Risk of progression in Barrett’s esophagus indefinite for dysplasia: a systematic review and meta-analysis

Published:August 14, 2019DOI:https://doi.org/10.1016/j.gie.2019.07.037

      Background and Aims

      Risk of progression in Barrett's esophagus (BE) with low-grade dysplasia (LGD) and high-grade dysplasia (HGD) has been established. However, the natural history of BE with indefinite dysplasia (BE-IND) remains unclear. We performed a systematic review and meta-analysis to estimate the pooled risk of progression to HGD and/or esophageal adenocarcinoma (EAC) in BE-IND.

      Methods

      We performed a systematic search of multiple databases to June 2018 to identify studies reporting the incidence of HGD, EAC, or HGD/EAC as an outcome in patients with BE-IND undergoing endoscopic surveillance. The pooled incidence rate of HGD and/or EAC and EAC alone was estimated.

      Results

      We identified 8 studies reporting the incidence of HGD and/or EAC and 5 studies reporting the incidence of EAC in BE-IND. The pooled incidence of HGD and/or EAC (89 cases in 1441 patients over 5306.2 person-years) was 1.5 per 100 person-years (95% confidence interval [CI], 1.0-2.0). The pooled incidence of EAC (40 cases in 1266 patients over 4520.2 person-years) was 0.6 per 100 person-years (95% CI, 0.1-1.1). Substantial heterogeneity was noted in the analyses. On subgroup analysis, the incidence of EAC was higher in studies from Europe compared with North America (0.9% vs 0.1%, P = .01). The pooled incidence of LGD was 11.4 per 100 person-years (95% CI, 0.06-0.2).

      Conclusion

      The estimated incidence of HGD and/or EAC and EAC alone in BE-IND is similar to the previously reported progression risk in BE-LGD. Based on these risk estimates, patients with BE-IND should be placed on active endoscopic surveillance.

      Graphical abstract

      Abbreviations:

      ACG (American College of Gastroenterology), BE (Barrett’s esophagus), CI (confidence interval), EAC (esophageal adenocarcinoma), LGD (low-grade dysplasia), HGD (high-grade dysplasia), IND (indefinite for dysplasia), NDBE (nondysplastic Barrett’s esophagus), PPI (proton pump inhibitor)

      Introduction

      Barrett’s esophagus (BE) is a well-established precursor lesion to esophageal adenocarcinoma (EAC),
      • Spechler S.J.
      • Sharma P.
      • Souza R.F.
      • et al.
      American Gastroenterological Association technical review on the management of Barrett's esophagus.
      a malignancy with a dismal 5-year survival rate of less than 20%.
      • Pohl H.
      • Welch H.G.
      The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence.
      Patients with BE undergo endoscopic surveillance with the goal of detecting dysplasia or early cancer. The presence of dysplasia increases the risk of EAC in BE.
      • Desai T.K.
      • Krishnan K.
      • Samala N.
      • et al.
      The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis.
      • Rastogi A.
      • Puli S.
      • El-Serag H.B.
      • et al.
      Incidence of esophageal adenocarcinoma in patients with Barrett's esophagus and high-grade dysplasia: a meta-analysis.
      • Singh S.
      • Manickam P.
      • Amin A.V.
      • et al.
      Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta- analysis.
      The degree of dysplasia is the most widely accepted predictor of progression, and hence the surveillance intervals recommended by GI societies are based on the dysplasia grade.
      • Spechler S.J.
      • Sharma P.
      • Souza R.F.
      • et al.
      American Gastroenterological Association technical review on the management of Barrett's esophagus.
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • et al.
      ACG Clinical Guideline: diagnosis and management of Barrett’s esophagus.
      • Krishnamoorthi R.
      • Singh S.
      • Ragunathan K.
      • et al.
      Factors associated with progression of Barrett’s esophagus: a systematic review and meta-analysis.
      It has been postulated that among most patients who develop neoplastic disease, intestinal metaplasia transforms from nondysplastic BE (NDBE) to low-grade dysplasia (LGD), to high-grade dysplasia (HGD) and eventually to intra-mucosal carcinoma.
      • Spechler S.J.
      • Souza R.F.
      Barrett's esophagus.
      • Schlemper R.
      • Riddell R.
      • Kato Yea
      • et al.
      The Vienna classification of gastrointestinal epithelial neoplasia.
      The reported risk of progression to EAC is estimated to be 0.3 per 100 person-years with NDBE, 0.5 per 100 person-years with LGD, and 6.6 per 100 person-years with HGD.
      • Desai T.K.
      • Krishnan K.
      • Samala N.
      • et al.
      The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis.
      • Rastogi A.
      • Puli S.
      • El-Serag H.B.
      • et al.
      Incidence of esophageal adenocarcinoma in patients with Barrett's esophagus and high-grade dysplasia: a meta-analysis.
      • Singh S.
      • Manickam P.
      • Amin A.V.
      • et al.
      Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta- analysis.
      An indeterminate category of dysplasia reported by pathologists is BE with indefinite for dysplasia (IND). There are no well-established diagnostic criteria for “indefinite for dysplasia.” Approximately 4.3% to 8.4% of BE biopsy specimens are diagnosed as BE-IND. This largely depends on the diagnostic thresholds used by pathologists.
      • Waters K.M.
      • Salimian K.J.
      • Voltaggio L.
      • et al.
      Refined criteria for separating low-grade dysplasia and nondysplastic Barrett esophagus reduce equivocal diagnoses and improve prediction of patient outcome: a 10-year review.
      For a definitive diagnosis of dysplasia, the epithelial abnormalities characteristic of dysplasia should not only be present in the crypts but also involve the surface epithelium.
      • Haggitt R.C.
      Barrett's esophagus, dysplasia, and adenocarcinoma.
      In BE-IND, reactive changes in the nucleus and cytoplasm show similarities to dysplasia, but maturation toward the luminal surface and/or the presence of clonality are not always established.
      • Haggitt R.C.
      Barrett's esophagus, dysplasia, and adenocarcinoma.
      Studies have shown that the reproducibility and inter-reader reliability of BE-IND is poor among pathologists, resulting in variation of histologic categorization.
      • Coco D.P.
      • Goldblum J.R.
      • Hornick J.L.
      • et al.
      Interobserver variability in the diagnosis of crypt dysplasia in Barrett esophagus.
      • Montgomery E.
      • Goldblum J.R.
      • Greenson J.K.
      • et al.
      Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study.
      The current recommendation for surveillance in patients with BE-IND is to treat inflammation with acid suppression for 8 to 12 weeks followed by endoscopy with repeat biopsies to reassess the histologic diagnosis.
      • Schlemper R.
      • Riddell R.
      • Kato Yea
      • et al.
      The Vienna classification of gastrointestinal epithelial neoplasia.
      There is wide variation in the reported rates of malignant progression in BE-IND. A large population-based cohort study by Kestens et al
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      reported the risk of progression to HGD and/or EAC in BE-IND as 1.4 per 100 person-years and EAC alone as 0.8 per 100 person-years. On the other hand, a well-conducted study by Sinh et al,
      • Sinh P.
      • Anaparthy R.
      • Young P.E.
      • et al.
      Clinical outcomes in patients with a diagnosis of “indefinite for dysplasia” in Barrett’s esophagus: a multicenter cohort study.
      using a multicenter database with a prior standardized definition for BE-IND, reported the incidence of HGD/EAC and EAC alone as 0.8 and 0.2 per 100 person-years, respectively.
      As the actual risk of malignant progression in BE-IND is unclear, patients with persistent BE-IND on repeat biopsies after optimization of anti-reflux measures are managed the same way as BE-LGD in clinical practice.
      • Rastogi A.
      • Puli S.
      • El-Serag H.B.
      • et al.
      Incidence of esophageal adenocarcinoma in patients with Barrett's esophagus and high-grade dysplasia: a meta-analysis.
      • Wani S.
      • Falk G.W.
      • Post J.
      • et al.
      Risk factors for progression of low-grade dysplasia in patients with Barrett's esophagus.
      As a result, surveillance endoscopies are performed at shorter intervals in patients with BE-IND compared with NDBE. Frequent endoscopies can lead to increased cumulative risk of adverse events and health care costs. Hence, reliably estimating the risk of progression in BE-IND is important for both patient care and cost effectiveness.
      We conducted a systematic review and meta-analysis to estimate the pooled risk of progression to HGD and/or EAC in patients with BE-IND.

      Methods

      This systematic review was performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions.
      • Higgins J.
      • Green S.
      Cochrane handbook for systematic reviews of interventions version 5.1.0.
      It is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

      Search strategy

      We conducted a comprehensive search of several databases and conference proceedings, including PubMed, EMBASE, and Web of Science databases (earliest inception to June 2018) to identify studies that reported the incidence of HGD, EAC, HGD, and/or EAC as an outcome in patients with BE-IND undergoing endoscopic surveillance. An experienced medical librarian using input from the study authors helped with the literature search. The details of the search strategy and data sources are reported in Appendix 1 (available online at www.giejournal.org).
      Key words used in the search included a combination of “Barrett’s esophagus,” “Barrett’s epithelium,” “indefinite dysplasia,” “high-grade dysplasia,” and “esophageal adenocarcinoma.” The search was restricted to studies with human subjects published in the English language. Two authors (M.B., K.R.) independently reviewed the title and abstract of studies identified in the primary search and excluded studies that did not address the research question, based on prespecified exclusion and inclusion criteria. The full text of remaining articles was reviewed to determine whether it contained relevant information. Any discrepancy in article selection was resolved by consensus and in discussion with a co-author.
      The bibliographic sections of the selected articles, as well as systematic and narrative articles on the topic, were also manually searched for additional relevant articles.

      Study selection

      In this meta-analysis, we included cohort studies that met the following criteria: (1) study population consisted of patients with BE-IND undergoing endoscopic surveillance with biopsies without endoscopic therapy; (2) studies that reported progression to HGD and/or EAC as an outcome; and (3) studies that reported total person-years of follow-up to permit calculation of incidence rates of HGD and/or EAC.
      We excluded (1) studies with insufficient data to allow calculation of the incidence rate of HGD and/or EAC, (2) studies that included patients who had previously undergone endoscopic therapy or provided unclear information on whether some of the patients underwent endoscopic therapy, and (3) letters to the editor, editorials, and review articles. In the case of multiple publications from the same cohort, data from the most recent comprehensive report were included. This was the case with Ma et al
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      and Sinh et al.
      • Sinh P.
      • Anaparthy R.
      • Young P.E.
      • et al.
      Clinical outcomes in patients with a diagnosis of “indefinite for dysplasia” in Barrett’s esophagus: a multicenter cohort study.

      Data abstraction and quality assessment

      After identifying relevant studies, data on the study characteristics, patient characteristics, and relevant study outcomes were abstracted onto a standardized form by 2 authors (M.B., K.R.). The quality of the individual studies was independently assessed by 2 authors (M.B., M.J.) using a scale modified from the Newcastle-Ottawa scale for cohort studies.
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      • Wells G.
      • Shea B.
      • O’Connell D.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
      The quality scale consisted of 7 questions, the details of which are provided in Supplementary Table 1 (available online at www.giejournal.org). A score of ≥5, 3 to 4, and ≤2 was considered suggestive of high-quality, medium-quality, and low-quality study, respectively.

      Outcomes assessed

      The primary outcome of the current study was to estimate the incidence rate of combined HGD and/or EAC in patients with BE-IND. The secondary outcome was to estimate the incidence rate of EAC alone in patients with BE-IND. We performed preplanned subgroup analyses based on geographic location (Europe vs North America) and study quality (high vs medium). In addition, to assess whether there was a difference in the reported incidence of progression based on the IND/BE ratio, we performed a stratified analysis using a prespecified cut-off IND/BE ratio of 0.05. Given the lack of IND/BE data from population-based studies, an IND/BE cut-off of 0.05 was believed to be appropriate based on expert opinion (from gastroenterologists and GI pathologists) and nonpopulation-based studies.
      • Waters K.M.
      • Salimian K.J.
      • Voltaggio L.
      • et al.
      Refined criteria for separating low-grade dysplasia and nondysplastic Barrett esophagus reduce equivocal diagnoses and improve prediction of patient outcome: a 10-year review.

      Statistical analysis

      The pooled incidence of HGD and/or EAC per person-year and 95% confidence intervals (CIs) were calculated using the random-effects model described by DerSimonian and Laird,
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      and our application can be seen to fit within their general approach (where effect is measured by the probability of risk). We assessed heterogeneity between study-specific estimates using the inconsistency index (I2 statistic), which estimates the proportion of total variances across studies because of heterogeneity rather than by chance. Values of <30%, 30% to 60%, 61% to 75%, and >75% were considered suggestive of low, moderate, substantial, and considerable heterogeneity, respectively.
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines: 7. Rating the quality of evidence–inconsistency.
      Once heterogeneity was noted, we investigated between-study sources of heterogeneity using subgroup analyses by stratifying the original estimates according to the study characteristics (as described earlier). A P value for differences between subgroups <.10 was considered statistically significant. This meant that stratifying based on those subgroups could potentially explain the heterogeneity observed in the overall analysis. If there were ≥10 studies included in a meta-analysis, we planned to assess for publication bias qualitatively, by visual inspection of a funnel plot, and quantitatively by the Egger test.
      • Easterbrook P.J.
      • Gopalan R.
      • Berlin J.A.
      • et al.
      Publication bias in clinical research.
      All analyses and graphs were performed using Comprehensive Meta-Analysis (CMA) software, version 3 (BioStat, Englewood, NJ, USA).

      Results

      Search results and population characteristics

      From a total of 5716 studies identified by our search strategy, 8 studies
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      were included in the meta-analysis. Forty full-text studies were reviewed for eligibility. Two studies were excluded due to overlapping cohorts with studies already included. Three studies were excluded because they did not report sufficient data to calculate follow-up duration in person-years. The schematic diagram of study selection is illustrated in Figure 1.

      Characteristics and quality of the studies

      Table 1 describes the characteristics and quality of the studies included. Supplementary Table 1 describes the quality assessment of individual studies. Of the studies included, 1 study
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      was population based, 1 study
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      was multicenter, and the remaining were single-center studies. Four studies
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      were from the United States, and 4 studies
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      were from Europe. Overall, 3 studies
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      were considered high quality, and 5 studies
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      were considered medium quality. None were considered low quality.
      Table 1Study and population characteristics
      StudyCountryStudy typeAgeMale %Total no. of patients with BEPatients with BE-IND (total no.)Follow-up timeTotal person-years of follow-upEACEAC and/or HGDQuality
      Chan et al, 2016
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      IrelandRetrospective cohortMean 63.1 ± 11.47013831105.9 years100067High
      Ma et al, 2017
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      USARetrospective cohort54 to 69663541062.3 years22202Medium
      Horvath et al, 2015
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      USARetrospective cohort54 to 8673NR1075 years41725High
      Choi et al, 2015
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      USARetrospective cohort39 to 8678NR963 years174NR5Medium
      Callaway et al, 2015
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      USARetrospective cohortNRNR848797.1 years612NR13Medium
      Kestens et al, 2015
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      HollandRetrospective cohortMean 60.970NR8422585 person- years25853051High
      Sonwalkar et al, 2010
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      UKRetrospective cohort43 to 8175101413.2 years131.224Medium
      Abradu-Berchie et al, 2017
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      UKRetrospective cohortNRNR14360165 person-years165NR2Medium
      BE, Barrett’s esophagus; EAC, esophageal adenocarcinoma; IND, indefinite for dysplasia; HGD, high-grade dysplasia; NR, not reported.

      BE-IND diagnosis and surveillance endoscopy

      In all of the studies included, esophageal biopsy specimens were reviewed by at least 2 expert GI pathologists, and histologic diagnosis was made using the revised Vienna classification.
      • Schlemper R.
      • Riddell R.
      • Kato Yea
      • et al.
      The Vienna classification of gastrointestinal epithelial neoplasia.
      Most of the patients received twice-daily proton pump inhibitor (PPI) therapy and underwent surveillance endoscopies at 3- to 6-month intervals with biopsy specimens obtained per the Seattle protocol.

      HGD and/or EAC in BE-IND

      In the 8 studies
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      that reported the incidence of HGD and/or EAC as an outcome, there were 89 incident cases in 1441 BE-IND patients over 5306.2 person-years of follow-up. The pooled annual incidence of HGD and/or EAC was 1.5 per 100 person-years (95% CI, 1.0-2.0) (Fig. 2). Moderate heterogeneity (I2 = 56.5%) was noted in the analysis.
      Figure thumbnail gr2
      Figure 2Forest plot, high-grade dysplasia and/or EAC in Barrett’s esophagus indefinite for dysplasia. Pooled rate: 1.5 per 100 person-years; I2 = 56.5%. CI, Confidence interval.

      EAC in BE-IND

      In the 5 studies
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      that reported the incidence of EAC as an outcome, there were 40 incident cases in 1266 BE-IND patients over 4520.2 person-years of follow-up. The pooled annual incidence of EAC was 0.6 per 100 person-years (95% CI, 0.1-1.1) (Fig. 3). Considerable heterogeneity (I2= 89.0%) was noted in the analysis.
      Figure thumbnail gr3
      Figure 3Forest plot, EAC in Barrett’s esophagus indefinite for dysplasia. Pooled rate: 0.6 per 100 person-years; I2 = 89%. CI, Confidence interval.

      LGD in BE-IND

      Four studies (1165 BE-IND patients)
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      reported specific data on the incidence of LGD as an outcome. The pooled incidence of LGD was 11.4 per 100 person-years (95% CI, 0.06-0.2; I2=83.6). Only 1 study
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      reported on the regression of BE-IND to NDBE, and therefore a pooled rate could not be calculated. The reported regression of BE-IND to NDBE was 58.4% in that study.

      Subgroup analysis by country and study quality

      Table 2 summarizes the subgroup analysis for the pooled incidence rate of HGD and/or EAC. There was no difference in the incidence rates of HGD and/or EAC in the subgroup analysis based on study location (Europe vs North America: 1.4% vs 1.6%, P = .83) and study quality (high vs medium quality: 1.3% vs 1.7%, P = .48).
      Table 2Subgroup analyses: incidence of HGD and/or EAC in BE-IND
      SubgroupNo. of studiesIncidence of HGD and/or EAC per 100 person-years (95% CI)I2
      Country (P = .82)
      North America
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      4 studies, 388 patients1.6 (0.6-2.5)13.4
      Europe
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      4 studies, 1053 patients,1.4 (0.6-2.3)75.8
      Study quality (P = .48)
      High
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      3 studies, 1059 patients1.3 (0.5-2.1)82
      Medium
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      5 studies, 382 patients1.7 (0.8-2.7)1
      EAC, Esophageal adenocarcinoma; HGD, high-grade dysplasia; BE-IND, Barrett’s esophagus indefinite for dysplasia.
      Table 3 summarizes the subgroup analysis for the pooled incidence rate of EAC. The incidence rate of EAC was higher in the studies from Europe compared with North America, and the difference was statistically significant (0.9% vs 0.1%, P = .01). The incidence rate of EAC was numerically higher in the high-quality studies compared with the medium-quality studies without a statistically significant difference (0.8% vs 0.1%, P = .10). Both analyses were limited by the small number of studies in each subgroup.
      Table 3Subgroup analyses: incidence of EAC in Barrett’s esophagus indefinite for dysplasia
      SubgroupNo. of studiesIncidence of EAC per 100 person-years (95% CI)I2
      Country (P = .01)
      North America
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      2 studies, 213 patients0.1 (0.01-0.5)48.1
      Europe
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      3 studies, 993 patients0.9 (0.5-1.4)39.4
      Study quality (P = .10)
      High
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      3 studies, 1059 patients0.8 (0.3-1.3)54.3
      Medium
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      2 studies, 147 patients0.1 (0.01-0.7)49.6
      EAC, Esophageal adenocarcinoma.
      In the 5 studies that reported data to calculate IND/BE, the ratios were more than the 0.05 cut-off in all of them.
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      On analysis of the studies with IND/BE >0.05, the pooled rate of HGD and/or EAC was 1.2% (95% CI, 0.5-1.9; I2 = 41) and EAC alone was 0.3% (95% CI, 0.1-0.9; I2 = 74). The pooled rates from this analysis were numerically lower than the estimates from the overall analysis but the differences were not statistically significant. A mild decrease in heterogeneity (I2) was also noted in this analysis.

      Sensitivity analysis and publication bias

      One study at a time was excluded sequentially to assess for any potential dominant effect by an individual study. On this analysis, no single study significantly affected the summary estimates. Assessment for publication bias was not performed because there were <10 studies included in the analysis.

      Discussion

      Currently, there are no reliable estimates of progression risk to HGD/EAC in patients with BE-IND. Hence, management strategies for BE-IND are unclear, and endoscopy is not routinely recommended. In this systematic review and meta-analysis of 8 studies with 1441 patients with BE-IND, the estimated incidence of HGD and/or EAC in BE-IND was 1.5 per 100 person-years. The estimated incidence of EAC in BE-IND was 0.6 per 100 person-years.
      The current study is the first systematic review and meta-analysis evaluating the risk of progression in BE-IND. The American Gastroenterological Association guidelines do not recommend a specific surveillance interval for BE-IND.
      • Spechler S.J.
      • Sharma P.
      • Souza R.F.
      • et al.
      American Gastroenterological Association medical position statement on the management of Barrett's esophagus.
      The more recent American College of Gastroenterology (ACG) guidelines recommend that surveillance in BE-IND should follow that of BE-LGD and hence, they suggest a surveillance interval of 12 months in patients with confirmed BE-IND.
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • et al.
      ACG Clinical Guideline: diagnosis and management of Barrett’s esophagus.
      However, the ACG guidelines on BE-IND management are based on expert opinion with a low level of evidence. The current study attempts to fill this evidence gap. A previous meta-analysis of patients with BE-LGD estimated the annual risk of HGD/EAC and EAC as 1.7% and 0.5%, respectively.
      • Singh S.
      • Manickam P.
      • Amin A.V.
      • et al.
      Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta- analysis.
      The current study’s estimates of the risk of HGD/EAC and EAC in BE-IND are similar to the corresponding risk estimates reported for BE-LGD (1.5% vs 1.7% and 0.6% vs 0.5%, respectively). As the progression risks are similar between BE-IND and BE-LGD, surveillance intervals for BE-IND should be similar to BE-LGD. Also, there might be a role for endoscopic therapy in BE-IND similar to BE-LGD if these results are confirmed in larger prospective studies.
      In our subgroup analysis, the incidence rate of EAC in studies from Europe was higher compared with studies from North America (0.9% vs 0.1%, P = .01), and this difference was statistically significant. Although the small number of studies in each subgroup weakens the statistical validity, differences in histologic criteria for the diagnosis of BE-IND between North America and Europe could be a contributing factor. Similar to current findings on BE-IND, European studies have reported a higher risk of malignant progression in BE-LGD compared with North American studies.
      • Curvers W.L.
      • ten Kate F.J.
      • Krishnadath K.K.
      • et al.
      Low-grade dysplasia in Barrett's esophagus: overdiagnosed and underestimated.
      • Duits L.C.
      • Phoa K.N.
      • Curvers W.L.
      • et al.
      Barrett's oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel.
      The pooled incidence of LGD in patients with BE-IND was relatively high at 11.4 per 100 person-years. Our estimate supports active surveillance of patients with BE-IND, because recent ACG guidelines recommend endoscopic therapy in patients with confirmed LGD.
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • et al.
      ACG Clinical Guideline: diagnosis and management of Barrett’s esophagus.
      Data on risk factors for progression in BE-IND, like BE segment length, unifocal versus multifocal dysplasia, presence of hiatal hernia, smoking status, body mass index, and use of nonsteroidal anti-inflammatory drugs, were limited in individual studies. This limited our ability to perform a meta-regression analysis to assess for their influence on progression rates. Four of the studies included reported information on previous use of PPI medications.
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      Based on our meta-regression analysis, previous treatment with PPIs had no significant influence on progression risk in BE-IND (meta-regression 2-tailed P values: PPI treatment = .32 and for no previous treatment with PPI = .23, with no statistical significance to the intercept). Given the small number of studies in this analysis, this observation has to be interpreted with caution. The findings highlight the importance of surveillance in BE-IND irrespective of PPI use.
      This systematic review and meta-analysis has several strengths. These include a systematic literature search with well-defined inclusion criteria, careful exclusion of redundant studies, rigorous evaluation of study quality, calculation of incidence rates by person-years, and subgroup analysis to assess the cause of heterogeneity.
      There were several limitations, most of which are inherent to any meta-analysis. The analyses were done assuming that the incidence rate was constant over time, which may not be accurate. The studies included reported wide variability in the incidence of IND in a cohort of patients with BE with potential for misclassification bias because of interobserver variability in the diagnosis of BE-IND. The confirmation of the IND diagnosis by expert GI pathologists mitigates this to some extent. Studies also did not consistently report endoscopic surveillance intervals, raising concern for inter-study differences.
      Data on risk factors for progression in BE-IND in individual studies were limited. The heterogeneity in the overall analysis was high. Subgroup analysis based on study location and study quality explained the heterogeneity to some extent.
      The current study provides the best available risk estimates that may be used in counseling patients with persistent BE-IND after optimization of anti-reflux treatment. The risk estimates of malignant progression in BE-IND are similar to previously reported risk estimates in BE-LGD. This may be due to the fact that a major proportion of patients who were diagnosed with BE-IND actually had underlying BE-LGD. The relatively high progression rate to LGD (11.4%) noted in our meta-analysis provides some support to this argument. Although endoscopic therapy is currently a management option in BE-LGD, its role in BE-IND is not clear given the limitations of existing data on progression risk in BE-IND. Based on the current study’s risk estimates of progression, patients with BE-IND should be placed on active endoscopic surveillance after their anti-reflux regimen is optimized. Prospective studies to define the natural history of BE-IND are needed to confirm these data.

      Appendix 1

      Epub ahead of print, in-process, and other non-indexed citations, Ovid MEDLINE Daily and Ovid MEDLINE 1946 to present
      Tabled 1
      Searches
      1(barrett* adj (esophagus or oesophagus)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
      2esophageal stenosis/ or esophagitis, peptic/
      31 or 2
      43 and dysplas*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
      53 and (ind or indefinite).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
      63 and atypia.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
      74 or 6
      87 and progress*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
      98 and (carcinoma* or malign* or invasive* or adenocarcinoma*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
      105 or 6 or 9
      1110 and (surveillance or follow* or risk*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
      1210 and ((cohort* or incidence).mp. or follow-up studies/ or prospective*.mp. or retrospective*.mp. or random*.mp.) [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
      1311 or 12
      14remove duplicates from 13
      EMBASE
      Tabled 1
      1(barrett* adj (esophagus or oesophagus)).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]
      2esophageal stenosis/ or esophagitis, peptic/
      31 or 2
      43 and dysplas*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]
      53 and (ind or indefinite).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]
      63 and atypia.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]
      74 or 6
      87 and progress*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]
      98 and (carcinoma* or malign* or invasive* or adenocarcinoma*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]
      105 or 6 or 9
      1110 and (surveillance or follow* or risk*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]
      1210 and ((cohort* or incidence).mp. or follow-up studies/ or prospective*.mp. or retrospective*.mp. or random*.mp.) [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]
      1311 or 12
      14remove duplicates from 13
      15limit 14 to human
      1615 not case report/
      1716 not (letter or note or comment*).pt.
      18*barrett esophagus/ and 17

      Web of Science

      TOPIC: (barrett* SAME (eosphag* OR oesophag* OR metaplas*)) AND TOPIC: (dysplasia* SAME (ind OR indefinite OR "low grade")) AND TOPIC: (progress*) AND TOPIC: (outcome* OR carcinoma* OR adenocarcinoma* OR follow* OR surveill*)

      Scopus

      (TITLE-ABS-KEY (barrett* W/2 (esophag* OR oesophag* OR metaplas*)) AND TITLE-ABS-KEY (dysplas* W/3 (ind OR indefinite OR "low grade")) AND TITLE-ABS-KEY (progress* AND (malign* OR outcome* OR carcinoma* OR adenocarcinoma* OR risk* OR surveill* OR follow* OR incidence)))
      Supplementary Table 1Study quality assessment of individual studies
      QuestionScoring schemeChan et al, 2016
      • Chan G.
      • Chin J.L.
      • O'Brien M.
      • et al.
      Sa1253 Incidence rate and predictors of progression in patients with Barrett's esophagus: experience from a large Irish tertiary centre.
      Ma et al, 2017
      • Ma M.
      • Shroff S.
      • Feldman M.
      • et al.
      Risk of malignant progression in Barrett's esophagus indefinite for dysplasia.
      Horvath et al, 2015
      • Horvath B.
      • Singh P.
      • Xie H.
      • et al.
      Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.
      Choi et al, 2015
      • Choi W.-T.
      • Emond M.J.
      • Rabinovitch P.S.
      • et al.
      “Indefinite for dysplasia” in Barrett’s esophagus: inflammation and DNA content abnormality are significant predictors of early detection of neoplasia.
      Callaway et al, 2015
      • Callaway J.K.
      • Kommineni V.T.
      • Kahn A.
      • et al.
      Tu1564 Indefinite dysplasia in Barrett's esophagus confers a similar risk of progression to high grade dysplasia or esophageal adenocarcinoma as low grade dysplasia [abstract].
      Kestens et al, 2015
      • Kestens C.
      • Leenders M.
      • Offerhaus G.J.A.
      • et al.
      Risk of neoplastic progression in Barrett’s esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study.
      Sonwalkar et al, 2010
      • Sonwalkar S.A.
      • Rotimi O.
      • Scott N.
      • et al.
      A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase).
      Abradu-Berchie et al, 2017
      • Abradu-Berchie B.
      • Ragunath K.
      • Card T.
      • et al.
      PWE-116 Progression of Barrett's oesophagus with low-grade dysplasia and indefinite for dysplasia.
      Representative of the average adult in the community1 point, population-based studies; 0.5 point, multicenter studies; 0 point, single-center hospital-based study00000100.5
      Cohort size1 point, cohort size >2000; 5 points, cohort size 100-200; 0 point, cohort size <10011100100
      Histologic confirmation of BE1 point, confirmed by consensus of 2 expert pathologists; 0.5 point, reviewed by 1 expert pathologist; 0 point, reviewed by community pathologist only or not reported in the study11111111
      Follow-up of cohort for outcome to occur1 point, mean follow-up of entire cohort >5 years; 0.5 point, cohort follow-up 3-5 years; 0 point, mean follow-up of cohort <3 years1010100.50.5
      Information on duration of follow-up of patients with BE-IND1 point, reported in study in total person-years; 0.5 point, reported as mean follow-up of BE-IND cohort; 0 point, imputed from entire BE cohort1110.50.510.50.5
      Attrition rate1 point, >80% of cohort followed up; 0.5 point, 60%-80% of cohort followed up; 0 point, >40% lost to follow-up00111111
      Information on progression of BE-IND1 point, adequate information on rate of progression from BE-IND to BE-HGD and EAC separately; 0.5 point, only information on rate of progression to EAC, without information on BE-HGD11111111
      TotalTotal score (maximum = 7; high quality ≥5; medium quality 3-4; low quality ≤2)5463.54.5644.5
      BE, Barrett's esophagus; IND, indefinite for dysplasia; HGD, high-grade dysplasia; EAC, esophageal adenocarcinoma.

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