4-quadrant biopsies at least every 2 cm and additional targeted biopsies or resection or outlining a plan for resection for any visible lesions)80 (0)1 (4)24 (96)0.6Values are n (%). MAD-M, mean absolute deviation from the median. Open table in a new tab Values are n (%). MAD-M, mean absolute deviation from the median. The group agreed to define 2 terms for BE-related neoplasia after index endoscopy: include EAC only (PEEC) and include both HGD and EAC (post-endoscopy esophageal neoplasia [PEEN]). Inclusion of HGD in the PEEN definition was driven by the fact that the goal of endoscopic screening and surveillance programs, as recommended by professional societies, is detection of HGD and early EAC.5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (; quiz 51): 30-50Crossref PubMed Scopus (816) Google Scholar,8Spechler S.J. Sharma P. et al.American Gastroenterological AssociationAmerican Gastroenterological Association medical position statement on the management of Barrett's esophagus.Gastroenterology. 2011; 140: 1084-1091Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar Further, up to 40% of patients with HGD have prevalent EAC (most diagnosed with stage I or stage IIa), many of whom have an actionable recommendation for endoscopic eradication therapy, underscoring the importance of capturing this population.7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (; quiz 51): 30-50Crossref PubMed Scopus (816) Google Scholar,9Konda V.J. Ross A.S. Ferguson M.K. et al.Is the risk of concomitant invasive esophageal cancer in high-grade dysplasia in Barrett's esophagus overestimated?.Clin Gastroenterol Hepatol. 2008; 6: 159-164Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar,10Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar On the other hand, using EAC is a more clinically meaningful singular endpoint (similar to post-colonoscopy colorectal cancer), is the most impactful, and is the most serious missed lesion. In addition, the potential for different phenotypes of EAC11Sawas T. Killcoyne S. Iyer P.G. et al.Identification of prognostic phenotypes of esophageal adenocarcinoma in 2 independent cohorts.Gastroenterology. 2018; 155: 1720-1728Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar raises the possibility that some subset of interval HGD may represent truly incident, rapidly growing neoplasia, especially when these lesions are detected near the end of a 3–5-year surveillance interval. Inclusion of low-grade dysplasia was considered inappropriate because of interobserver variability among pathologists, variable natural history outcomes, and the need for risk stratification to determine ideal candidates likely to benefit from endoscopic eradication therapy compared with surveillance.12Wani S. Rubenstein J.H. Vieth M. et al.Diagnosis and management of low-grade dysplasia in Barrett's esophagus: expert review from the Clinical Practice Updates Committee of the American Gastroenterological Association.Gastroenterology. 2016; 151: 822-835Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar The time interval of 6 months to 3 years after screening or surveillance endoscopy was rated as an appropriate window for occurrence of PEEN/PEEC. A minimum of 6 months was recommended to document healing and exclude BE in patients with erosive esophagitis. An upper limit of 3 years was selected because data from a national benchmarking quality registry suggest that endoscopists recommend a 3-year interval more commonly than a 5-year interval for endoscopic surveillance of nondysplastic BE patients.13Wani S. Williams J.L. Komanduri S. et al.Over-utilization of repeat upper endoscopy in patients with non-dysplastic Barrett's esophagus: a quality registry study.Am J Gastroenterol. 2019; 114: 1256-1264Crossref PubMed Scopus (16) Google Scholar Lesions detected beyond this window are likely incident rather than missed at the index endoscopy. Two analyses were conducted to provide contemporary estimates of PEEN/PEEC. In a retrospective US cohort study performed among 50,817 individuals diagnosed with incident BE and 366 with EAC, EAC was classified as prevalent, PEEC, and incident EAC in 67.2%, 13.7%, and 19.1% of cases, respectively.14Vajravelu RK, Kolb JM, Thanawala SU, et al. Characterization of prevalent, post-endoscopy, and incident esophageal cancer in the United States: a large retrospective cohort study [published online ahead of print February 5, 2021]. Clin Gastroenterol Hepatol https://doi.org/10.1016/j.cgh.2021.02.005.Google Scholar In other words, the magnitude of PEEC approached that of incident cancer. An updated systematic review and meta-analysis of 145,726 patients revealed a PEEC and PEEN rate of 21% (95% confidence interval, 13–31) and 26% (95% confidence interval, 19–34), respectively. Interestingly, meta-regression analysis demonstrated a strong inverse association between PEEC and incident EAC, suggesting that measures augmenting neoplasia detection will reduce the subsequent incidence of EAC detected in surveillance.4Sawas T, Majzoub AM, Haddad J, et al. Magnitude and time-trend analysis of post-endoscopy esophageal adenocarcinoma: a systematic review and meta-analysis [published online ahead of print April 23, 2021]. Clin Gastroenterol Hepatol https://doi.org/10.1016/j.cgh.2021.04.032.Google Scholar Although most cases of PEEN/PEEC may be attributed to missed HGD/EAC, rapidly progressive cancer due to accelerated pathways of neoplasia may also exist.11Sawas T. Killcoyne S. Iyer P.G. et al.Identification of prognostic phenotypes of esophageal adenocarcinoma in 2 independent cohorts.Gastroenterology. 2018; 155: 1720-1728Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,15Jammula S. Katz-Summercorn A.C. Li X. et al.Identification of subtypes of Barrett's esophagus and esophageal adenocarcinoma based on DNA methylation profiles and integration of transcriptome and genome data.Gastroenterology. 2020; 158: 1682-1697Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Inadequate data on the natural history of progression of nondysplastic BE to HGD limit our ability to estimate these proportions. Intuitively, the shorter the interval between the endoscopic finding of HGD or EAC and the endoscopy finding of nondysplastic BE, the greater the likelihood the neoplasia was missed on the screening or surveillance endoscopy. As with post-colonoscopy colorectal cancer, investigators need to operationalize definitions and attempt to identify time intervals that distinguish missed from incident PEEN/PEEC. Further, BE-associated neoplasia may be diagnosed after successful endoscopic eradication therapy. The panelists acknowledged several factors that contribute to the finding of neoplasia after complete eradication of intestinal metaplasia including missed resectable lesions, incomplete resection or ablation, failure to complete recommended follow-up treatments, and failure to achieve complete eradication of intestinal metaplasia, among others.2Wani S. Gyawali C.P. Katzka D.A. AGA clinical practice update on reducing rates of post-endoscopy esophageal adenocarcinoma: commentary.Gastroenterology. 2020; 159: 1533-1537Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,16Sawas T. Alsawas M. Bazerbachi F. et al.Persistent intestinal metaplasia after endoscopic eradication therapy of neoplastic Barrett's esophagus increases the risk of dysplasia recurrence: meta-analysis.Gastrointest Endosc. 2019; 89: 913-925Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Given the increasing use of endoscopic eradication therapy in patients with BE-associated neoplasia, quality indicators for endoscopic eradication therapy have been developed using an evidence-based approach endorsed by gastroenterology societies.17Wani S. Muthusamy V.R. Shaheen N.J. et al.Development of quality indicators for endoscopic eradication therapies in barrett's esophagus: the TREAT-BE (Treatment With Resection and Endoscopic Ablation Techniques for Barrett's Esophagus) Consortium.Am J Gastroenterol. 2017; 112: 1032-1048Crossref PubMed Scopus (21) Google Scholar Classification practices are surrogates for performing a high-quality endoscopy exam. The Prague classification system (see www.iwgco.net) is a validated grading system associated with high interobserver agreement among expert and nonexpert endoscopists to document the circumferential and maximal extent of the BE segment.18Sharma P. Dent J. Armstrong D. et al.The development and validation of an endoscopic grading system for Barrett's esophagus: the Prague C & M criteria.Gastroenterology. 2006; 131: 1392-1399Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar The Paris classification is a standardized morphology categorization, recommended by the US Multi-Society Task Force on colorectal cancer, and can provide relevant information regarding the risk of a lesion harboring submucosal invasion. Endoscopists are encouraged to use the Prague and Paris classifications in descriptive terms for BE-associated lesions.3Rutter M.D. Beintaris I. Valori R. et al.World Endoscopy Organization consensus statements on post-colonoscopy and post-imaging colorectal cancer.Gastroenterology. 2018; 155: 909-925Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Nevertheless, future studies are needed to assess whether use of these classifications leads to reduced rates of PEEN/PEEC. Consistent with recent guidelines,5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar the panelists rated the statement on the use of chromoendoscopy (virtual or traditional) in addition to high-definition white-light endoscopy during screening and surveillance endoscopy for BE patients as appropriate. In an updated meta-analysis that included 504 patients, chromoendoscopy with high-definition white-light endoscopy was associated with a higher detection rate of HGD/EAC compared with high-definition white-light endoscopy alone (14.7% vs 10.1%; relative risk, 1.44) (Supplementary Table 1, Appendix 5). There was low certainty of evidence because of risk of bias and imprecision associated with a low event rate. Available data suggest comparable rates of dysplasia detection between virtual and traditional chromoendoscopy techniques. Virtual chromoendoscopy (narrow-band imaging) is available in most endoscopes and thus requires no additional costs. Problems associated with dye-based chromoendoscopy include the need for dye-spraying equipment, additional time required, cumbersome nature of the procedure, difficulty in achieving uniform coating of the mucosal surface with the dye, and inability to detect superficial vascular patterns.5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Incorporation of training in virtual and traditional chromoendoscopy during fellowship and training programs for the practicing endoscopists is important for widespread routine implementation in clinical practice. Although data are limited, there was agreement that adequate inspection time would potentially increase detection of BE-associated neoplasia.19Gupta N. Gaddam S. Wani S.B. et al.Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett's esophagus.Gastrointest Endosc. 2012; 76: 531-538Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Future studies need to define the optimal inspection time per centimeter of the BE segment. Although the panel purposefully did not provide a time period comprising an adequate exam because of lack of data on this issue, European societies recommend a procedure time of ≥7 minutes for upper endoscopy and inspection time of ≥1 min/cm of the circumferential extent of the Barrett’s mucosa.20Bisschops R. Areia M. Coron E. et al.Performance measures for upper gastrointestinal endoscopy: a European Society of Gastrointestinal Endoscopy (ESGE) quality improvement initiative.Endoscopy. 2016; 48: 843-864Crossref PubMed Scopus (110) Google Scholar With regards to evidence supporting the routine use of the Seattle biopsy protocol in patients undergoing screening or surveillance for BE, data from 2 observational studies that included 506 patients demonstrated that the use of the Seattle biopsy protocol was associated with a higher dysplasia detection rate (19.1% vs 2.6%; relative risk, 2.75) (Supplementary Table 2). Selection bias and imprecision and indirectness of evidence (because detection of dysplasia was used as a surrogate for PEEN/PEEC) limited interpretation. Endoscopists may avoid biopsy of a visible lesion with referral for endoscopic resection. Several studies have consistently demonstrated suboptimal compliance rates to the Seattle biopsy protocol.6Wani S. Williams J.L. Komanduri S. et al.Endoscopists systematically undersample patients with long-segment Barrett's esophagus: an analysis of biopsy sampling practices from a quality improvement registry.Gastrointest Endosc. 2019; 90: 732-741Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Using a community-based pathology database, Abrams et al21Abrams J.A. Kapel R.C. Lindberg G.M. et al.Adherence to biopsy guidelines for Barrett's esophagus surveillance in the community setting in the United States.Clin Gastroenterol Hepatol. 2009; 7 (quiz 710): 736-742Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar reported that the odds of detecting dysplasia significantly decreased with noncompliance with the Seattle biopsy protocol (odds ratio, 0.53; 95% confidence interval, 0.35–0.82).21Abrams J.A. Kapel R.C. Lindberg G.M. et al.Adherence to biopsy guidelines for Barrett's esophagus surveillance in the community setting in the United States.Clin Gastroenterol Hepatol. 2009; 7 (quiz 710): 736-742Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar A recent analysis using a national quality benchmarking registry that included 58,709 endoscopies showed that nearly 20% of endoscopies were not compliant with the Seattle biopsy protocol and that endoscopists were less compliant with increasing BE length; the odds of noncompliance increased by 31% with every 1-cm increase in length.6Wani S. Williams J.L. Komanduri S. et al.Endoscopists systematically undersample patients with long-segment Barrett's esophagus: an analysis of biopsy sampling practices from a quality improvement registry.Gastrointest Endosc. 2019; 90: 732-741Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The panelists also acknowledged the significant interobserver variability in the interpretation of dysplasia among pathologists and the importance of high-quality expert pathology review in the diagnosis of dysplasia.5Qumseya B. Sultan S. et al.ASGE Standards of Practice CASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,10Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar An accurate diagnosis of dysplasia is critical for clinical decision-making and risk stratification, including the selection of endoscopic eradication therapy vs intensive surveillance. Guidelines recommend that dysplasia of any grade should be confirmed by a second pathologist with expertise in gastroenterology pathology.7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (; quiz 51): 30-50Crossref PubMed Scopus (816) Google Scholar,10Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Services and individual endoscopists are encouraged to review PEEN/PEEC cases periodically and identify areas for improvement. We provide a consensus-based categorization construct and acknowledge that this construct will need to be validated in future studies. An adequate examination was defined as one that met the prerequisites of documentation of landmarks, use of high-definition white-light endoscopy and chromoendoscopy, and complete sampling using the Seattle biopsy protocol. Similar to the disclaimer provided by the World Endoscopy Organization for post-colonoscopy colorectal cancer, the panelists recommended using the above construct of explanations to facilitate quality assurance but not to be used to support medicolegal decision-making or to define accountability at an individual level.3Rutter M.D. Beintaris I. Valori R. et al.World Endoscopy Organization consensus statements on post-colonoscopy and post-imaging colorectal cancer.Gastroenterology. 2018; 155: 909-925Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar An essential theme of this project was the development of consistent strategies to optimize detection of PEEN and PEEC, not to develop metrics for punitive use. In addition to the research directives outlined above, the panelists also discussed and voted on statements for which there was not sufficient agreement (Supplementary Table 3) but consensus that some of these statements were important for future discussion and resolution (Appendix 6). Panelists discussed that operationalizing PEEN/PEEC as a quality indicator for providers may be challenging given the low number of endoscopies performed for BE screening and surveillance and low annual number of incident EAC cases. Future efforts will need to focus on standardizing how PEEN/PEEC rates should be calculated in an automated fashion and establishing a minimum performance standard. The panelists acknowledged that the field would benefit from the BE equivalent of the adenoma detection rate, used to measure quality in colorectal cancer screening. Neoplasia detection rate, defined as the prevalence of HGD or EAC among BE patients at index upper endoscopy, has also been proposed as a quality indicator in the management of BE.22Parasa S. Desai M. Vittal A. et al.Estimating neoplasia detection rate (NDR) in patients with Barrett's oesophagus based on index endoscopy: a systematic review and meta-analysis.Gut. 2019; 68: 2122-2128Crossref PubMed Scopus (19) Google Scholar Nevertheless, significant work is needed to establish if the neoplasia detection rate can be adopted as a quality indicator to reliably differentiate between endoscopists (or endoscopy centers) with discordant detection rates of PEEN and PEEC, enable accountability between providers, and demonstrably improve the quality of care provided to patients. To be considered a high-value quality indicator, the neoplasia detection rate must be shown to correlate with important clinical outcomes such as interval development of EAC and/or mortality. In addition, although benchmarking thresholds need to be defined, it is imperative that these thresholds account for the different rates of neoplasia in the underlying population undergoing an upper endoscopy. This will most likely require risk adjustment based on well-established risk factors for the development and progression in BE. The routine use of wide-area transepithelial sampling in reducing rates of PEEN/PEEC in clinical practice was voted as uncertain. An updated systematic review and meta-analysis of the use of wide-area transepithelial sampling in BE screening and surveillance in 13,950 patients demonstrated an increase in detection of dysplasia among patients undergoing sampling using wide-area transepithelial sampling and forceps biopsies compared with forceps biopsies alone (3.2% vs 1.2%; relative risk, 2.13) (Supplementary Table 4). The certainty of evidence was reduced because of risk of bias (evidence largely driven by observational data), inconsistency (high heterogeneity, variability in detection rates of dysplasia), indirectness (detection of dysplasia was deemed as a surrogate for PEEN/PEEC), and uncertainty interpreting dysplasia diagnosed alone with wide-area transepithelial sampling. No study yet has evaluated the addition of wide-area transepithelial sampling to forceps biopsies for detection of dysplasia during BE surveillance when forceps biopsies are guided by both white-light and chromoendoscopy. There are also limited data on longitudinal follow-up of patients with nondysplastic biopsies but positive wide-area transepithelial sampling analyses to fully understand the prognostic significance of these discrepant findings. Inherent in this need is the evaluation of other proposed sampling or diagnostic techniques to predict development of neoplasia, such as TissueCypher, or more generic approaches including identification of additional methylation or other biomarkers.23Davison J.M. Goldblum J. Grewal U.S. et al.Independent blinded validation of a tissue systems pathology test to predict progression in patients with Barrett's esophagus.Am J Gastroenterol. 2020; 115: 843-852Crossref PubMed Scopus (10) Google Scholar Efforts are also needed to determine if implementation of further BE training leads to increased detection of PEEN/PEEC and a reduction in cancer mortality. It is critical that BE training courses designed to enhance detection of PEEN/PEEC undergo internal and external validation to achieve this goal. The “Barrett’s Oesophagus-Related Neoplasia” web-based training course is an available validated training course that primarily focuses on improving early neoplasia detection.24Bergman J. de Groof A.J. Pech O. et al.An interactive web-based educational tool improves detection and delineation of Barrett's esophagus-related neoplasia.Gastroenterology. 2019; 156: 1299-1308Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar This tool can be accessed at www.iwgco.net, www.ueg.eu, or www.best-academia.eu. No comprehensive training course is currently available that covers all facets of best practices in BE, and this deficit is the focus of ongoing research. Similarly, pathologist training may be needed to improve interobserver agreement when assessing Barrett’s dysplasia. One study from the Netherlands demonstrated that benchmarks defined previously by a group of core expert BE pathologists was validated by demonstrating consistency and training potential when enlisting other core pathologists to the group of BE experts.25van der Wel M.J. Klaver E. Duits L.C. et al.Adherence to pre-set benchmark quality criteria to qualify as expert assessor of dysplasia in Barrett's esophagus biopsies—towards digital review of Barrett's esophagus.United Eur Gastroenterol J. 2019; 7: 889-896Crossref PubMed Scopus (5) Google Scholar Finally, a checklist for future articles on this topic is proposed in Appendix 7. Using an evidence-based consensus process, an international multidisciplinary panel provided comprehensive guidance on standardizing the definition and etiology for PEEN/PEEC, potential explanations, and a template for the performance and improvement of high-quality endoscopy to reduce rates of PEEN/PEEC in clinical practice.