American Gastroenterological Association Technical Review on the Management of Barrett's Esophagus

Abstract

This article has an accompanying continuing medical education activity on page e13. Learning Objective: At the end of this activity, the successful learner should: 1Identify the risk factors associated with development of esophageal adenocarcinoma.2Determine who should undergo surveillance after being diagnosed with Barrett's esophagus.3Assess the role of endoscopic therapy for patients with Barrett's esophagus. The aim of evidence-based medicine is to improve the quality of health care by integrating the best research evidence with clinical expertise and patient values. Evidence-based clinical guidelines are sets of recommendations intended to assist health care providers and patients in selecting the best management for common clinical situations while accounting for patient-specific circumstances. In addition to providing optimal, patient-centered care and improved outcomes, guidelines can reduce practice variability, identify gaps in evidence, enhance efficiency of resource use, and facilitate development of outcome and performance measures. The American Gastroenterological Association Institute (AGAI) Medical Position Statement Procedure Manual, released in 2007, endorses the 2003 version of the US Preventive Services Task Force system to grade strength of recommendations. Although an excellent standard for producing recommendations regarding preventive services, the US Preventive Services Task Force has limitations when used to assess interventions that are not based on prevention. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (http://www.gradeworkinggroup.org/index.htm) has been adopted by several national and international societies and was constructed to address the shortcomings of existing grading systems, including the US Preventive Services Task Force system. GRADE separates quality of evidence from the strength of recommendation to ensure that the magnitude of benefits and harms is assessed as rigorously as the efficacy of interventions. With regard to strength of recommendations, GRADE has 2 categories: strong and weak (Table 1). Strong recommendations are meant to signify interventions that should be received by most individuals with a particular condition and can be adopted as policy in most circumstances. Weak recommendations require individualized scrutiny of the evidence and policy making would require substantial debate and involvement from multiple stakeholders. The classification requires consideration of 4 factors: quality of evidence, uncertainty about the balance between desirable and undesirable effects, variability in values and preferences, and uncertainty about whether the intervention represents a wise use of resources (Table 2). Of importance to our current health care debate is that interventions receiving a strong recommendation may be targets for development of performance measures.Table 1GRADE: Strength of RecommendationStrength of recommendationClinical implicationPolicy implicationStrong“Do it” or “Don't do it”Adherence to this recommendation could be used as a quality or performance measureWeak“Probably do it” or “Probably don't do it”Recommendation not suitable for quality or performance measure Open table in a new tab Table 2GRADE: Quality of EvidenceQuality of evidenceEstimate of certainty of effectHighFurther research is very unlikely to change the estimate of effectModerateFurther research is likely to have an important impact and may change the estimate of effectLowFurther research is very likely to have an important impact and is likely to change the estimate of effectVery lowAny estimate of effect is uncertain Open table in a new tab Quality of evidence is assessed on a 4-point scale: high, moderate, low, and very low. Instead of being classified strictly on the basis of study design (ie, randomized, controlled clinical trials automatically receiving “high” quality marks), these levels reflect the likelihood that further research would change our confidence in the estimate of the beneficial effect of a particular intervention. Five factors that determine quality include study limitations, inconsistency of results between studies, indirectness (generalizability) of results, imprecision, and publication bias. For this reason, randomized, controlled clinical trials that have methodological flaws may be downgraded, whereas well-done observational studies that have large effect sizes (ie, relative risk [RR] >2–5 or <0.5–0.2) may be upgraded. The AGAI Clinical Practice and Quality Management Committee (CPQMC) chooses a topic by consensus discussion, votes after reviewing a list of potential topics derived from AGAI member recommendations, and develops the specific questions the guideline will answer. The CPQMC committee chair, with support of AGA staff, then contacts the AGAI clinical counsel chair and requests the input of the counsel for authorship and external reviewers. Authors are selected and write a technical review (TR), which is an evidence-based document that provides the basis for clinical practice recommendations. For each of the specific questions raised by the CPQMC, authors conduct an independent systematic review of the literature using published guidelines (PRISMA). Articles selected for inclusion in the TR are based on a priori inclusion and exclusion criteria agreed on by all authors. Data extraction is shared among TR authors, and the individual study and summary results are reviewed and approved by all authors. The search terms for each topic included in the TR are included in the Appendix. It is not the function of the TR to provide a summary estimate for each variable included in the review. For this reason, results are summarized in the text of the TR and not subjected to a formal meta-analysis. The draft TR is compiled by the lead author and approved by all authors before submission for publication. A medical position panel composed of the TR authors, additional content experts, practicing gastroenterologists, other specialists (eg, surgeon, pathologist), a patient representative, a payer representative, and American Gastroenterological Association staff meet through a series of face-to-face and telephone meetings to construct the medical position statement, which is based on the TR but also reflects these discussions by the medical position panel. The medical position panel approves the medical position statement, after which this document and the TR are reviewed by the CPQMC. Based on the vote of the committee, a recommendation is submitted to the AGAI Governing Board, which provides final approval. When approval is granted, the medical position statement is published in Gastroenterology and is also posted on the American Gastroenterological Association web site. The objectives of the AGAI TR on the management of patients with Barrett's esophagus were to evaluate diagnostic and management strategies for patients at risk for or diagnosed with Barrett's esophagus. Specifically, 10 broad questions were developed by interaction among the authors, the AGAI, the Clinical Practice and Quality Management Committee, and representatives from the AGAI Council. The questions were designed to encapsulate the major management issues leading to consultations for Barrett's esophagus and esophageal adenocarcinoma in clinical practice in 2010. For each question, a comprehensive literature search was conducted, pertinent evidence reviewed, and a summary of relevant data produced. The conclusions of this review were based on the best available evidence or, in the absence of quality evidence, the expert opinion of the authors of the TR. Authorities generally have defined Barrett's esophagus conceptually as the condition in which metaplastic columnar epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus.1Sharma P. McQuaid K. Dent J. et al.AGA Chicago WorkshopA critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop.Gastroenterology. 2004; 127: 310-330Google Scholar, 2Vakil N. van Zanten S.V. Kahrilas P. et al.Global Consensus GroupThe Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.Am J Gastroenterol. 2006; 101: 1900-1920Google Scholar, 3Wang K.K. Sampliner R.E. Practice Parameters Committee of the American College of GastroenterologyUpdated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus.Am J Gastroenterol. 2008; 103: 788-797Google Scholar, 4Shaheen N.J. Richter J.E. Barrett's oesophagus.Lancet. 2009; 373: 850-861Abstract Full Text Full Text PDF Scopus (272) Google Scholar Unfortunately, this deceptively simple conceptual definition does not translate readily into clinically useful diagnostic criteria for 2 major reasons. (1) There are no universally accepted, precise, and validated landmarks that delimit the distal extent of the esophagus (ie, that identify the gastroesophageal junction [GEJ]). If it cannot be determined precisely where the esophagus ends and the stomach begins, then it may not be possible to ascertain the type of epithelium that lines the most distal esophagus. (2) There is no way to verify that gastric-type columnar epithelia found in the distal esophagus are metaplastic. These 2 factors become major confounders when attempting to establish a diagnosis of Barrett's esophagus for patients with only short segments of esophageal columnar epithelium. The diagnosis of Barrett's esophagus can be suspected when, during endoscopic examination, columnar epithelium (which has a characteristic endoscopic appearance) is observed to extend above the GEJ into the esophagus. Of course, this diagnostic suspicion is based on the assumption that the endoscopist can identify the GEJ. Few studies have addressed specifically the issue of how to localize the GEJ, and even those that have the accuracy of the criteria used cannot be assessed meaningfully in the absence of a validated landmark (ie, a gold standard). Western endoscopists generally identify the GEJ as the most proximal extent of the gastric folds, a landmark first proposed in 1987 in a report of a small and methodologically flawed study.5McClave S.A. Boyce Jr, H.W. Gottfried M.R. Early diagnosis of columnar-lined esophagus: a new endoscopic criterion.Gastrointest Endosc. 1987; 33: 413-416Google Scholar The location of the proximal extent of the gastric folds is affected by respiration, gut motor activity, and the degree of distention of the esophagus and stomach, all of which can change from moment to moment. Endoscopists in Asia often use the distal extent of the palisade vessels, which are fine longitudinal veins located in the lamina propria of the distal esophagus, as their landmark for the GEJ.6Choi do W. Oh S.N. Baek S.J. et al.Endoscopically observed lower esophageal capillary patterns.Korean J Intern Med. 2002; 17: 245-248Google Scholar, 7Vianna A. Hayes P.C. Moscoso G. et al.Normal venous circulation of the gastroesophageal junction A route to understanding varices.Gastroenterology. 1987; 93: 876-889Crossref Scopus (185) Google Scholar The palisade vessels can be obscured by esophagitis, their level of termination can be irregular and difficult to localize with precision, and conceptually it is not clear why the distal end of the palisade vessels should be considered the end of the esophagus. Thus, the scientific validity of the 2 most widely used landmarks for the GEJ is dubious. The issue of the “best” landmark for the GEJ is likely to remain controversial indefinitely because, ultimately, the choice of any such landmark will be arbitrary. The majority of published studies on Barrett's esophagus conducted over the past 20 years have used the proximal extent of the gastric folds as the landmark for the GEJ and, in the absence of compelling data for the use of alternative markers, we presently recommend the continued use of this landmark despite its shortcomings. Barrett's esophagus is judged to develop through the process of metaplasia in which one adult cell type replaces another. For reasons that are not clear, Barrett's metaplasia is predisposed to cancer development. Three types of columnar epithelia have been described in Barrett's esophagus: (1) a gastric fundic-type epithelium that has mucus-secreting cells, parietal cells, and chief cells; (2) a cardia-type (also known as junctional-type) epithelium composed almost exclusively of mucus-secreting cells; and (3) an intestinal-type epithelium (sometimes called specialized columnar epithelium or specialized intestinal metaplasia) that contains prominent goblet cells.8Paull A. Trier J.S. Dalton M.D. et al.The histologic spectrum of Barrett's esophagus.N Engl J Med. 1976; 295: 476-480Google Scholar The fundic- and cardia-type epithelia in Barrett's esophagus can be morphologically indistinguishable from columnar epithelia found in the stomach. If biopsy specimens of suspected Barrett's esophagus reveal only fundic- and cardia-type epithelia, then it can be difficult to establish that those epithelial types are metaplastic because (1) biopsy sampling error can result in inadvertent biopsy of the stomach instead of the esophagus, especially when only short segments of columnar epithelium appear to extend above the GEJ, and (2) some authorities have argued that the normal distal esophagus can have short segments of a gastric-type columnar lining.9Hayward J. The lower end of the oesophagus.Thorax. 1961; 16: 36-41Google Scholar With no precise landmark for the GEJ, it is difficult to support or refute that contention. If biopsy specimens of suspected Barrett's esophagus reveal intestinal-type epithelium, in contrast, then there is little doubt that the epithelium is abnormal and metaplastic. This finding does not obviate the issue of biopsy sampling error, however, because intestinal metaplasia is common in the stomach that is chronically infected with Helicobacter pylori.10Spechler S.J. Intestinal metaplasia at the gastroesophageal junction.Gastroenterology. 2004; 126: 567-575Google Scholar Intestinal-type epithelium can be readily identified by the pathologist and, unlike the gastric-type epithelia, intestinal-type epithelium is clearly abnormal when located in the esophagus. Furthermore, early reports suggested that the intestinal-type epithelium in Barrett's esophagus was the one predisposed to malignancy. For those reasons, practical more than scientific or conceptual, investigators and clinicians adopted the policy of requiring the demonstration of intestinal metaplasia in esophageal biopsy specimens as a sine qua non for the diagnosis of Barrett's esophagus. However, recent findings have challenged the validity of that practice. There are data to suggest that cardia-type epithelium may not be normal, but rather may be a metaplastic lining that develops as a consequence of chronic gastroesophageal reflux disease (GERD).11Chandrasoma P. Pathophysiology of Barrett's esophagus.Semin Thorac Cardiovasc Surg. 1997; 9: 270-278Google Scholar Histochemical and genetic studies of cardia-type epithelium have revealed molecular abnormalities, similar to those found in specialized intestinal metaplasia, that may predispose to cancer development.12Liu W. Hahn H. Odze R.D. et al.Metaplastic esophageal columnar epithelium without goblet cells shows DNA content abnormalities similar to goblet cell-containing epithelium.Am J Gastroenterol. 2009; 104: 816-824Google Scholar, 13Hahn H.P. Blount P.L. Ayub K. et al.Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus.Am J Surg Pathol. 2009; 33: 1006-1015Google Scholar Recent clinical studies also suggest that cardia-type epithelium has malignant potential. In one such study of 141 patients who underwent endoscopic mucosal resection (EMR) for small esophageal adenocarcinomas, 71% had cardia-type epithelium, not intestinal metaplasia, found adjacent to the cancer, and 57% had no intestinal metaplasia whatsoever found in the EMR specimen.14Takubo K. Aida J. Naomoto Y. et al.Cardiac rather than intestinal-type background in endoscopic resection specimens of minute Barrett adenocarcinoma.Hum Pathol. 2009; 40: 65-74Google Scholar The columnar-lined esophagus has clinical importance only because it predisposes to the development of esophageal cancer. The debate about whether patients who have only cardia-type epithelium lining the distal esophagus have “Barrett's esophagus” is primarily a semantic issue. The key unanswered clinical question for those patients is this: What is the risk of developing esophageal cancer? The great majority of studies on the risk of cancer in Barrett's esophagus have included patients with specialized intestinal metaplasia either primarily or exclusively.15Shaheen N.J. Crosby M.A. Bozymski E.M. et al.Is there publication bias in the reporting of cancer risk in Barrett's esophagus?.Gastroenterology. 2000; 119: 333-338Abstract Full Text Full Text PDF Scopus (740) Google Scholar Although recent data suggest that cardia-type epithelium may well predispose to malignancy, the magnitude of that risk is not yet clear. A reasonable estimate of cancer risk is needed to make rational management decisions for patients with Barrett's esophagus, and no such estimate is available for patients who have only cardia-type epithelium in their columnar-lined esophagus. Despite reasonable arguments supporting the concept that Barrett's esophagus might be defined by the presence of cardia-type as well as by intestinal-type epithelium in the esophagus, there are substantial practical reasons for not adopting this definition into clinical practice at this time. The inclusion of patients with cardia-type epithelium under the rubric of “Barrett's esophagus” would substantially increase the number of patients with that disorder, which would substantially increase treatment costs. The benefits of surveillance and treatment programs for Barrett's esophagus are debated, even for patients with intestinal metaplasia, whose cancer risk is far better defined. The likelihood of finding intestinal-type epithelium in Barrett's esophagus varies directly with the extent of the esophageal columnar lining, and the issue of whether to consider cardia-type epithelium a marker for Barrett's esophagus usually concerns only patients with short segments of esophageal columnar epithelium (generally segments considerably less than 3 cm in extent). The clinical benefit of biopsy sampling for patients with such short segments of esophageal columnar epithelium has not been established. Any definition of Barrett's esophagus necessarily will have an arbitrary component. If Barrett's esophagus is to be considered a medical condition rather than merely an anatomic curiosity, then it should have clinical importance. The columnar-lined esophagus has clinical importance only if it predisposes to esophageal cancer. Therefore, we believe that Barrett's esophagus can be defined conceptually as the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus. Presently, intestinal metaplasia is the only one of the 3 types of esophageal columnar epithelia described that clearly predisposes to malignancy; therefore, we suggest that the term “Barrett's esophagus” presently should be used only for patients who have intestinal metaplasia in the esophagus. Circumstantial evidence suggests that cardia-type epithelium also may be predisposed to cancer development, but presently that predisposition has not been established and there are insufficient data to make meaningful recommendations regarding the management of patients who have a columnar-lined esophagus with cardia-type epithelium alone. If future studies establish a malignant predisposition for cardia-type epithelium, then those patients also can be considered to have Barrett's esophagus by our proposed definition. For now, however, only patients with intestinal-type columnar metaplasia in the esophagus are known to have an increased cancer risk, and only those patients meet our criteria for the diagnosis of Barrett's esophagus. Barrett's esophagus has been categorized as long segment (when the metaplastic epithelium extends at least 3 cm above the GEJ) or short segment (when there is <3 cm of metaplastic epithelium lining the esophagus).16Sharma P. Morales T.G. Sampliner R.E. Short segment Barrett's esophagus The need for standardization of the definition and of endoscopic criteria.Am J Gastroenterol. 1998; 93: 1033-1036Google Scholar Another more recently proposed system for categorizing Barrett's esophagus, the Prague C and M criteria, identifies both the circumferential extent (C) and the maximum extent (M) of Barrett's metaplasia.17Sharma 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: 1392-1399Google Scholar One study has shown excellent interobserver agreement among endoscopists using the Prague C and M criteria when columnar epithelium extends at least 1 cm above the GEJ but poor agreement for shorter segments of esophageal columnar lining.17Sharma 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: 1392-1399Google Scholar There may be clinical value in measuring the extent of Barrett's metaplasia visualized during endoscopic examination (ie, the distance between the GEJ and the squamocolumnar junction in the esophagus). Data suggest that the likelihood of finding intestinal metaplasia in the columnar-lined esophagus and the magnitude of the cancer risk vary directly with the extent of the metaplastic lining (see the following text). For patients found to have dysplasia in Barrett's esophagus, furthermore, the extent of metaplasia is a factor that may influence the choice among the therapeutic options (see the following text). Therefore, we advocate the use of a system, like the Prague C and M criteria, that provides information on the extent of Barrett's metaplasia. However, the clinical benefit of using any proposed endoscopic system for classifying Barrett's esophagus has not been established by formal investigation and, presently, patients with any extent of intestinal metaplasia are managed similarly. A number of older reports linking Barrett's esophagus to esophageal adenocarcinoma described an inordinately high incidence of cancer, in the range of 20 to 40 per 1000 person-years (2%–4% per year).18Robertson C.S. Mayberry J.F. Nicholson D.A. et al.Value of endoscopic surveillance in the detection of neoplastic change in Barrett's oesophagus.Br J Surg. 1988; 75: 760-763Google Scholar, 19Reid B.J. Blount P.L. Rubin C.E. et al.Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort.Gastroenterology. 1992; 102: 1212-1219Crossref Google Scholar, 20Bartlesman J.F. Hameeteman W. Tytgat G.N. Barrett's oesophagus.Eur J Cancer Prev. 1992; 1: 323-325Google Scholar A variety of confounding factors, including selection bias, the inclusion of prevalent cancers, and publication bias, may have contributed to the overestimation of cancer risk in those studies.15Shaheen N.J. Crosby M.A. Bozymski E.M. et al.Is there publication bias in the reporting of cancer risk in Barrett's esophagus?.Gastroenterology. 2000; 119: 333-338Abstract Full Text Full Text PDF Scopus (740) Google Scholar Subsequent reports of larger series generally have described a substantially lower cancer risk for patients with Barrett's esophagus, but even some modern reports describe very high cancer incidence rates.21Aldulaimi D.M. Cox M. Nwokolo C.U. et al.Barrett's surveillance is worthwhile and detects curable cancers A prospective cohort study addressing cancer incidence, treatment outcome and survival.Eur J Gastroenterol Hepatol. 2005; 17: 943-950Google Scholar National health statistics cannot be used to estimate cancer risk because the denominator (ie, the total number of persons with Barrett's esophagus in the general population) is not known. Nevertheless, a reasonable estimate of the incidence of cancer in Barrett's esophagus is needed to formulate rational management strategies for patients with this condition. A number of systematic reviews of studies on the incidence of cancer in patients with Barrett's esophagus have been published.15Shaheen N.J. Crosby M.A. Bozymski E.M. et al.Is there publication bias in the reporting of cancer risk in Barrett's esophagus?.Gastroenterology. 2000; 119: 333-338Abstract Full Text Full Text PDF Scopus (740) Google Scholar, 22Chang E.Y. Morris C.D. Seltman A.K. et al.The effect of antireflux surgery on esophageal carcinogenesis in patients with Barrett esophagus: a systematic review.Ann Surg. 2007; 246: 11-21Google Scholar, 23Thomas T. Abrams K.R. De Caestecker J.S. et al.Meta analysis: cancer risk in Barrett's oesophagus.Aliment Pharmacol Ther. 2007; 26: 1465-1477Google Scholar, 24Yousef F. Cardwell C. Cantwell M.M. et al.The incidence of esophageal cancer and high-grade dysplasia in Barrett's esophagus: a systematic review and meta-analysis.Am J Epidemiol. 2008; 168: 237-249Google Scholar A recent review described outcomes for 47 studies that met inclusion criteria from an initial search that yielded 7780 publications from MEDLINE and EMBASE databases (years 1950–2006).24Yousef F. Cardwell C. Cantwell M.M. et al.The incidence of esophageal cancer and high-grade dysplasia in Barrett's esophagus: a systematic review and meta-analysis.Am J Epidemiol. 2008; 168: 237-249Google Scholar The overall estimate of cancer incidence was based on 209 cancers discovered in 11,279 patients with Barrett's esophagus who were followed up for 47,496 person-years. The average incidence of cancer was 6.1 per 1000 person-years, but this estimate may have been spuriously high because it included patients in whom cancer was discovered within the first year after the diagnosis of Barrett's esophagus. Such patients likely had prevalent cancers that were missed on their initial endoscopic examinations. After adjusting the results to exclude those patients, the incidence of cancer was 5.3 per 1000 person-years (0.5% per year), an estimate well aligned with the results of prior systematic reviews. Among 4 studies published since the aforementioned systematic review was a report of a cohort of 502 patients with Barrett's esophagus from Leeds in the United Kingdom.25Cook M.B. Wild C.P. Everett S.M. et al.Risk of mortality and cancer incidence in Barrett's esophagus.Cancer Epidemiol Biomarkers Prev. 2007; 16: 2090-2096Google Scholar The annual incidence of cancer among patients who had Barrett's esophagus with specialized intestinal metaplasia was 16 per 1000 person-years (1.6% per year). Another single-center cohort from Birmingham in the United Kingdom calculated an incidence of 3.1 per 1000 person-years (0.3% per year) based on 3 cancers diagnosed among 188 patients with Barrett's esophagus.26Cooper B.T. Chapman W. Neumann C.S. et al.Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence.Aliment Pharmacol Ther. 2006; 23: 727-733Google Scholar A third study from the United Kingdom reported statistics from a multicenter national registry involving 738 patients with a combined follow-up of 3697 years. The overall annual incidence of esophageal adenocarcinoma was 0.5% (95% confidence interval [CI], 0.3–0.8).27Gatenby P.A. Ramus J.R. Caygill C.P. et al.Treatment modality and risk of development of dysplasia and adenocarcinoma in columnar-lined esophagus.Dis Esophagus. 2009; 22: 133-142Google Scholar Finally, an endoscopic and pathology-based database in Spain was retrospectively examined to calculate a cancer risk in patients with Barrett's esophagus of 5.2 per 1000 person-years (0.5% per year).28Alcedo J. Ferrandez A. Arenas J. et al.Trends in Barrett's esophagus diagnosis in Southern Europe: implications for surveillance.Dis Esophagus. 2009; 22: 239-248Google Scholar The risk of cancer in Barrett's esophagus appears to vary with the extent of esophageal metaplasia; therefore, patients with long-segment disease may have a higher incidence of adenocarcinoma than those with short-segment Barrett's esophagus.23Thomas T. Abrams K.R. De Caestecker J.S. et al.Meta analysis: cancer risk in Barrett's oesophagus.Aliment Pharmacol Ther. 2007; 26: 1465-1477Google Scholar In the aforementioned Spanish cohort, for example, the annual risk of esophageal adenocarcinoma was 0.57% for patients with long-segment Barrett's esophagus compared with only 0.26% for patients with short-segment disease.28Alcedo J. Ferrandez A. Arenas J. et al.Trends in Barrett's esophagus diagnosis in Southern Europe: implications for surveillance.Dis Esophagus. 2009; 22: 239-248Google Scholar The risk of cancer development also is lower in women than in men with Barrett's esophagus (4.5 vs 10.2 cancers per 1000 person-years).24Yousef F. Cardwell C. Cantwell M.M. et al.The incidence of esophageal cancer and high-grade dysplasia in Barrett's esophagus: a systematic review and meta-analysis.Am J Epidemiol. 2008; 168: 237-249Google Scholar The precise risk of cancer in Barrett's esophagus remains unclear. Reported estimates of cancer risk continue to vary widely, and it is not clear how biases, statistical aberrations, and regional differences in incidence rates contribute to the disparities among the published reports. Methodologically, larger studies (ie, 500 or more person-years of obs