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Barrett Esophagus

      Abstract

      Barrett esophagus is a metaplastic change in the lining of the distal esophageal epithelium, characterized by replacement of the normal squamous epithelium by specialized intestinal metaplasia. The presence of Barrett esophagus increases the risk of esophageal adenocarcinoma several-fold. Esophageal adenocarcinoma is a malignancy with rapidly rising incidence and persistently poor outcomes when diagnosed after the onset of symptoms. Risk factors for Barrett esophagus include chronic gastroesophageal reflux, central obesity, white race, male gender, older age, smoking, and a family history of Barrett esophagus or esophageal adenocarcinoma. Screening for Barrett esophagus in those with several risk factors followed by endoscopic surveillance to detect dysplasia or adenocarcinoma is currently recommended by society guidelines. Minimally invasive nonendoscopic tools for the early detection of Barrett esophagus are currently being developed. Multimodality endoscopic therapy—using a combination of endoscopic resection and ablation techniques—for the treatment of dysplasia and early adenocarcinoma is successful in eliminating intestinal metaplasia and preventing progression to adenocarcinoma, with outcomes comparable to those after esophagectomy. Risk stratification of those diagnosed with Barrett esophagus is a challenge at present, with active research focused on identifying clinical and biomarker panels to identify those with low and high risk of progression. This narrative review highlights some of the challenges and recent progress in this field.

      Abbreviations and Acronyms:

      BE (Barrett esophagus), CR-IM (complete remission of intestinal metaplasia), EAC (esophageal adenocarcinomas), EMR (endoscopic mucosal resection), ESD (endoscopic submucosal dissection), HGD (high-grade dysplasia), IM (intestinal metaplasia), LGD (low-grade dysplasia), PPI (proton pump inhibitor), RFA (radiofrequency ablation)
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      Learning Objectives: On completion of this article, you should be able to (1) obtain state of the art information related to screening and surveillance in Barrett esophagus, (2) acquire a good understanding of the various modalities of treatment available for dysplastic Barrett esophagus and early esophageal neoplasia, and (3) identify the key best practices and guideline based recommendations for management of Barrett esophagus.
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      Dr Iyer has received research funding from Exact Sciences, C2 Therapeutics, and Medtronic. He has received consulting fees from Medtronic and Symple Surgical. Dr Kaul has received research funding from CSA Medical and is a consultant for Medtronic, Olympus, CSA Medical, and Cook-Medical.
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      Barrett esophagus (BE) refers to the metaplastic transformation of esophageal squamous epithelium to specialized columnar epithelium with intestinal metaplasia in the distal esophagus. This is thought to occur as a consequence of chronic injury, likely mediated by reflux of gastric contents.
      • Spechler S.J.
      • Souza R.F.
      Barrett's esophagus.
      The significance of BE lies in it being the strongest risk factor for and precursor of most esophageal adenocarcinomas (EAC). It is presumed that EAC arises as the end result of a stepwise transformation from metaplasia to dysplasia (low grade and high grade) to carcinoma.
      • Cameron A.J.
      • Carpenter H.A.
      Barrett's esophagus, high-grade dysplasia, and early adenocarcinoma: a pathological study.
      • Cameron A.J.
      • Zinsmeister A.R.
      • Ballard D.J.
      • Carney J.A.
      Prevalence of columnar-lined (Barrett's) esophagus: comparison of population-based clinical and autopsy findings.
      The clinical significance of BE is related to the increasing incidence of EAC over the past few decades, relative to other solid malignancies. This increase has been estimated to be approximately 600% over the past 3 to 4 decades. This increased incidence has also been paralleled by an increase in disease related mortality.
      • Hur C.
      • Miller M.
      • Kong C.Y.
      • et al.
      Trends in esophageal adenocarcinoma incidence and mortality.
      The outcomes of patients with EAC diagnosed after the onset of symptoms remains grim, with a 5-year survival not exceeding 20%. This has remained relatively unchanged over the past several decades.
      This situation has led to substantial interest in understanding the risk factors for BE and early detection followed by surveillance for the detection of prevalent /incident dysplasia and adenocarcinoma. Substantially improved outcomes (5-year survival rates greater than 80%) in patients diagnosed with T1 esophageal adenocarcinoma (treated endoscopically or surgically)
      • Prasad G.A.
      • Wu T.T.
      • Wigle D.A.
      • et al.
      Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus.
      — and randomized trials showing the ability of endoscopic ablation techniques to eliminate BE in up to 80% of patients and reduce the risk of progression to EAC
      • Shaheen N.J.
      • Sharma P.
      • Overholt B.F.
      • et al.
      Radiofrequency ablation in Barrett's esophagus with dysplasia.
      • Phoa K.N.
      • van Vilsteren F.G.
      • Weusten B.L.
      • et al.
      Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.
      —have added further interest and momentum to these efforts.

      Diagnosis

      Normally, the esophagus is lined by squamous epithelium (which appears pale white endoscopically). Columnar metaplasia is reflected by change of this epithelium to pale pink columnar metaplasia (Figure 1). The diagnosis of BE requires 2 components. The first component is that of columnar metaplasia measuring at least 1 cm above the gastric folds (the anatomic landmark for the gastroesophageal junction). The second component is that of intestinal metaplasia characterized by the presence of goblet cells in biopsies obtained from the area of columnar metaplasia at endoscopy (Figure 2).
      • Spechler S.J.
      • Souza R.F.
      Barrett's esophagus.
      Fulfillment of both of these criteria is essential to the diagnosis of BE.
      Figure thumbnail gr1
      Figure 1Endoscopic appearance of Barrett esophagus. (A) Squamous epithelium. (B) Columnar metaplasia suggestive of Barrett esophagus.
      Figure thumbnail gr2
      Figure 2Diagnostic criteria for BE. Endoscopic ( >1 cm of columnar metaplasia in the distal esophagus) and histological criteria (intestinal metaplasia on histology) need to be met.
      • Spechler S.J.
      • Souza R.F.
      Barrett's esophagus.
      Of note, the second criterion has been deemed to be optional in some society recommendations such as the British Society of Gastroenterology. Recent guidelines from the American College of Gastroenterology
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • Gerson L.B.
      ACG clinical guideline: diagnosis and management of Barrett's esophagus.
      have, however, retained the requirement for intestinal metaplasia to be seen on histology, given that cohort studies have demonstrated a substantially lower risk of progression to EAC in the absence of intestinal metaplasia.
      • Bhat S.
      • Coleman H.G.
      • Yousef F.
      • et al.
      Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study.
      Careful examination of the gastroesophageal junction and distal esophagus is critical to making appropriate diagnoses of BE. The endoscopic criteria for BE was set at 1 cm of columnar mucosa in the tubular esophagus, given previous studies documenting poor inter-agreement among endoscopists for lengths less than 1 cm.
      • Sharma 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.
      In addition, population-based
      • Jung K.W.
      • Talley N.J.
      • Romero Y.
      • et al.
      Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett’s esophagus: a population-based study.
      and multicenter cohort studies
      • Thota P.N.
      • Vennalaganti P.
      • Vennelaganti S.
      • et al.
      Low risk of high-grade dysplasia or esophageal adenocarcinoma among patients with Barrett's esophagus less than 1 cm (irregular Z line) within 5 years of index endoscopy.
      have shown that the risk of progression to dysplasia or adenocarcinoma in patients with less than 1 cm of columnar mucosa in the distal esophagus is substantially lower than that of patients meeting criteria for the diagnosis of BE. Moreover, studies have shown that a substantial proportion of patients diagnosed with BE in the community (up to 33%) can have this diagnosis reversed on careful examination by well-trained gastroenterologists.
      • Ganz R.A.
      • Allen J.I.
      • Leon S.
      • Batts K.P.
      Barrett's esophagus is frequently overdiagnosed in clinical practice: results of the Barrett's Esophagus Endoscopic Revision (BEER) study.
      This is particularly important, given implications of a Barrett diagnosis in terms of the need for endoscopic surveillance with associated procedural risks, costs, and adverse effects on health care-related quality of life and, potentially, the ability to obtain health insurance.
      • Rubenstein J.H.
      • Inadomi J.M.
      Defining a clinically significant adverse impact of diagnosing Barrett's esophagus.
      • Shaheen N.J.
      • Dulai G.S.
      • Ascher B.
      • Mitchell K.L.
      • Schmitz S.M.
      Effect of a new diagnosis of Barrett's esophagus on insurance status.
      A reporting system for BE has been developed (Prague Classification, Supplemental Figure 1) and may help in making reporting BE length and endoscopic appearance more uniform. It was developed using an international consortium of experts.
      • Sharma 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.
      The BE segment length is expressed as the maximal (M) and circumferential (c) components.

      Epidemiology and Risk Factors

      Several studies have attempted to assess the prevalence of BE in different populations. Large population based studies in Europe (Scandinavia
      • Ronkainen J.
      • Aro P.
      • Storskrubb T.
      • et al.
      Prevalence of Barrett's esophagus in the general population: an endoscopic study.
      and Italy
      • Zagari R.M.
      • Fuccio L.
      • Wallander M.A.
      • et al.
      Gastro-oesophageal reflux symptoms, oesophagitis and Barrett's oesophagus in the general population: the Loiano-Monghidoro study.
      ) have screened the general population with upper endoscopy and have reported BE prevalence estimates ranging from 1.3 to 1.6%. However, a more recent population based screening study in Olmsted County, Minnesota, reported that 8.5% of adults above the age of 50 had evidence of BE.
      • Sami S.S.
      • Dunagan K.T.
      • Johnson M.L.
      • et al.
      A randomized comparative effectiveness trial of novel endoscopic techniques and approaches for Barrett's esophagus screening in the community.
      Other cross-sectional studies from tertiary care institutions in the Unites States have also reported higher rates of BE prevalence from 8 to 17%.
      • Gerson L.B.
      • Shetler K.
      • Triadafilopoulos G.
      Prevalence of Barrett's esophagus in asymptomatic individuals.
      These estimates suggest that there are potentially 3 to 5 million patients with BE in the United States.
      The incidence of endoscopically detected BE appears to be increasing as well. Although studies from the United States have revealed that this incidence has increased in parallel with increasing endoscopy volume,
      • Jung K.W.
      • Talley N.J.
      • Romero Y.
      • et al.
      Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett’s esophagus: a population-based study.
      other studies have shown that the proportion of patients diagnosed with BE, adjusted for endoscopy volume, has increased.
      • van Soest E.M.
      • Dieleman J.P.
      • Siersema P.D.
      • Sturkenboom M.C.
      • Kuipers E.J.
      Increasing incidence of Barrett's oesophagus in the general population.
      However, it remains unclear if this is truly an actual increase in incidence or a manifestation of increasing awareness among endoscopists and a reflection of detection bias.
      Despite the increasing detection of BE, population studies suggest that only one third of patients with prevalent long-segment BE in the community have been clinically diagnosed.
      • Cameron A.J.
      • Zinsmeister A.R.
      • Ballard D.J.
      • Carney J.A.
      Prevalence of columnar-lined (Barrett's) esophagus: comparison of population-based clinical and autopsy findings.
      This suggests that only a minority of prevalent cases of BE are receiving clinical attention in terms of surveillance and detection of dysplasia.
      Several risk factors have been identified for BE. Endoscopic database studies have reported that the prevalence of BE sharply increases in the fourth and fifth decades of life. Male gender, white race, chronic symptomatic reflux (defined the symptoms occurring more than once a week for more than 5 years), central obesity (measured by waist hip ratio or waist circumference),
      • Singh S.
      • Sharma A.N.
      • Murad M.H.
      • et al.
      Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis.
      current or past history of smoking, and a confirmed family history of BE or EAC are other documented risk factors for BE. There is significant overlap between these risk factors and those for EAC. Alcohol consumption has not been found to be a consistent risk factor for BE.
      • Anderson L.A.
      • Cantwell M.M.
      • Watson R.G.
      • et al.
      The association between alcohol and reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.
      Indeed, some studies have shown that wine consumption may be protective against the development of BE. A recent study also suggests that Helicobacter pylori infection may have a protective effect against development of BE.
      • Wang Z.
      • Shaheen N.J.
      • Whiteman D.C.
      • et al.
      Helicobacter pylori infection is associated with reduced risk of Barrett's esophagus: an analysis of the Barrett's and Esophageal Adenocarcinoma Consortium.

      Screening for BE

      The rationale for BE screening is based on the predicate that most EACs arise in a background of BE and that if BE is diagnosed early, effective endoscopic surveillance would detect dysplasia/early EAC, which can then be treated endoscopically or surgically. Although there is, at present, no Level 1 evidence demonstrating the effectiveness of screening, the efficacy of endoscopic therapy in preventing progression to EAC in randomized trials—and consistent evidence establishing excellent survival of patient's diagnosed with early stage EA—have provided support to the strategy of BE screening followed by surveillance. Several modeling studies have shown that this approach may be cost effective, particularly with the recent availability of minimally invasive tools for screening.
      • Benaglia T.
      • Sharples L.D.
      • Fitzgerald R.C.
      • Lyratzopoulos G.
      Health benefits and cost effectiveness of endoscopic and nonendoscopic cytosponge screening for Barrett's esophagus.
      Current society guidelines suggest considering BE screening in patients with chronic reflux and other risk factors such as male gender, older age (>50 years), central obesity, current or past smoking, and family history of BE or EAC (Table 1).
      • Prasad G.A.
      • Wu T.T.
      • Wigle D.A.
      • et al.
      Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus.
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • Gerson L.B.
      ACG clinical guideline: diagnosis and management of Barrett's esophagus.
      • Spechler S.J.
      • Sharma P.
      • Souza R.F.
      • Inadomi J.M.
      • Shaheen N.J.
      American Gastroenterological Association technical review on the management of Barrett's esophagus.
      • Fitzgerald R.C.
      • di Pietro M.
      • Ragunath K.
      • et al.
      British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus.
      • Sami S.S.
      • Subramanian V.
      • Ortiz-Fernandez-Sordo J.
      • et al.
      Performance characteristics of unsedated ultrathin video endoscopy in the assessment of the upper GI tract: systematic review and meta-analysis.
      • Atkinson M.
      • Das A.
      • Faulx A.
      • Kinnard M.
      • Falck-Ytter Y.
      • Chak A.
      Ultrathin esophagoscopy in screening for Barrett's esophagus at a veterans administration hospital: easy access does not lead to referrals.
      • Ross-Innes C.S.
      • Debiram-Beecham I.
      • O'Donovan M.
      • et al.
      Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.
      Although there are several limitations and weaknesses in this approach, there has been recent progress on several fronts.
      Table 1Society Recommendations for Screening for Barrett Esophagus
      American College of Gastroenterology (2016)
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • Gerson L.B.
      ACG clinical guideline: diagnosis and management of Barrett's esophagus.
      • Screening may be considered in male patients with chronic ( ≥5 years) and/or frequent (>1/week) reflux and 2 or more risk factors (strong recommendation, moderate level of evidence)
        • White race
        • Central obesity
        • Smoking (current or past history)
        • Confirmed family history in a first degree relative
      • Screening is not recommended in female patients (may consider in those with multiple risk factors).
      • Unsedated transnasal esophagoscopy is an alternative to sedated esophagogastroduodenoscopy (EGD) for Barrett esophagus screening.
      • Before screening is performed, overall life expectancy of patient should be considered.
      British Society of Gastroenterology (2013)
      • Fitzgerald R.C.
      • di Pietro M.
      • Ragunath K.
      • et al.
      British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus.
      Screening can be considered in patients with chronic reflux symptoms and multiple risk factors (at least 3 of age 50 years or older, white race, male sex, obesity). Decrease by 1 in presence of at least 1 first-degree relative with Barrett esophagus or esophageal adenocarcinoma

      Screening with endoscopy is not feasible or justified for an unselected population with gastroesophageal reflux symptoms.
      • Prasad G.A.
      • Wu T.T.
      • Wigle D.A.
      • et al.
      Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus.
      American Gastroenterological Association (2011)
      • Spechler S.J.
      • Sharma P.
      • Souza R.F.
      • Inadomi J.M.
      • Shaheen N.J.
      American Gastroenterological Association technical review on the management of Barrett's esophagus.
      In patients with multiple risk factors for esophageal adenocarcinoma, screening is recommended (weak recommendation, moderate quality evidence).

      Screening the general population not recommended (strong recommendation, moderate quality evidence).
      American Society of Gastrointestinal Endoscopy (2012)
      • Atkinson M.
      • Das A.
      • Faulx A.
      • Kinnard M.
      • Falck-Ytter Y.
      • Chak A.
      Ultrathin esophagoscopy in screening for Barrett's esophagus at a veterans administration hospital: easy access does not lead to referrals.
      Consider screening with EGD in select patients with multiple risk factors.

      Inform patients there is insufficient evidence that screening prevents cancer or prolongs life.
      American College of Physicians (2012)
      • Ross-Innes C.S.
      • Debiram-Beecham I.
      • O'Donovan M.
      • et al.
      Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.
      Screening with EGD for Barrett esophagus and esophageal adenocarcinoma may be considered in men older than 50 years of age, with symptoms of chronic gastroesophageal reflux disease (for more than 5 years) and additional risk factors: nocturnal reflux symptoms, hiatal hernia, elevated body mass index, tobacco use, and intra-abdominal distribution of fat.
      Sedated endoscopy (at present, the most used technique for screening) is an invasive and expensive tool and hence unsuitable for widespread application. Given evidence from multiple studies and clinical trials suggesting excellent sensitivity and specificity (for the diagnosis of BE), along with excellent safety and tolerability,
      • Sami S.S.
      • Subramanian V.
      • Ortiz-Fernandez-Sordo J.
      • et al.
      Performance characteristics of unsedated ultrathin video endoscopy in the assessment of the upper GI tract: systematic review and meta-analysis.
      unsedated transnasal endoscopy has been accepted as an alternative to sedated endoscopy for BE screening. However, its use remains low because of perceived physician and patient barriers.
      • Atkinson M.
      • Das A.
      • Faulx A.
      • Kinnard M.
      • Falck-Ytter Y.
      • Chak A.
      Ultrathin esophagoscopy in screening for Barrett's esophagus at a veterans administration hospital: easy access does not lead to referrals.
      More recently, minimally invasive tools such as capsule sponges (Figure 3) and swallowed balloons (which are swallowed, expand, and then pulled with attached cords, providing circumferential sampling of the esophagus) have been developed in conjunction with molecular biomarkers (such as epithelial protein markers: trefoil factor 3
      • Ross-Innes C.S.
      • Debiram-Beecham I.
      • O'Donovan M.
      • et al.
      Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.
      and methylated DNA markers
      • Iyer P.G.
      • Taylor W.R.
      • Johnson M.L.
      • et al.
      Highly discriminant methylated DNA markers for the non-endoscopic detection of Barrett's esophagus.
      ) to diagnose BE in a minimally invasive fashion, with moderate to excellent sensitivity (78% to 100%) and specificity (90% to 100%). These devices are also well tolerated and likely substantially less expensive than sedated endoscopy. Studies performed in screening populations are ongoing and awaited. Exhaled volatile organic compounds have also been used to detect BE in pilot proof-of-concept studies, with moderate sensitivity and specificity.
      Figure thumbnail gr3
      Figure 3Capsule sponge device intact (left) and expanded to 25 mm (right) with attached string.
      In addition, Barrett risk assessment scores, which integrate risk factors—such as age, gender, waist hip ratio, and smoking history—have also been developed and validated in multiple cohorts.
      • Rubenstein J.H.
      • Morgenstern H.
      • Appelman H.
      • et al.
      Prediction of Barrett's esophagus among men.
      Although these scores can assist in identifying the at-risk population, the risk score at which BE screening should be recommended is still to be determined. Importantly, life expectancy and performance status need to be considered carefully while making a decision to screen for BE, given other implications after its diagnosis.

      Management of Patients with BE

      Proton Pump Inhibitor Therapy

      The goal of proton pump inhibitor (PPI) therapy in patients with BE is to control symptoms of gastroesophageal reflux and heal esophagitis. This is somewhat challenging, given the known hyposensitivity of patients with BE to reflux, which makes assessment of symptoms unreliable as a measure of reflux control. Physiologic studies have also demonstrated that patients with BE have the most severe reflux in the continuum of phenotypes from normal to nonerosive disease, erosive disease, and BE. Current society guidelines recommend placing patients diagnosed with BE on a dose of PPI that is adequate to control symptoms and heal esophagitis. There is some evidence from nonrandomized observational studies that PPIs may reduce the risk of progression to esophageal adenocarcinoma.
      • Singh S.
      • Garg S.K.
      • Singh P.P.
      • Iyer P.G.
      • El-Serag H.B.
      Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis.
      Randomized controlled trials to test this association are ongoing, and results are awaited.

      Endoscopic Surveillance

      The goal of endoscopic surveillance in BE is to detect incident or prevalent dysplasia/adenocarcinoma early, enabling treatment and improved outcomes. Several society guidelines recommend endoscopic biopsies of the Barrett mucosa in a 4-quadrant fashion every 1 to 2 cm, depending on the presence of previously known dysplasia (Seattle protocol), in addition to sampling any visible lesions separately.
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • Gerson L.B.
      ACG clinical guideline: diagnosis and management of Barrett's esophagus.
      • Spechler S.J.
      • Sharma P.
      • Souza R.F.
      • Inadomi J.M.
      • Shaheen N.J.
      American Gastroenterological Association technical review on the management of Barrett's esophagus.
      Various imaging modalities have been investigated to assist in and enhance the endoscopic detection of dysplasia in BE. These include dye-based chromoendoscopy using methylene blue or acetic acid, which is somewhat cumbersome, given the need for dye spraying and suctioning. Electronic chromoendoscopy using optical imaging technologies such as narrow-band imaging (Figure 4B), i scan or blue-laser imaging are also available and more commonly used, given their convenience (given integration into the endoscope and activation with buttons, without the need for additional dyes and spray catheters) and ease of use. A recent systematic review and meta-analysis reported that use of any of these adjunctive imaging modalities increases dysplasia yield by 33%.
      • Qumseya B.J.
      • Wang H.
      • Badie N.
      • et al.
      Advanced imaging technologies increase detection of dysplasia and neoplasia in patients with Barrett's esophagus: a meta-analysis and systematic review.
      In addition, imaging modalities, such as confocal laser endomicroscopy (Figure 4C), are also used, which provide real-time histology at the microscopic level and can be used to discriminate between normal and dysplastic tissue. However, the importance of a careful and methodical white-light endoscopic examination after washing and cleaning the mucosa cannot be overemphasized.
      Figure thumbnail gr4
      Figure 4(A): White light endoscopy view of Barrett esophagus (BE) segment (B): Narrow band imaging view of BE segment (illumination with blue and green light, highlighting mucosal and vascular details) (C): Image of confocal laser endomicroscopy, showing dark, irregular, and distorted glands suggestive of dysplasia.
      A more recent development in BE screening/surveillance has been the use of wide area transepithelial sampling (WATS-3D). This adjunctive (to forceps biopsies) tissue sampling technique in BE uses a stiff endoscopic brush catheter, which increases the surface area of the BE epithelium sampled and provides cellular samples, which are scanned first by an artificial neural network computerized algorithm before presenting the 200 most abnormal cells for evaluation by a pathologist. This technique has been shown to increase the yield of dysplasia and neoplasia in patients with BE in a multicenter prospective randomized crossover trial by Vennalganti.
      • Vennalaganti P.R.
      • Kaul V.
      • Wang K.K.
      • et al.
      Increased detection of Barrett's esophagus-associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial.
      Additional data on validation of these findings in a lower risk (nondysplastic patients with BE) cohort are awaited.
      Recommended intervals of surveillance of patients with BE vary, depending on the grade of dysplasia, given variation in the risk of progression to cancer (Table 2). The estimated annual risk of progression in nondysplastic BE is low, at 0.33%,
      • Desai T.K.
      • Krishnan K.
      • Samala N.
      • et al.
      The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis.
      whereas that in patients with low-grade dysplasia (LGD) is higher and more variably estimated from 0.7% to 1%.
      • 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.
      This risk of progression in patients with LGD applies to cases confirmed by an expert gastrointestinal pathologists. The annual progression risk in high-grade dysplasia (HGD) is highest, estimated at 7% to 8%.
      • Rastogi A.
      • Puli S.
      • El-Serag H.B.
      • Bansal A.
      • Wani S.
      • Sharma P.
      Incidence of esophageal adenocarcinoma in patients with Barrett's esophagus and high-grade dysplasia: a meta-analysis.
      Table 2Recommendations for Management of Patients With Barrett Esophagus Stratified by Dysplasia Grade and Risk of Progression
      Grade of dysplasiaRisk of progression to high-grade dysplasia/esophageal adenocarcinomaRecommendation for management
      No dysplasia0.33% per yearEndoscopic surveillance every 3 to 5 years
      Low-grade dysplasia0.7% to 1.0% per yearConfirm diagnosis by expert gastrointestinal pathologist

      Discuss endoscopic ablation

      Endoscopic surveillance every 6 to 12 months
      High-grade dysplasia8% per year
      • Confirm diagnosis by expert gastrointestinal pathologist
      • Refer for endoscopic therapy to center with expertise for
        • -
          Endoscopic resection of visible lesions
        • -
          Endoscopic ablation
      T1a (mucosal) adenocarcinomaNARefer for staging (with endoscopic ultrasound and CT/PET) and potentially endoscopic therapy to center with expertise
      T1b (submucosal) adenocarcinomaNARefer for staging (with endoscopic ultrasound and CT/PET) and evaluation by multidisciplinary (gastrointestinal, thoracic surgery, and oncology) team
      CT = computed tomography; PET = positron emission tomography
      Given the low risk of progression, patients with BE without dysplasia are recommended to undergo endoscopic surveillance every 3 to 5 years, unless there is a family history of BE or EAC, suggestive of a familial syndrome, in which case ablation can be considered on a case-by-case basis. Endoscopic ablation of nondysplastic BE is not currently recommended by guidelines and should only be considered on a case-by-case basis, typically at expert centers with a clinical and research interest in BE. Diagnosis of dysplasia (low grade or high grade) should be confirmed by expert gastrointestinal pathologists, as most dysplasia diagnosed in the community is usually downgraded by expert gastrointestinal pathologists to nondysplasia with low rates of progression.
      Patients with LGD may undergo endoscopic surveillance annually, given the somewhat increased risk of progression to HGD/EAC. However, evidence from recent randomized control trials
      • Phoa K.N.
      • van Vilsteren F.G.
      • Weusten B.L.
      • et al.
      Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.
      and cohort studies
      • Small A.J.
      • Araujo J.L.
      • Leggett C.L.
      • et al.
      Radiofrequency ablation is associated with decreased neoplastic progression in patients with Barrett's esophagus and confirmed low-grade dysplasia.
      has shifted the recommendation for the management of patients with LGD to endoscopic ablation, although close surveillance (every 6 to 12 months) may be reasonable as per patient preference and in cases of medical comorbidities limiting life expectancy or performance status.
      • Qumseya B.J.
      • Wani S.
      • Gendy S.
      • Harnke B.
      • Bergman J.J.
      • Wolfsen H.
      Disease progression in Barrett's low-grade dysplasia with radiofrequency ablation compared with surveillance: systematic review and meta-analysis.
      Typically, those patients with BE and LGD who have long segments with multifocal (at more than 1 level in the BE segment), persistent (present at more than 1 endoscopy), and confirmed (by a pathologist with gastrointestinal expertise) LGD would be at highest risk for progression and hence also the best candidates for ablation. Patients with HGD are recommended to undergo endoscopic therapy and ablation to eliminate BE and reduce the risk of progression to EAC.
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • Gerson L.B.
      ACG clinical guideline: diagnosis and management of Barrett's esophagus.
      Additional details on BE endoscopic therapy are provided in subsequent sections.
      Despite these theoretical advantages and rationales, the effectiveness of endoscopic surveillance is limited because of the patchy nature of dysplasia in BE mucosa (making dysplasia and carcinoma hard to localize),
      • Cameron A.J.
      • Carpenter H.A.
      Barrett's esophagus, high-grade dysplasia, and early adenocarcinoma: a pathological study.
      lack of compliance with surveillance biopsy recommendations leading to missed dysplasia,
      • Abrams 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.
      • Visrodia K.
      • Singh S.
      • Krishnamoorthi R.
      • et al.
      Magnitude of missed esophageal adenocarcinoma after Barrett's esophagus diagnosis: a systematic review and meta-analysis.
      and the relatively poor interobserver agreement even among expert gastrointestinal pathologists for the diagnosis of dysplasia.
      • Montgomery E.
      • Bronner M.P.
      • Goldblum J.R.
      • et al.
      Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation.
      A recent systematic review and meta-analysis of more than 20 studies suggested that although endoscopic surveillance was associated with detection of EAC at earlier stages, there was only a modest improvement in EAC-related mortality. Moreover, this modest benefit in esophageal cancer-related mortality was likely susceptible to underlying biases (such as length and lead time), given the retrospective observational nature of most of these studies.
      • Codipilly D.C.
      • Chandar A.K.
      • Singh S.
      • et al.
      The effect of endoscopic surveillance in patients with Barrett's esophagus: a systematic review and meta-analysis.

      Risk Stratification in BE

      Histological grade of dysplasia is, at present, the only currently clinically used tool to stratify risk of progression in BE. However, several patients with no dysplasia and LGD do progress to adenocarcinoma, and several patients with HGD do not. Similarly, some patients with LGD may regress to “no dysplasia” on continued surveillance. Hence, several studies have attempted to develop clinical risk scores to predict progression in BE. Advanced age, male gender, increasing segment length, endoscopic presence of nodularity, and low-grade dysplasia have been identified factors as increasing the risk of progression in BE.
      • Krishnamoorthi R.
      • Singh S.
      • Ragunathan K.
      • et al.
      Factors associated with progression of Barrett's esophagus: a systematic review and meta-analysis.
      Indeed, a recent study has developed a progression in BE (PIB) score, integrating some of these clinical factors into a single score predictive of the risk of progression.
      • Parasa S.
      • Vennalaganti S.
      • Gaddam S.
      • et al.
      Development and validation of a model to determine risk of progression of Barrett's esophagus to neoplasia.
      In addition, the use of biomarkers to predict the risk of progression has been studied extensively. However, none of these biomarkers is currently recommended or available for clinical use. Some of these candidate markers include P53 expression,
      • Murray L.
      • Sedo A.
      • Scott M.
      • et al.
      TP53 and progression from Barrett's metaplasia to oesophageal adenocarcinoma in a UK population cohort.
      • Sikkema M.
      • Kerkhof M.
      • van Dekken H.
      • et al.
      Evaluation of p53, Ki67 and flow cytometry for prediction of neoplastic progression in Barrett esophagus.
      copy number changes in chromosomes detected by fluorescent in situ hybridization (FISH), methylated DNA markers, and other panels of molecular epithelial and stromal markers.
      • Krishnamoorthi R.
      • Iyer P.G.
      Molecular biomarkers added to image-enhanced endoscopic imaging: will they further improve diagnostic accuracy?.
      The ultimate goal of these clinical and biomarker panels would be to identify low-risk and high-risk groups that could be either discharged from surveillance (low-risk group) or managed with intensive surveillance or proactive ablation (high-risk group).

      Endoscopic Therapy

      Patient Selection

      The evolution of endoscopic resection techniques and the advent of esophageal ablation technology have transformed our approach to this disease in a monumental way. The decision whether to proceed with endotherapy vs continued endoscopic surveillance in patients with BE is primarily based upon the presence and degree of dysplasia. In nondysplastic BE, the risk of progression to neoplasia is very low,
      • Desai T.K.
      • Krishnan K.
      • Samala N.
      • et al.
      The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis.
      and therefore it is thought that the risks and cost of the procedures outweigh the benefits.
      There remains some controversy among professional societies regarding treatment of patients with LGD. For LGD that is confirmed by 2 pathologists (including 1 with expertise in gastrointestinal pathology), the American College of Gastroenterology and the American Gastroenterological Association recommend consideration of endotherapy, whereas the British Society of Gastroenterology advises endoscopic surveillance.
      • Shaheen N.J.
      • Falk G.W.
      • Iyer P.G.
      • Gerson L.B.
      ACG clinical guideline: diagnosis and management of Barrett's esophagus.
      • Benaglia T.
      • Sharples L.D.
      • Fitzgerald R.C.
      • Lyratzopoulos G.
      Health benefits and cost effectiveness of endoscopic and nonendoscopic cytosponge screening for Barrett's esophagus.
      • Spechler S.J.
      • Sharma P.
      • Souza R.F.
      • Inadomi J.M.
      • Shaheen N.J.
      American Gastroenterological Association technical review on the management of Barrett's esophagus.
      In general, expert opinion favors proceeding with treatment of persistent, confirmed multifocal LGD in a patient with long-segment BE, especially in younger patients with acceptable overall comorbidities.
      When repeat endoscopic surveillance reveals persistent LGD confirmed by an expert pathologist, endoscopic therapy should be considered strongly.
      Best-practice recommendations also dictate that a thorough discussion should take place between the physician and the patient, during which the risks, benefits, and alternatives of surveillance vs treatment are discussed in detail with patients who have BE with LGD.
      In patients with HGD, the risk of progression to neoplasia is elevated, and hence treatment is recommended universally as per current guidelines. Although surgery was previously the standard of care for patients with BE and HGD, endotherapy is now the standard of care, given high degree of success, significantly less morbidity and mortality, and overall long-term survival comparable with esophagectomy.
      • Prasad G.A.
      • Wu T.T.
      • Wigle D.A.
      • et al.
      Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus.

      Principles of Endoscopic Therapy

      The basic principles of endoscopic therapy include identification of focal lesions (which may reflect more advanced neoplasia such as carcinoma), resection of these visible lesions (to characterize the histology of these lesions accurately), followed by endoscopic ablation, while ensuring maximal acid-reflux control medically, leading to replacement of the metaplastic BE epithelium by neosquamous epithelium. This multistep approach has been shown to reduce the risk of progression to EAC in randomized controlled trials and leads to comparable survival for early stage (mucosal) adenocarcinoma vis-à-vis esophagectomy in cohort studies.

      Endoscopic Resection

      The rationale for endoscopic resection (ER) is based on the need for accurate histological characterization of visible lesions (30 % to 40% of which may harbor early-stage adenocarcinoma). The somewhat poor interobserver agreement for the identification of dysplasia in biopsies among pathologists is substantially improved with larger endoscopic resection specimens.
      • Wani S.
      • Mathur S.C.
      • Curvers W.L.
      • et al.
      Greater interobserver agreement by endoscopic mucosal resection than biopsy samples in Barrett's dysplasia.
      In addition, accurate T staging (primarily distinguishing between T1a (mucosally confined) and T1b (submucosally invasive EAC) and margin assessment (lateral and deep) can be performed.
      • Prasad G.A.
      • Buttar N.S.
      • Wongkeesong L.M.
      • et al.
      Significance of neoplastic involvement of margins obtained by endoscopic mucosal resection in Barrett's esophagus.
      Importantly, prognostic information, such as degree of differentiation and lymphovascular invasion, can also be provided.
      • Leggett C.L.
      • Lewis J.T.
      • Wu T.T.
      • et al.
      Clinical and histologic determinants of mortality for patients with Barrett's esophagus-related T1 esophageal adenocarcinoma.
      Finally, if the margins are negative, and the tumor is confined to the mucosa, the resection can be curative.
      Endoscopic resection can be achieved by band- (Figure 5A) or cap- (Figure 5B) assisted endoscopic mucosal resection (EMR) technique or by endoscopic submucosal dissection (ESD); the latter allows en bloc resection of larger (>1.5 cm size) visible lesions. ESD is more time consuming, and the risk of complications may be higher, although ESD more frequently achieves en bloc, R0, and curative resection.
      • Terheggen G.
      • Horn E.M.
      • Vieth M.
      • et al.
      A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett's neoplasia.
      However, the decision between continued endoscopic therapy vs referral for esophagectomy depends on depth of invasion of the tumor; this information is provided equally well by both EMR and ESD. Metastatic lymphadenopathy is uncommon in T1a EAC (<2%), making endoscopic therapy suitable but substantially higher in T1b EAC (20% to 30%), making esophagectomy the primary modality of treatment, except in those patients with life-limiting medical comorbidities and favorable histological features.
      Figure thumbnail gr5
      Figure 5Endoscopic mucosal resection sites (A) using band-ligation device and (B) using plastic cap and snare.
      EMR is the most frequently used resection technique, either with a banding device (band-EMR) or with the use of an endoscopic resection cap (cap-EMR). With band-EMR, the nodular lesion is sucked into the banding device to create a “pseudopolyp” and then resected with a snare, using electrocautery. In the cap-EMR technique, following the injection of submucosal saline solution to lift the lesion away from the muscularis propria, a flexible snare is seated on the inner edge of a dedicated EMR cap, the lesion is suctioned into the cap, and then resected using electrocautery.
      • Namasivayam V.
      • Wang K.K.
      • Prasad G.A.
      Endoscopic mucosal resection in the management of esophageal neoplasia: current status and future directions.
      ESD, which involves lifting the lesion with submucosal injection, followed by dissection in the submucosal plane, using specialized endoscopic “knives,” has emerged as an option for resecting larger nodular lesions and early neoplasia in BE, although experience in the Western world is still evolving. Recent studies have shown ESD to be superior to EMR in achieving complete en bloc and curative resection. However, it is technically more demanding; leads to longer procedure times; and carries greater risk for bleeding, perforation, and formation of stricture, especially if circumferential ESD is performed for complete BE eradication.
      • Terheggen G.
      • Horn E.M.
      • Vieth M.
      • et al.
      A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett's neoplasia.
      ER is safe but associated with some complications. These include perforation (<1% for EMR, 1% to 3% for ESD), bleeding (5%), and formation of stricture. The risk of formation of stricture is low if the resection area is limited to focal lesions and less than 50% of the esophageal circumference. Strictures can be successfully treated endoscopically with dilation.
      • Tomizawa Y.
      • Iyer P.G.
      • Wong Kee Song L.M.
      • Buttar N.S.
      • Lutzke L.S.
      • Wang K.K.
      Safety of endoscopic mucosal resection for Barrett's esophagus.
      If the histology from the resected EMR/ESD specimen reveals LGD, HGD, or EAC (T1a histology with no lymphovascular invasion [LVI], and negative deep and lateral margins), endoluminal ablative therapy is recommended for complete eradication of any residual intestinal metaplasia (IM). Ablative therapy may be a consideration in patients with well-differentiated T1b EAC with superficial submucosal invasion (<500 μm, sm1) and without LVI and well-to-moderately differentiated, especially for those patients who are poor surgical candidates.
      • Manner H.
      • May A.
      • Pech O.
      • et al.
      Early Barrett's carcinoma with "low-risk" submucosal invasion: long-term results of endoscopic resection with a curative intent.
      However, this decision should be made after consultation with a multidisciplinary surgical oncology team.

      Ablation Modalities

      Following the resection of visible focal lesions, elimination of residual BE mucosa is essential to reduce the risk of recurrent neoplasia. A variety of techniques are available to accomplish this (Table 3). Despite the emergence of several new modalities, radiofrequency ablation (RFA) remains the most commonly performed endoscopic ablation procedure for BE, owing to its ease of use and high degree of efficacy. RFA is a thermal technique for mucosal ablation using bipolar electrodes arranged on circumferential (balloon) or focal ablation devices (Figure 6A, B, and C ).
      • Eluri S.
      • Shaheen N.J.
      Barrett's esophagus: diagnosis and management.
      Table 3Different Modalities for Barrett Ablation
      Thermal Devices
       Radiofrequency ablation (RFA)
      Circumferential RFA
      Focal RFA (60, 90, Ultra)
      Channel RFA catheter
       Argon plasma coagulation
       Multipolar electrocoagulation
      Cryotherapy Devices
       Spray cryotherapy (liquid nitrogen)
       Balloon cryotherapy (nitrous oxide)
      Historical
       Photodynamic therapy
      Figure thumbnail gr6
      Figure 6(A) Circumferential balloon radiofrequency ablation (RFA) catheter. (B) Focal ablation RFA catheter. (C) Focal ablation catheter being used to ablate the gastroesophageal junction. (D) Endoscopic liquid nitrogen spray cryotherapy being administered via spray catheter.
      Liquid nitrogen based endoluminal spray cryotherapy is another ablation modality that is highly effective in eradicating BE and appears very useful in managing cases refractory to initial RFA treatment.
      • Trindade A.J.
      • Inamdar S.
      • Kothari S.
      • Berkowitz J.
      • McKinley M.
      • Kaul V.
      Feasibility of liquid nitrogen cryotherapy after failed radiofrequency ablation for Barrett's esophagus.
      • Sengupta N.
      • Ketwaroo G.A.
      • Bak D.M.
      • et al.
      Salvage cryotherapy after failed radiofrequency ablation for Barrett's esophagus-related dysplasia is safe and effective.
      Balloon-based cryotherapy uses nitrous oxide and is a relatively newer device that also appears promising in treatment of BE.
      • Canto M.I.
      • Shaheen N.J.
      • Almario J.A.
      • Voltaggio L.
      • Montgomery E.
      • Lightdale C.J.
      Multifocal nitrous oxide cryoballoon ablation with or without EMR for treatment of neoplastic Barrett's esophagus (with video).
      Argon plasma coagulation and multipolar electrocautery are used mostly for treatment of focal areas of IM and are less often used in the United States and more popular in Europe and Asia. Photodynamic therapy caused mucosal ablation using photochemical energy but is no longer used because of cost, associated morbidity (photosensitivity and strictures), and lack of availability.

      Radiofrequency Ablation

      Radiofrequency ablation is the most commonly used ablation technique to treat dysplastic BE. In RFA, radiofrequency energy is directly applied to the esophageal mucosa, either using a balloon or focal catheter. This technique has been well studied and is highly effective at eradicating IM and dysplasia. A multicenter randomized controlled trial in the United States found that 81% of patients with HGD and 91% with LGD achieved complete eradication of dysplasia within 12 months, with a statistically significant decrease in progression to EAC in the ablation arm.
      • Shaheen N.J.
      • Sharma P.
      • Overholt B.F.
      • et al.
      Radiofrequency ablation in Barrett's esophagus with dysplasia.
      The most common adverse events of RFA include postablation stricture and postprocedure chest pain, especially if a long segment of BE has been treated at a single session. Bleeding and perforation are extremely uncommon.

      Cryoablation

      Endoscopic cryoablation is another option for ablative therapy that has emerged in the past decade, with recent studies suggesting less postprocedural chest pain and better patient tolerance compared with RFA.
      • Solomon S.S.
      • Kothari S.
      • Smallfield G.B.
      • et al.
      Liquid nitrogen spray cryotherapy is associated with less postprocedural pain than radiofrequency ablation in Barrett's esophagus: a multicenter prospective study.
      • van Munster S.N.
      • Overwater A.
      • Haidry R.
      • Bisschops R.
      • Bergman J.
      • Weusten B.
      Focal cryoballoon versus radiofrequency ablation of dysplastic Barrett's esophagus: impact on treatment response and postprocedural pain.
      At least 2 platforms for cryotherapy are now commercially available and in use.
      In the case of spray cryotherapy (Figure 6D), liquid nitrogen is delivered at –196° C (–320° F) through a novel spray catheter, which is introduced through the working channel of a standard endoscope. In the newer balloon-based cryotherapy system, nitrous oxide is used to achieve ablation by direct contact with the tissue via an inflated balloon with an internal spray catheter. Studies have shown eradication of HGD in 81% to 94% of patients with cryotherapy.
      • Greenwald B.D.
      • Dumot J.A.
      • Horwhat J.D.
      • Lightdale C.J.
      • Abrams J.A.
      Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus.
      Successful endotherapy is defined by both absence of visible IM at endoscopy and on histology. This milestone is referred to as complete remission of intestinal metaplasia (CR-IM). Despite high rates of successful endotherapy in BE, there remains significant risk of recurrence of IM and/or dysplasia in certain patients, warranting close postablation surveillance in all patients after treatment has been deemed complete. Those at highest risk for recurrence include patients with long-segment BE and those with HGD or worse pathology on initial histology. A recent meta-analysis reviewed all modalities of BE endotherapy and showed that the annual incidence of recurrent IM was 7.1%, recurrent dysplastic BE was 1.3%, and recurrent HGD and/or EAC was 0.8%. It is reassuring to note that more than 95% of all recurrences were endoscopically treatable.
      • Krishnamoorthi R.
      • Singh S.
      • Ragunathan K.
      • et al.
      Risk of recurrence of Barrett's esophagus after successful endoscopic therapy.
      Hence, continued endoscopic surveillance after successful endotherapy is currently recommended to detect and treat recurrent BE. Recommendations on intervals of follow-up after successful ablation are expert-opinion based and suggest that those with CR-IM after endotherapy for BE-HGD/EAC should be surveyed endoscopically every 3 months for the first year, every 6 months for the second year, and then once a year thereafter. Patients reaching CR-IM after endotherapy for BE-LGD should be surveyed endoscopically every 6 months for the first year and then annually. There is no consensus at this time on whether surveillance can be extended or discontinued after a certain interval following CR-IM.

      Challenges in BE Endotherapy

      Endoluminal therapy is highly effective in the majority of patients. Treatment failures are infrequent (10% failure in achieving CR-D and 20 % failure in achieving CR-IM) and are defined as those patients who do not achieve CR-IM or CR-D after completing 3 to 5 ablation sessions. Management options for such patients have included continued treatment with the same modality, with documentation of adequate acid reflux control (by ambulatory pH testing); resecting the residual BE mucosa by endoscopic resection; reverting to surveillance; or referral to surgery (especially if persistent or recurrent HGD or neoplasia is present in patients who are surgical candidates). More recently, cryotherapy has emerged as an effective tool for managing this cohort of difficult-to-treat patients with BE.
      • Trindade A.J.
      • Inamdar S.
      • Kothari S.
      • Berkowitz J.
      • McKinley M.
      • Kaul V.
      Feasibility of liquid nitrogen cryotherapy after failed radiofrequency ablation for Barrett's esophagus.
      In a recently published systematic review and meta-analysis, 46% of all patients with RFA failure achieved CR-IM, and 76% achieved CR-D with cryotherapy.
      • Visrodia K.
      • Zakko L.
      • Singh S.
      • Leggett C.L.
      • Iyer P.G.
      • Wang K.K.
      Cryotherapy for persistent Barrett's esophagus after radiofrequency ablation: a systematic review and meta-analysis.
      In addition, although there is concern regarding “buried” Barrett mucosa (underneath squamous epithelium, persisting after apparent successful ablation, and rarely progressing to EAC), the rates of this phenomenon appear to be low (0.9%) within limitations of data as reported.
      • Gray N.A.
      • Odze R.D.
      • Spechler S.J.
      Buried metaplasia after endoscopic ablation of Barrett's esophagus: a systematic review.

      Conclusions

      BE is an established precursor to EAC, with malignant transformation potentially occurring in a stepwise fashion from nondysplastic BE to LGD, HGD, and ultimately invasive adenocarcinoma. This provides the window for early detection by screening and surveillance. Substantial recent progress has been made in the development of minimally invasive nonendoscopic approaches in the detection of BE and related dysplasia, along with effective endoscopic therapy of dysplasia (reducing risk of progression to EAC) and early EAC (with excellent survival rates comparable with esophagectomy). The most effective treatment regimen can be multimodal and individualized to the patient, with endoscopic resection (EMR/ESD) of nodular/raised lesions, followed by ablation of residual IM. It is recommended that BE endotherapy is performed in high-volume centers of excellence to ensure optimal outcomes. Ongoing endoscopic surveillance after successful endotherapy is essential to detect and treat recurrences. Challenges that likely need to be addressed in the coming years include making surveillance more efficient and effective (likely using novel imaging and molecular strategies), integrating risk stratification, identification of likely nonresponders to treatment, and the integration of quality measures (assessing diagnosis, surveillance and treatment of dysplastic BE) into clinical practice.

      Supplemental Online Material

      • Supplemental Figure 1

        Diagrammatic representation of endoscopic Barrett’s esophagus showing an area classified as C2M5. C = extent of circumferential metaplasia; M = maximal extent of the metaplasia (C plus a distal “tongue” of 3 cm); GEJ = gastroesophageal junction1

      Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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