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doi: 10.1136/gutjnl-2013-305372published online October 28, 2013Gut

Rebecca C Fitzgerald, Massimiliano di Pietro, Krish Ragunath, et al.management of Barrett's oesophagusguidelines on the diagnosis andBritish Society of Gastroenterology

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British Society of Gastroenterology guidelines on thediagnosis and management of Barretts oesophagus

Rebecca C Fitzgerald,1 Massimiliano di Pietro,1 Krish Ragunath,2 Yeng Ang,3

Jin-Yong Kang,4 Peter Watson,5 Nigel Trudgill,6 Praful Patel,7 Philip V Kaye,8

Scott Sanders,9

Maria ODonovan,

10

Elizabeth Bird-Lieberman,11

Pradeep Bhandari,12

Janusz A Jankowski,13 Stephen Attwood,14 Simon L Parsons,15 Duncan Loft,16

Jesper Lagergren,17 Paul Moayyedi,18 Georgios Lyratzopoulos,19 John de Caestecker20

Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/gutjnl-2013-305372).

For numbered afliations seeend of article

Correspondence toProfessor Rebecca C Fitzgerald,

MRC Cancer Unit, University ofCambridge, Box 197,Cambridge BiomedicalCampus, Cambridge,CB2 0XZ, UK;[email protected]

Received 31 May 2013Revised 14 August 2013Accepted 1 September 2013

To cite:Fitzgerald RC, diPietro M, Ragunath K, et al.GutPublished Online First:[please includeDay MonthYear] doi:10.1136/gutjnl-

2013-305372

ABSTRACTThese guidelines provide a practical and evidence-basedresource for the management of patients with Barrettsoesophagus and related early neoplasia. The Appraisalof Guidelines for Research and Evaluation (AGREE II)instrument was followed to provide a methodologicalstrategy for the guideline development. A systematicreview of the literature was performed for Englishlanguage articles published up until December 2012 inorder to address controversial issues in Barrettsoesophagus including denition, screening anddiagnosis, surveillance, pathological grading fordysplasia, management of dysplasia, and early cancerincluding training requirements. The rigour and quality ofthe studies was evaluated using the SIGN checklistsystem. Recommendations on each topic were scored byeach author using a ve-tier system (A+, strongagreement, to D+, strongly disagree). Statements thatfailed to reach substantial agreement among authors,dened as >80% agreement (A or A+), were revisitedand modied until substantial agreement (>80%) wasreached. In formulating these guidelines, we took into

consideration benets and risks for the population andnational health system, as well as patient perspectives.For the rst time, we have suggested stratication ofpatients according to their estimated cancer risk basedon clinical and histopathological criteria. In order toimprove communication between clinicians, werecommend the use of minimum datasets for reportingendoscopic and pathological ndings. We advocateendoscopic therapy for high-grade dysplasia and earlycancer, which should be performed in high-volumecentres. We hope that these guidelines will standardiseand improve management for patients with Barrettsoesophagus and related neoplasia.

PURPOSE AND METHODS

The purpose of this guideline is to provide a prac-tical and evidence-based resource for the manage-ment of patients with Barretts oesophagus andrelated early neoplasia. This document is thereforeaimed at gastroenterologists, physicians and nursepractitioners, as well as members of multidisciplin-ary teams (MDTs; surgeons, radiologists, patholo-gists), who take decisions on the management ofsuch patients. The population covered by theseguidelines includes: patients with gastro-

oesophageal reux disease or other risk factors for

Barretts (obesity, family history for Barretts andoesophageal adenocarcinoma (OAC)); every patientwith incident or prevalent Barretts oesophagusregardless of their age, sex or comorbidities; patientswith early OAC and patients with intestinal metapla-sia (IM) at the gastro-oesophageal junction (GOJ)with no endoscopic evidence of Barrettsoesophagus. The previous British Society ofGastroenterology (BSG) guidelines were publishedin 2005 and since then there have been advances inthe diagnostic and management tools available.Within these guidelines, we have systematicallyreviewed the literature in order to address contro-versial issues in Barretts oesophagus and to formu-late practical recommendations to guide patientmanagement. In particular, we have covered the fol-lowing key questions.1. How should Barretts oesophagus be dened

and which patients should undergo regularsurveillance?

2. Are there clinical features associated withincreased cancer risk in Barretts oesophagus,

which should inuence the frequency of endo-scopic surveillance?

3. Are there diagnostic tools that should be uti-lised to screen the population at risk forBarretts oesophagus?

4. Which imaging modality should be used forthe endoscopic diagnosis and surveillance ofBarretts oesophagus?

5. How should we best manage dysplasia inBarretts oesophagus?

6. Which staging modality is preferred forBarretts-related early OAC?

7. What are the indications for endoscopic and/or surgical therapy in Barretts-relatedadenocarcinoma?

8. Are there minimum standards for training andmaintenance of skills in the eld of endoscopictherapy?

9. How should patients be followed-up afterendoscopic therapy?

10. Are there chemopreventive interventionsrecommended to reduce the likelihood of theprogression of Barretts oesophagus?

11. What are the priorities for research and devel-opment in the eld of Barretts carcinogenesis?

The Appraisal of Guidelines for Research andEvaluation (AGREE II) instrument1 was used to

provide a methodological strategy for the

Fitzgerald RC,et al.Gut2013;0:136. doi:10.1136/gutjnl-2013-305372 1

Guidelines

Gut Online First, published on October 28, 2013 as 10.1136/gutjnl-2013-305372

Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd (& BSG) under licence.

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development of the guidelines and to aid assessment of thequality of the guidelines. Three appraisers in the author listassessed the compliance of the guidelines to the AGREE IIdomains. As part of the AGREE II criteria, external review ofthis manuscript was also performed by two internationallyrenowned experts in the eld (Dr L Lovat and Professor JBergman). The authors comprised gastroenterologists, endosco-pists, surgeons, pathologists, economists, public health physicians

and patient representatives. Individuals were selected on the basisof their current membership of the relevant BSG committees ortheir expertise in the eld in order to ensure representationacross all the relevant disciplines. A working group was formedfor each topic (working groups listed under Contributors) andthe authors of that group were then responsible for conducting acomprehensive literature search to identify references relevant toindividual topics. Studies were divided according to their meth-odologies (systematic reviews and meta-analyses, randomisedcontrolled trials (RCTs), cohort studies, diagnostic studies andeconomic studies), and the rigour and quality of the study wasevaluated using the SIGN checklist system (http://www.sign.ac.uk/methodology/checklists.html). The authors included as manystudies as possible to support the evidence; however, studies withsuboptimal quality were excluded, or included if they repre-sented the only evidence to address particular clinical questions.Cohort studies with very small patient groups, feasibility studies,systematic reviews without meta-analysis and biomarker pilot dis-covery studies were excluded from evidence-generating literature,as well as studies with methodological aws that were consideredunacceptable after careful review. Evidence was nally scoredusing the North of England evidence-based guidelines2 asfollows. Ia: Evidence obtained from meta-analysis of RCTs. Ib: Evidence obtained from at least one RCT. IIa: Evidence obtained from at least one well-designed con-

trolled study without randomisation.

IIb: Evidence obtained from at least one other type of well-designed quasi-experimental study.

III: Evidence obtained from well-designed descriptive studiessuch as comparative studies, correlative studies and casestudies.

IV: Evidence obtained from expert committee reports, oropinions or clinical experience of respected authorities.

The literature search was performed for Nursing and AlliedHealth Literature (CINAHL) for English language articles pub-lished up until December 2012. We performed additionalsearches of Medline using the Ovid database, including OvidMedline 1948 to the present and Ovid Medline (R) in-processand other non-indexed citations. The principal search termswere Barretts (o)esophagus, dysplasia, screening, surveil-lance, high-grade dysplasia(HGD), intramucosal carcinoma,radiofrequency ablation, endoscopic mucosal resection,photodynamic therapy (PDT), argon plasma coagulation,(o)esophagectomy, biomarkers, p53, model, economicand Markov. The panel graded each of the recommendationson the basis of the strength of the evidence, taking into consid-eration limitations of the studies and weighing the differencebetween the estimated benets and risks of the intervention.Therefore recommendations were graded as follows. Grade A requires at least one RCT of good quality addressing

the topic of recommendation. Grade B requires the availability of clinical studies without

randomisation on the topic of recommendation.

Grade C requires evidence from category IV in the absenceof directly applicable clinical studies.

Recommendations were scored by each individual author onthe basis of a ve-tier system comprising the following agree-ment categories: A+, strong agreement; A, agree with reserva-tion; U, undecided; D, disagree; D+, strongly disagree.Statements that failed to reach substantial agreement amongauthors, dened as >80% agreement (A or A+), on the rstround of voting were revisited and modied according toauthors comments. Further rounds of voting were then contin-

ued until substantial agreement (>80%) was reached. Onlinesupplementary appendix 1 shows the percentage of authorsagreement on individual statements and the number votingrequired to meet the minimum threshold of 80%.

Detailed attention has been paid to other published guide-lines, in particular the American Gastroenterology Association(AGA) Medical position Statement,3 a recent systematic reviewwith consensus statements (BADCAT)4 and National Institute ofHealth and Care Exellence (NICE) guidelines for managementof dysplastic Barretts,5 6 in order to try to align internationalpractices and to aid useful comparisons of clinical outcomes foraudit and research.

In formulating these guidelines, we took into considerationbenets and risks for the population and national health systemas well as side effects. For example, we considered the benetsto the population derived from the reduction of the incidenceand mortality for OAC achievable through screening, endo-scopic surveillance for Barretts and endoscopic therapy for dys-plasia. We considered risks inherent in invasive interventions,such as endoscopic surveillance and therapy. We also took intoaccount implications for the healthcare system, which can arisefrom expensive interventions, such as endoscopic screening orsurveillance, and economic considerations using existing data inthe eld. We considered psychological morbidity and reductionof quality of life (QOL) resulting from repeated interventions(surveillance and endotherapy for dysplasia as a preventivemeasure for cancer development). Patient perspectives were

taken into consideration by consulting with two patient repre-sentatives. These lay members were consulted from the outsetto ensure that patient perspectives were taken into accountduring the literature review process and in deciding whichtopics should be addressed before the literature review process.Draft guidelines were then resubmitted to the lay members, andmodications made in accordance with their comments.

After completion, the guidelines underwent appraisal andexternal review in accordance with the AGREE II instrument, asdiscussed above. The recommendations were then posted on theBSG website for open consultation and reviewed by BSG and

Association of Upper GI Surgeons (AUGIS) Clinical ServicesCommittee reviewers before publication. It is anticipated that athorough review of these guidelines will be required in about5 years, and specic sections may need reviewing in the interimas new data emerge when results from the ongoing trials, suchas Aspirin Esomeprazole Chemoprevention Trial (AspECT)(UKCRN ID 1339), BEST (UKCRN ID 9461), BOSS (UKCRNID 4943) and SURF (NTR1198), are available.

DISSEMINATION AND IMPLEMENTATIONOF THE GUIDELINESThese guidelines have been written to be as practical as possibleand it is intended that this will be supplemented by endoscopicand histopathological images for educational purposes.Dissemination will be achieved through publication in the peer-reviewed journalGut and through presentations at national BSG

conferences as well as at relevant training courses. Some of thestatements in these guidelines, particularly those concerning

2 Fitzgerald RC,et al.Gut2013;0:136. doi:10.1136/gutjnl-2013-305372

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endoscopic therapy, are in line with NICE recommendations,6 7

which represent an additional source of guidance for the man-agement of this disease. In this article, we have provided tablesthat should help guide practitioners to acquire the minimumdataset of clinical information in order to optimise patient man-agement (endoscopy and pathology proforma) and ensure con-sistency among hospitals. There is also a patient informationsheet explaining the diagnosis of Barretts oesophagus

(Appendix 4) and the latest surveillance recommendations.These can be easily adapted to individual clinical settings. Auditand monitoring of these guidelines will be carried out throughusers feedback on the BSG website forum (http://www.bsg.org.uk/forum). This is a list of elements in clinical practice that canbe subjected to monitoring and auditing activity. Adherence of endoscopists to the Seattle protocol Use of a minimum dataset for endoscopy reporting Use of a minimum dataset for pathology reporting Revision of diagnoses of dysplasia by second GI pathologist Adherence to recommendations for endoscopic surveillance Volume of cases of endoscopic therapy to assess tness of

service provision Safety and efcacy of endoscopic therapy for Barretts dys-

plasia and early neoplasia MDT discussion of cases with HGD and Barretts early

cancer

EXECUTIVE SUMMARY OF KEY RECOMMENDATIONSDiagnosis Barretts oesophagus is dened as an oesophagus in which

any portion of the normal distal squamous epithelial lininghas been replaced by metaplastic columnar epithelium, whichis clearly visible endoscopically (1 cm) above the GOJ andconrmed histopathologically from oesophageal biopsies(Recommendation grade C).

The proximal limit of the longitudinal gastric folds with

minimal air insufation is the easiest landmark to delineatethe GOJ and is the suggested minimum requirement(Recommendation grade B).

Endoscopic reporting should be performed using a minimumdataset including a record of the length using the Prague cri-teria (circumferential extent (C), maximum extent (M) ofendoscopically visible columnar-lined oesophagus in centi-metres and any separate islands above the main columnar-lined segment noted) (Recommendation grade B).

In order to improve the standard of care and to ease discus-sion between experts, the use of a minimum dataset isrecommended to report histopathological ndings(Recommendation grade C).

Screening for Barretts oesophagus Screening with endoscopy is not feasible or justied for an

unselected population with gastro-oesophageal reux symp-toms (Recommendation grade B).

Endoscopic screening can be considered in patients withchronic GORD symptoms and multiple risk factors (at leastthree of age 50 years or older, white race, male sex, obesity).However, the threshold of multiple risk factors should belowered in the presence of family history including at leastone rst-degree relative with Barretts or OAC(Recommendation grade C).

Surveillance Although RCT data are lacking, given the evidence from the

published studies that surveillance correlates with earlier

stage and improved survival from cancer, surveillance is gen-erally recommended (Recommendation grade B).

Endoscopic monitoring with histopathological assessment ofdysplasia is the only current method of surveillance withsufcient evidence to be recommended (Recommendationgrade B).

Surveillance regimens should take into account the presenceof IM and length of the Barretts segment (Recommendationgrade B).

Dysplasia conrmed by two GI pathologists is currently the

best tissue biomarker for the assessment of cancer risk(Recommendation grade B).

Until randomised controlled evidence is available, biomarkerpanels cannot yet be recommended as routine of care(Recommendation grade C).

Practicalities of endoscopic surveillance Patients should have early access to an outpatient clinic to be

informed about a new diagnosis of Barretts oesophagus and tohave an initial discussion about the pros and cons of surveil-lance with written information provided (Recommendationgrade C).

For a given patient, whether or not surveillance is indicatedshould be determined on the basis of an estimate of the like-lihood of cancer progression and patient tness for repeatendoscopies, as well as patient preference (Recommendationgrade C).

High-resolution endoscopy should be used in Barrettsoesophagus surveillance (Recommendation grade C).

There is insufcient evidence to recommend transnasalendoscopy as a replacement for transoral endoscopy(Recommendation grade C).

Advanced imaging modalities, such as chromoendoscopy orvirtual chromoendoscopy, are not superior to standardwhite light endoscopy in Barretts oesophagus surveillanceand are therefore not recommended for routine use(Recommendation grade A).

Adherence to a quadrantic, 2 cm biopsy protocol in addition

to sampling any visible lesions is recommended for allpatients undergoing surveillance. This should also apply tolong segments (Recommendation grade B).

Surveillance is generally not recommended in patients with IMat the cardia or in those with an irregular Z-line regardless ofthe presence of IM (Recommendation grade C).

For patients with Barretts oesophagus shorter than 3 cm,without IM or dysplasia, a repeat endoscopy with quadranticbiopsies is recommended to conrm the diagnosis. Ifrepeat endoscopy conrms the absence of IM, dischargefrom surveillance is encouraged as the risks for endoscopyprobably outweigh the benets (Recommendation grade C).

Patients with Barretts oesophagus shorter than 3 cm, withIM, should receive endoscopic surveillance every 35 years(Recommendation grade C).

Patients with segments of 3 cm or longer should receivesurveillance every 23 years (Recommendation grade C).

Histopathological diagnosis of dysplasia Given the important management implications for a diagno-

sis of dysplasia, we recommend that all cases of suspecteddysplasia are reviewed by a second GI pathologist, withreview in a cancer centre if intervention is being considered(Recommendation grade C).

Given the difculties associated with the management of theindenite for dysplasia category, all such cases should alsobe reviewed by a second GI pathologist, and the reasons foruse of the indenite for dysplasia category should be given

in the histology report in order to aid patient management(Recommendation grade C).


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The addition of a p53 immunostain to the histopathologicalassessment may improve the diagnostic reproducibility of adiagnosis of dysplasia in Barretts oesophagus and should beconsidered as an adjunct to routine clinical diagnosis(Recommendation grade B).

Management of dysplasia and early cancer Patients with a diagnosis of indenite for dysplasia should be

managed with optimisation of antireux medication and

repeat endoscopy in 6 months. If no denite dysplasia isfound on subsequent biopsies, then the surveillance strategyshould follow the recommendation for non-dysplasticBarretts oesophagus (Recommendation grade C).

Management of low-grade dysplasia (LGD) is unclear in viewof limited data about the natural history. It is essential that thediagnosis is conrmed by two pathologists, and patientsshould be surveyed endoscopically at 6 monthly intervals.Currently, ablation therapy cannot be recommended routinelyuntil more data are available (Recommendation grade C).

Expert high-resolution endoscopy (HRE) should be carriedout in all Barretts patients with biopsy-detected HGD inorder to detect visible abnormalities suitable for endoscopicresection (ER) (Recommendation grade B).

Visible lesions should be considered malignant until provenotherwise (Recommendation grade C).

Description of lesion morphology using the Paris classica-tion gives an indication of the likelihood of invasive cancerand aids communication between clinicians. This shouldtherefore be used for all visible lesions but cannot at presentbe used to predict prognosis (Recommendation grade C).

All patients with dysplasia or early cancer, for whom therapyis considered, should be discussed at the specialist MDT foroesophago-gastric cancer. This team should include an inter-ventional endoscopist, upper GI cancer surgeon, radiologistand a GI pathologist (minimum standard) (Recommendationgrade C).

Patients with dysplasia or early cancer should be informed oftreatment options and have access to consultation with allspecialists as required (Recommendation grade C).

Endoscopic therapy for Barretts-related neoplasia For HGD and Barretts-related adenocarcinoma conned to

the mucosa, endoscopic therapy is preferred over oesophagect-omy or endoscopic surveillance (Recommendation grade B).

Endoscopic therapy of Barretts neoplasia should be per-formed at centres where endoscopic and surgical options canbe offered to patients (Recommendation grade C).

A minimum of 30 supervised cases of ER and 30 cases ofendoscopic ablation should be performed to acquire compe-tence in technical skills, management pathways and compli-cations (Recommendation grade C).

ER should be performed in high-volume tertiary referralcentres. Radiofrequency ablation (RFA) should be performedin centres equipped with ER facilities and expertise(Recommendation grade C).

ER for Barretts-related neoplasia associated with visible lesions Endoscopic assessment will usually identify the area with the

most advanced neoplasia. ER should aim to resect all visibleabnormalities (Recommendation grade C).

ER is recommended as the most accurate staging interventionfor Barretts early neoplasia (Recommendation grade B).

ER should be considered the therapy of choice for dysplasiaassociated with visible lesions and T1a adenocarcinoma(Recommendation grade B).

For patients at high surgical risk, endoscopic therapy can beoffered as an alternative to surgery for treatment of good

prognosis T1b adenocarcinomas (T1b sm1, well differen-tiated and without lymph vascular invasion)(Recommendation grade C).

For T1b adenocarcinomas with involvement of the secondsubmucosal layer or beyond (T1b sm2-sm3), endoscopictherapy should not be considered curative (Recommendationgrade B).

The cap and snare technique with submucosal injection and

the band ligation technique without submucosal injection areconsidered to be equally effective (Recommendation grade A).

Pathology reporting of ER Use of a minimum dataset for the reporting of ER specimens

is recommended to ensure that all prognostic information isincluded in reports (Recommendation grade C).

The presence of tumour cells at the deep margin indicatesincomplete resection and warrants further treatment(Recommendation grade C).

Imaging for HGD and T1 carcinoma: role of CTpositron emis-sion tomography (PET) and endoscopic ultrasound (EUS) Before ER, neither CT nor PETCT have a clear role in the

staging of patients with Barretts HGD or suspected T1cancer and neither is routinely required (Recommendationgrade B).

Since EUS can both overstage and understage T1 lesions, itsroutine use cannot be recommended for staging before ERfor suspected early lesions (Recommendation grade B).

In selected cases where the endoscopist cannot excludeadvanced stage on the basis of the endoscopic appearance ofnodular lesions, EUS with or without ne needle aspiration(FNA) is recommended to inform the therapeutic decision(Recommendation grade C).

EUS with or without FNA of visible lymph nodes is recom-mended in selected cases with T1b (sm1) disease on stagingER for which endoscopic therapy is selected, because of thesignicant risk of lymph nodal involvement

(Recommendation grade C).Ablative therapy forat HGD and residual Barretts after ER In the presence of HGD or intramucosal cancer without

visible lesions (at HGD/intramucosal cancer), these shouldbe managed with an endoscopic ablative technique(Recommendation grade A).

There are few comparative data among ablative techniques,but RFA currently has a better safety and side-effect proleand comparable efcacy (Recommendation grade C).

Eradication of residual Barretts oesophagus after focal ERreduces the risk of metachronous neoplasia and is recom-mended (Recommendation grade B).

Endoscopic follow-up is recommended after endoscopictherapy of Barretts neoplasia, with biopsies taken from theGOJ and within the extent of the previous Barretts oesopha-gus (Recommendation grade B).

Surgical management of early Barretts neoplasia Surgical therapy is considered the treatment of choice for

early adenocarcinoma that has extended into submucosabecause of the signicant risk of lymph node metastasis(Recommendation grade B).

Oesophagectomy should be performed in high-volumecentres, as these are associated with lower in-hospital mortal-ity than low-volume centres (Recommendation grade B).

There is currently no evidence to support one techniqueof oesophagogastrectomy over another. It is recommendedthat the procedure is tailored to the particular case and

the expertise available in that centre (Recommendationgrade C).


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There are not sufcient data to recommend endoscopic sur-veillance after oesophagectomy for HGD or T1 adenocarcin-oma provided that surgery has removed all the Barrettsmucosa. Until further evidence is available, endoscopyshould be performed on a symptomatic basis(Recommendation grade C).

Documentation and audit of treatment for HGD and early cancer Findings and management decisions for HGD and early

cancer should be entered into the National Audit(Recommendation grade C).

Economic considerations There are insufcient data to indicate that endoscopic screen-

ing and surveillance for Barretts oesophagus are cost-effective. Further studies on non-endoscopic diagnosticmethods are awaited (Recommendation grade C).

Endoscopic therapy for dysplastic Barretts oesophagus andearly OAC is cost-effective compared with oesophagectomy(Recommendation grade B).

Strategies for chemoprevention and symptom control There is not yet sufcient evidence to advocate acid-

suppression drugs as chemopreventive agents(Recommendation grade C).

Use of medication to suppress gastric acid production is recom-mended for symptom control (Recommendation grade A).

Proton pump inhibitors (PPIs) have the best clinical prolefor symptomatic management (Recommendation grade A).

Antireux surgery is not superior to pharmacological acidsuppression for the prevention of neoplastic progression ofBarretts oesophagus (Recommendation grade C).

Antireux surgery should be considered in patients withpoor or partial symptomatic response to PPIs(Recommendation grade A).

There is currently insufcient evidence to support the use ofaspirin, non-steroidal anti-inammatory drugs (NSAIDs) orother chemopreventive agents in patients with Barretts

oesophagus (Recommendation grade C).Patient perspective All patients should be offered an appointment to discuss

management decisions. When intervention is considered,therapeutic options should be discussed with an endoscopistas well as a surgeon (Recommendation grade C).

Future developmentsThe following developments would revolutionise the care of

individuals with Barretts oesophagus and should be prioritiesfor policy makers and funders. A non-endoscopic test(s) for diagnosis and surveillance Studies to determine whether surveillance actually reduces

mortality Better understanding of the impact of screening and surveil-

lance on QOL More research into the use of advanced imaging modalities

to improve dysplasia detection and cost-effectiveness ofsurveillance

Better risk stratication biomarkers to augment or replacethe reliance on a histopathological assessment of dysplasiaand better inform the indication for endoscopic ablativetherapy

More studies on the natural history of Barretts oesophagus,especially in the context of very short segments of columnarlined epithelium, LGD and cases with particular molecularproles

Research is required to inform the debate surrounding

whether patients with LGD or no dysplasia should receiveablation therapy

Evidence that endoscopic therapies are durable and do notrequire long-term endoscopic monitoring or that long-termsurveillance can be replaced with a cost-effectivenon-endoscopic technique

Studies to further delineate the role of chemoprevention Health-economic studies should be performed in parallel

with trials to evaluate new management algorithms Effects of current and future care pathways on patient QOL

should be formally evaluated.

INTRODUCTION AND HISTORICAL PERSPECTIVESince the original eponymous description in 1950, there havebeen numerous denitions of the condition, Barretts oesopha-gus, which have led to difculties in diagnosis and managementas well as hampering comparison between research studies.Between 1950 and 1970, it was established that Barrettsoesophagus is an acquired condition occurring in response togastro-oesophageal reux leading to a columnar lined distaloesophagus.810 It then became apparent that this entityembraced a spectrum of at least three different cellular types,which commonly occur as a mosaic. These are principally agastric fundic-type (oxyntocardiac) epithelium comprisingmucus-secreting, parietal and chief cells, a cardiac-type (transi-tional) mucosa comprising almost entirely mucus-secreting cells,and an intestinal type characterised by goblet cells. 11 A multi-layered columnar epithelium is also described, possibly specicfor an early phase in the development of Barretts oesophagus.12

The association with adenocarcinoma was established in the1970s, and, as a result of this endoscopic surveillance, protocolshave been introduced. However, there has been signicantdebate surrounding which features of Barretts oesophagus pre-dispose to malignant conversion and hence which patientsshould be classied as having Barretts oesophagus and the fre-quency of follow-up advised. For example, the length of theBarretts segment (ultra-short, short and long) and the different

cellular subtypes (gastric or intestinal) have been subclassiedover the years with different recommendations emerging overtime and between different countries and specialist societies.More recently, there has been interest in whether the relativecontribution of individual lifestyle, inherited factors andmolecular alterations of the tissue might also alter the potentialfor malignant conversion.

DIAGNOSISDenition summaryIn these guidelines, we have taken the view that the basic den-ition should be descriptive of the acquired metaplastic state andclearly separated from the question of malignant potential. Theestimated likelihood of cancer development is an evolving area,which the working group felt should be assessed on the basis ofa synthesis of the endoscopic, histopathological and molecularfeatures according to the current evidence in order to informthe precise follow-up or surveillance recommendations.

Barretts oesophagus is dened as an oesophagus in which anyportion of the normal distal squamous epithelial lining has beenreplaced by metaplastic columnar epithelium, which is clearly visibleendoscopically (1 cm) above the GOJ and conrmed histopatho-logically from oesophageal biopsies (Recommendation grade C).

Endoscopic diagnosis of Barretts oesophagusand irregular Z-lineDening the GOJ

At the present time, the gold standard diagnostic tool forBarretts oesophagus is endoscopy. The term endoscopy here


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refers to standard transoral endoscopy; however, transnasalendoscopy has also been investigated and recently been provento be an accurate and well-tolerated alternative.13 14 Transnasalendoscopy has been shown to have a sensitivity and specicityof 98% and 100%, respectively, for the endoscopic diagnosis ofBarretts oesophagus when compared with standard endoscopyin the study of Shariff and coworkers13 (Evidence grade Ib).The role of transnasal endoscopy in Barretts oesophagus sur-

veillance is a different question and will be discussed below.At endoscopy, in order to ascertain whether there is a

columnar-lined segment in the lower oesophagus, it is essentialto accurately delineate the GOJ. This can be achieved by visua-lising the distal end of the palisade vessels, which lie in theoesophageal mucosa but penetrate the submucosal layer atthe level of the GOJ,15 or by delineating the proximal end ofthe gastric folds16 17 (Evidence grade III). Theoretically, the twolandmarks should coincide at the GOJ; however, the presenceof oesophagitis, the degree of insufation, vascular anatomicalvariants of the oesophageal vessels, as well as respiration andperistalsis can make the correspondence between these twolandmarks inconsistent.3 In a study comparing these two diag-nostic methods, the palisading criteria resulted in an overallpoor diagnostic reproducibility with a value of 0.14; endo-scopic experience had no impact on the level of agreement. 18

After an explanation of the Prague C&M Criteria (see below)using the gastric folds, there was a statistically signicantimprovement in diagnostic agreement (Evidence grade III).

Barretts oesophagus should be endoscopically distinguishedfrom an irregular Z-line, whereby the squamocolumnar junctionappears with tongues of columnar epithelium shorter than 1 cmand with no conuent columnar-lined segment. In a casecontrol study, an irregular Z-line has been found with higherfrequency in patients with reux disease19 (Evidence grade IIa).

Although one study found that about 40% of cases of irregularZ-line harboured IM on biopsy samples, the signicance of this

endoscopicnding is still unclear20

(Evidence grade III). Onlinesupplementary appendix 2 shows examples of normal GOJ andirregular Z-lines in contrast with clearly visible Barrett s.

The proximal limit of the longitudinal gastric folds withminimal air insufation is the easiest landmark to delineate theGOJ and is the suggested minimum requirement (Recommendation

grade B).

Documentation of endoscopic ndings ( proformaof minimum dataset)It is important to measure the length and shape of thecolumnar-lined segment using a standardised methodology inorder to aid communication between clinicians and to helpdetermine the level of diagnostic condence and the perceivedrisk of adenocarcinoma development, which can alter withsegment length as discussed below (table 1). It is appreciatedthat distinguishing between an irregular Z-line within physiolo-gically normal limits and a short tongue of columnar-linedmucosa can be very difcult. Endoscopists need to ensure thatthey have carefully delineated the GOJ as discussed above and,if uncertain about whether the appearance of an irregular Z-lineis sufcient to support a condent endoscopic diagnosis ofBarretts oesophagus, then an endoscopic diagnosis of Barrettsoesophagus should not be made. As stated in the denition col-umnar epithelium should be clearly visible endoscopically abovethe gastro-oesophageal junction. Since the diagnosis of anirregular Z-line is subjective and there is no accepted length

cut-off to distinguish between an irregular Z-line and Barrettsoesophagus, we would suggest that 1 cm (M of Prague criteria)

should be the minimum length for an endoscopic diagnosis ofBarretts (Evidence grade IV). Biopsies are generally not recom-mended if there is an irregular Z-line. However, according tothe degree of suspicion, biopsies may be performed to aid thediagnosis. If the biopsy specimens are taken within an irregularZ-line, with no clear endoscopic evidence of Barretts, theyshould be then labelled as GOJ and not oesophageal biopsysamples. Since the presence of pure fundic/oxyntic mucosa is avery rare nding in Barretts oesophagus, this pathological

nding would suggest sampling of the GOJ (see section onMinimum dataset for histopathology diagnosis and clinico-pathological correlation).

The Prague C&M classication for Barretts length is basedon validated, explicit, consensus-driven criteria.21 TheInternational Working Group for Classication of Oesophagitis(IWGCO) developed criteria including assessment of the cir-cumferential (C) and maximal (M) extent of the endoscopicallyvisualised Barretts segment, as well as endoscopic landmarkssuch as the diaphragmatic hiatal pinch and the proximal extentof the gastric folds. Video recordings were scored by an inter-national panel of 29 endoscopists, and the overall reliabilitycoefcients for endoscopic recognition of Barretts 1 cm was0.72, whereas for Barretts


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Endoscopic reporting should be performed using a minimumdataset including a record of the length using the Prague criteria(circumferential extent (C), maximum extent (M) of endoscopic-

ally visible columnar-lined oesophagus in centimetres and anyseparate islands above the main columnar-lined segment noted)(Recommendation grade B).

Biopsy protocol and site mapping

The Seattle biopsy protocol, which entails four-quadrantrandom biopsies every 2 cm in addition to targeted biopsies onmacroscopically visible lesions, is recommended at the time ofdiagnosis and at subsequent surveillance 26 (Evidence grade III).If a patient is unable to tolerate this procedure at the initial diag-nostic evaluation, often performed under local anaesthetic spray,then it is recommended that the patient is brought back at theearliest opportunity for further evaluation including the fullbiopsy protocol in order to inform further management.

Targeted biopsy samples from visible lesions should be takenbefore random biopsies. Distal areas should be biopsied rststarting 12 cm above the GOJ and advancing proximally tominimise obscured view from bleeding.

Histopathological diagnosisHistological features indicative of an oesophageal originof the biopsy specimensFrom a histopathological perspective, it has been proposed that:the true GOJ is distal to the end of the tubular oesophagus andproximal to rugal folds as shown by the presence of submucosaloesophageal glands in this region. Hence, the distinctionbetween columnar-lined oesophagus and IM at the gastriccardia (CIM) can only be made denitively histologically whencolumnar mucosa with or without IM is seen juxtaposed withnative anatomical oesophageal structures such as submucosalglands and/or gland ducts.2729 Reports also suggest that multi-layered epithelium or squamous islands are helpful, as the

former is reported as pathognomonic of Barretts, and the latterare almost always seen in continuity with the supercial portionof gland ducts.1 2 2 8 3 0 In large studies, however, native struc-tures are seen in only 1015% of biopsy samples and thereforeare present in less than one in six diagnostic procedures; adenitive oesophageal or gastric origin can only therefore bedetermined in the minority of biopsy samples.27 31 32 The greatmajority of samples may include columnar mucosa of cardiac,oxyntic or intestinal type, often juxtaposed with squamousmucosa, but lacking native structures. The presence of IM inthese is highly corroborative but not specic for a diagnosis ofBarretts oesophagus, as CIM cannot be condently ruled out(see below). Owing to the relative paucity of native structures,it is no longer considered helpful to classify these patientsseparately as in the previous guidelines. However, this infor-mation should be recorded, and the diagnosis of Barrettsoesophagus should take into account the degree of condencebased on a combined analysis of endoscopic and histopatho-logical criteria.

The relevance of IMIM in Barretts is most commonly of an incomplete (type II orIII) subtype comprising mucous cells and goblet cells, althougha complete type (type I with absorptive cells) may also beseen.33 34

There is a body of evidence to suggest that, of the types ofmetaplastic columnar epithelium in the oesophagus, intestinal is

the most biologically unstable with the greatest risk of neoplasticprogression through dysplasia to adenocarcinoma. This comes

from early pathological studies35 36 and more recent population-based studies37 (Evidence grade III). It is this evidence that hasled the AGA to conclude in their most recent guidelines that:for the purposes of this statement the denition of Barrettsesophagus is the condition in which any extent of metaplasticcolumnar epithelium that predisposes to cancer developmentreplaces the stratied squamous epithelium that normally linesthe distal esophagus. Presently intestinal metaplasia is required

for the diagnosis of Barretts metaplasia because intestinal meta-plasia is the only one of the three types of oesophageal colum-nar epithelium that clearly predisposes to malignancy.therefore we suggest that the term Barretts oesophagus pres-ently should be used only for patients who have intestinal meta-plasia in the esophagus.

This AGA denition of Barretts oesophagus is at odds withthe denition in previous BSG guidelines38 (BSG 2005) becauseof concern that conrmation of the presence of IM can belimited by sampling error in mucosal biopsy samples. In a studyby Harrison et al39 of 1646 biopsy samples from 125 patientswith long-segment Barretts oesophagus, the optimum numberof samples needed to demonstrate goblet cells in 67.9% ofendoscopies was eight, but, in contrast, if only four wereobtained, only 34.7% of endoscopies yielded a positive resultfor identication of goblet cells. Thus there are some data toshow that the chance of detecting goblet cells is maximised bytaking a minimum of eight samples throughout the Barrettssegment (Evidence grade III). In addition, Gatenbyet al40 foundthat, although the rate of development of dysplasia and cancerin patients without IM at index biopsies (n=322) was equal tothat of patients with IM (n=612), they also found that >50%of the patients without IM had evidence of IM at the 5-yearfollow-up and >90% were diagnosed with IM at 10 years(Evidence grade III). These two studies indicate that a singleendoscopy with a low number of biopsy samples is not sufcientto exclude IM, particularly in a short segment of Barretts

oesophagus.Two additional studies challenged the notion that IM is the

most biologically unstable type of columnar metaplasia in theoesophagus. Takubo et al41 carefully analysed the columnarmucosa adjacent to 141 early OACs resected endoscopically andfound that fewer than half of them showed evidence of IM,concluding that cancer may also arise in a non-intestinalised col-umnar epithelium (Evidence grade III). This study, however,does not indicate whether these patients had evidence of IM inthe remainder of their Barretts segment and therefore onecannot exclude the possibility that cancer may be associatedwith loss of intestinal differentiation. In a retrospective study,Kelty and colleagues found that the cancer risk in a historicalcohort of 379 patients with oesophageal IM was similar to agroup of 319 patients with columnar-lined oesophagus withoutIM (Evidence grade III).42 This study, however, lacks informa-tion about endoscopic ndings and whether patients withoutIM did go on to develop IM during later surveillance. Inkeeping with data from these studies, there is also evidence thatthe non-goblet columnar epithelium may harbour similarmolecular abnormalities to goblet cell epithelium.4346

On the other hand, the recent population-based study fromthe Northern Ireland register found that the annual incidence ofHGD and cancer in patients with IM is signicantly higher thanin those without IM (0.38% vs 0.07%).37 Even though thisstudy has some of the same limitations as the study of Keltyet al, it is a population study with over 8000 patients, of which

40% had documented endoscopic evidence of Barrettsoesophagus, and 20% had information on the length of


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Barretts (Evidence grade III). In addition, there was no signi-cant difference in the cancer incidence between patients withand without endoscopic correlation, suggesting that the absenceof endoscopy data in 60% of the cohort is unlikely to affect theoverall results.

For these reasons, even though the insistence of the identica-tion of IM to dene or conrm a diagnosis of Barretts oesopha-gus is problematic, it is recognised that the inclusion of

gastric-type mucosa in short tongues of columnar-linedoesophagus is of less clinical importance in terms of the likeli-hood of malignant transformation and has the potential togreatly inuence the frequency of diagnosis of Barrettsoesophagus at index endoscopy and the number of patientsentering into follow-up and surveillance programmes. This mayin turn profoundly inuence our understanding of the naturalhistory and biology of the condition. However, whether or notIM is present can be taken into consideration when determiningthe frequency and necessity of follow-up of patients. Hence, wesuggest that the presence of IM is not a prerequisite for the def-inition of Barretts oesophagus, but should be taken intoaccount when deciding on the clinical management, as discussedin the surveillance section.

Distinguishing between true Barretts oesophagus and IM of thecardiaIt is not recommended that biopsy specimens from the cardiaare taken routinely. However, if there is concern about theappearance at that site or if specimens are taken in patientshaving ablation therapy, then the following considerations needto be taken into account. Differentiation of oesophageal IMfrom IM of the proximal stomach (cardia) in a mucosal biopsysample from the GOJ region on morphological grounds is dif-cult in most circumstances, apart from when oesophageal nativestructures are seen. The different forms of IM may occur atboth sites, and, similarly, studies suggesting a distinctive type of

cytokeratin 7 and 20 immunocytochemical staining in Barrettshave not been sufciently reproducible to apply in routine set-tings.27 4750 In view of the lack of reliable markers to distin-guish between IM of the cardia and oesophagus, this distinctionneeds to be made endoscopically, and the endoscopist is there-fore required to carefully label the site from which biopsysamples were taken in reference to the endoscopic landmarks, inorder to inform the clinicopathological correlation.

Minimum dataset for histopathology diagnosis andclinicopathological correlationThe histopathological information needs to be integrated withthe endoscopic ndings in order to reach an accurate clinicaldiagnosis and determine the ramications for follow-up. Thepathologist should record the following elements in the histo-pathological report: number of biopsy samples analysed at each level; the type of mucosa present (squamous or columnar); the presence of any native oesophageal structures; the presence of gastric- (cardiac/fundic) or intestinal-type

metaplasia; the presence and grade of dysplasia.

This minimum dataset is recommended to standardise thehistopathological reporting for Barretts oesophagus and toensure that all the information required for the assessment ofdisease is included. This dataset can be incorporated into a pro-forma to facilitate the interpretation of the report, which is par-

ticularly encouraged in the presence of dysplasia. Examples of ashort proforma (gure 1) and a more comprehensive proforma

(gure 2) are given, which may be adapted to suit particularclinical settings and practice.

We have taken the decision to abandon the previous nomen-clature from the 2005 guidelines, since, although academicallyappealing, it was cumbersome and the distinction between diag-nostic, corroborative of and in keeping with are difcult toremember. In particular, as discussed above, although nativeoesophageal structures do identify the oesophageal origin of thebiopsy samples, these only occur in a minority and hencecannot be relied upon to help reach a diagnosis.

In the context of biopsy specimens condently labelled by the

endoscopist as being taken within the tubular oesophagus and inthe presence of endoscopically visible Barrett's oesophagus, thefollowing diagnostic terms are advocated:1. Barretts oesophagus with gastric metaplasia only (glandu-

lar epithelium with cardiac/fundic metaplasia)2. Barretts oesophagus with IM (glandular epithelium with

IM)3. No evidence of Barretts oesophagus (squamous mucosa

without glandular tissue).Online supplementary appendix 3 shows histological exam-

ples of Barretts with gastric metaplasia and IM.Particular attention to exclude sampling from the hiatus

hernia or cardia should be given when fundic/oxyntic mucosaonly is found, since pure fundic metaplasia is a rare nding in

Barretts oesophagus51 (Evidence grade III). This can be usefulwhen trying to distinguish between an irregular Z-line and trueBarretts oesophagus.

The endoscopist should record whether the biopsy samples aretaken at the GOJ (irregular Z-line, without convincing endo-scopic evidence of Barretts oesophagus), as this will lead to thedistinct histopathological diagnosis of Junctional mucosa withcardiac or oxyntic epithelium with/without intestinal metaplasia.

In order to improve the standard of care and to ease discussionbetween experts, the use of a minimum dataset is recommendedto report histopathologicalndings (Recommendation grade C).

SCREENING FOR BARRETTS OESOPHAGUS

In order to determine the usefulness and potential feasibility ofscreening, it is necessary to consider: the population prevalence;

Figure 1 Example of a short proforma for reporting histopathologydiagnosis and surveillance biopsy ndings. This could be adapted to

suit your locality.


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the identiable risk factors that might help focus screening onsubgroups at higher risk; and the diagnostic tests available. 52

Prevalence of Barretts oesophagusThe prevalence of Barretts oesophagus in the population atlarge remains uncertain, which is due to the need for endoscopyto dene this condition. Two studies have attempted to assessthe prevalence via endoscopy screening of the unselected adultpopulation. An Italian study conducted endoscopies in 1033individuals, showing a prevalence of Barretts oesophagus of1.3%.53 A Swedish population study of 1000 people revealed aprevalence of 1.6%.54 However, the limited participation rateremained a concern in both these studies, since it introduced arisk of selection bias resulting in a possible overestimate of theprevalence.

Risk factors for Barretts oesophagusMale gender,5557 older age5 6 5 8 and history of reux symp-toms5661 are the main established predictors of increased riskof Barretts oesophagus (Evidence grade IIa). There is also anassociation with obesity, at least when assessed as waist to hipratio56 62 and abdominal circumference63 (Evidence grade IIa),while studies of body mass index only have shown more contra-dictory results.6265 A history of cigarette smoking is associatedwith Barretts oesophagus in some studies,56 59 60 but not all.65

Familial clustering for Barretts oesophagus is reported in about7% of individuals with Barretts oesophagus or OAC.66 A posi-tive family history of Barretts oesophagus or OAC is associated

with an increased risk of Barretts oesophagus,66 67

and up to28% of rst-degree relatives of patients with OAC or Barrett s

HGD also have Barretts oesophagus.68 (Evidence grade IIa).Studies on familial aggregation have implicated genetic factorsin the development of Barretts,67 and a recent genome-wideassociation study has identied the rst two loci associated withthe disease.69 Studies on this topic are summarised in table 2.

Diagnostic technologiesThe diagnostic technologies used for screening also affect thefeasibility and cost-effectiveness of such a programme. Forexample, ultrathin transnasal endoscopy may have advantagesover standard endoscopy, and non-endoscopic cytology devicesmay also be much more suitable for population-based screening.The data on the sensitivity of these devices and associated assaysare summarised in table 3. The use of an immuno-based assaysignicantly enhances the sensitivity and specicity of a cytologycollection device (Cytosponge), and this is promising, butresults of further trials, such as the ongoing BEST2 trial, arerequired before such technologies can be recommended forscreening outside of research.

Since the literature search was conducted, a study has beenpublished demonstrating that patients belonging to practiceswith the lowest rates of gastroscopy are at greater risk of pooroutcome when oesophagogastric cancer is diagnosed.68 Thishighlights the importance of referring patients appropriately forendoscopy when risk factors are present.

Screening with endoscopy is not feasible or justied for anunselected population with gastro-oesophageal reux symptoms(Recommendation grade B).

Endoscopic screening can be considered in patients withchronic GORD symptoms and multiple risk factors (at least

Figure 2 Example of acomprehensive proforma for reportinghistopathology diagnosis andsurveillance biopsy ndings.


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three of age 50 years or older, white race, male sex, obesity).However, the threshold of multiple risk factors should belowered in the presence of a family history including at least onerst-degree relative with Barretts or OAC (Recommendationgrade C).

SURVEILLANCERationale for endoscopic surveillanceSurvival rate for invasive OAC is very poor with 40Heartburn or regurgitationHeartburn >once a week

III

Avidanet al59 2002 256 Barretts229 non-erosiveGORD

Prospective casecontrol study NERD vsBarretts oesophagus

No of reflux episodesHiatus herniaExcess of smoking and alcohol

IIa

El-Seraget al64 2005 36 with Barretts93 without Barretts

Retrospective casecontrol studyPatients with endoscopy + CT

BMIBMI>30: OR for Barretts 4.0 (95% CI 1.4 to 11.1)

IIa

Smithet al60 2005 167 with Barretts261 controls

Population-based casecontrol Weekly acid reflux (OR 29.7)Smoking (OR 3.1)Positive interaction between reflux and obesity or smoking

IIa

Cooket al55 2005 Meta-analysis male vs female Male/female ratio 1.96:1 Ia

Edelsteinet al62 2007 193 with Barretts211 controls

Casecontrol study Obesity: waist-to-hip ratio (OR 2.4)Association with BMI weaker

IIa

Corleyet al63 2007 320 with Barretts

316 with GORD317 controls

Caseco ntrol study Ob esity: associ ation with abd omina l circumferen ce >8 0

No association with BMI

IIa

Anderson et al65 2007 224 with Barretts227 with OAC260 controls

Population-based casecontrol study GORD symptoms, BMI and smoking associated with OA butnot Barretts

IIa

Edelsteinet al56 2009 197 with Barretts418 controls

Casecontrol study Older ageMale genderObesity (waist-to-hip ratio)Smoking

IIa

Tayloret al61 2010 Meta-analysis of 26 studies GORD symptoms associated with long-segment Barretts(heterogeneous association with short-segment Barretts)

Ia

Chaket al67 2002 58 with Barretts106 controls

Caseco ntrol study In in dividu als with famil y histo ry, OR fo r Barretts 12.2 (95%CI 3.3 to 44.8)

IIa

Suet al69 2012 Discovery cohort1852 with Barretts5172 controls

GWAS 6p21 locus OR 1.2116q24 OR 1.14

IIa

BMI, body mass index; GWAS, genome-wide association study; NERD, non-erosive reflux disease; OAC, oesophageal adenocarcinoma; OR, odds ratio.


Guidelines
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with a mean follow-up of 7.0 years (59 784 patient years). Theoverall risk of HGD and OAC was 0.22% per year (or 0.16%per year for OAC only), which increased to 0.38% per yearwhen the analysis was restricted to those with IM.37 In a Danishstudy, the ascertainment was through histopathology recordsonly on the basis of a diagnosis of IM. A total of 11 028patients were identied with a median follow-up of 5.2 years(58 547 patient years).90 Here the annual risk for HGD andOAC was 0.26% per year (or 0.12% for OAC only). The risk inthis Danish cohort is similar to that in individuals with shortsegments (0.11% per annum for


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Clinical and demographic risk factors associatedwith malignant progression

As discussed above, there is evidence that the presence of IMcorrelates with greater biological instability. This has been con-rmed in the population study on the Northern Irish cohort,where the cancer risk in patients with IM was almost threetimes as high as that in patients without IM.37

There have been multiple studies published over the last

20 years demonstrating that men are at increased risk of devel-oping OAC compared with women, and the median age peaksin the 6th decade. In the largest population dataset available,the overall risk (with and without IM for all segment lengths)was 0.28% per year in men and 0.13% per year in women.37

However, there is a paucity of data and inconsistency across thestudies concerning the association of male sex and the progres-sion to cancer (table 5) and hence different management formen is not currently indicated.

The same group has examined the effect of lifestyle factorsand has shown that current tobacco smoking was signicantlyassociated with an increased risk of progression (HR=2.03;95% CI 1.29 to 3.17) compared with never smokers, and acrossall strata of smoking intensity99 (Evidence grade III). Alcoholconsumption was not related to risk of progression. Measures ofbody size were rarely reported in studies, and body size was notassociated with risk of progression.

The majority of the recent studies (three meta-analyses, 11cohort studies and two casecontrol studies) reported a positivecorrelation between the length of Barretts segment and the riskfor adenocarcinoma, although this did not reach statisticalsignicance in all of them3 7 5 7 8 4 1 00113 (Evidence grade III)(table 5). Traditionally, 3 cm has been used as a cut-off to distin-guish between long and short segments, and this has beenreected in the majority of the studies. While this is arbitrary,data suggest that interobserver agreement is reduced for veryshort segments, especially once they are


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Table 5 Studies reporting association with Barretts oesophagus length and sex with cancer progression

Study Year No of patients/studies Study design Length of Barretts oesophagus Gender (male (M) vs female (F))

Desaiet al91 2011 967 patients with SSBO (16studies) vs a pool of 11 434with NDBO (57 studies)

Meta-analysis The annual incidence of OAC was 0.19% (95%CI 0.08 to 0.34) in SSBO as opposed to 0.33%(95% CI 0.28 to 0.38) overall

Not reported

Yousefet al102 2008 6 studies with informationon SSBO vs 26 studies with

information on LSBO

Meta-analysis The annual incidence of OAC was 0.61% (95%CI 3.1 to 12.2) in SSBO as opposed to 0.67%

in LSBO (95% CI 5.2 to 8.6)

OAC incidence: 1.02% per year(95% CI 0.63% to 1.64%) in M

and 0.45% (95% CI 0.22% to0.92%) in F

Thomaset al101 2007 258 patients with SSBO vs960 with LSBO (6 studies)

Meta-analysis Non-significant trend towards reduction in riskof developing cancer in SSBO (RR 0.55, 95% CI0.19 to 1.5). Patients who developed cancerhad significantly longer Barretts segments(p


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Until randomised controlled evidence is available, biomarkerpanels cannot yet be recommended as routine of care(Recommendation grade C).

PRACTICALITIES OF ENDOSOPIC SURVEILLANCEPatient selection and informed consentWhen Barretts oesophagus is detected at endoscopy and con-rmed by histopathological ndings, this diagnosis should bediscussed with the patient in the clinic, so that patient prefer-ence can be taken into account. Patients should receive an earlyoutpatient appointment (ideally within 46 weeks) to discussthe implications of this diagnosis with a physician with a clinicalinterest in Barretts. Discussion should include the low but sig-nicant cancer risk, possible lifestyle changes, whether or notthere is an indication for endoscopic surveillance, and the thera-peutic options if dysplasia is detected (endoscopic and surgical).Family history for Barretts oesophagus and OAC should also berecorded. If there is still uncertainty about a diagnosis of

Barretts that requires further work up, this should be clearlyexplained to the patient to avoid confusion. Written information

should be provided for the patient to take away using BSG (seeonlinesupplementary appendix 4) or other approved materialssuch as from MacMillan CancerBACUP (http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Oesophagusgullet/Pre-cancerousconditions/Barrettsoesophagus.aspx) or H-CAS (http://www.h-cas.org/barretts.asp).

Before seeking informed consent for surveillance, the diagno-sis of Barretts oesophagus should have been conrmed onendoscopic and histopathological grounds based on the criteriaabove. Because of the recent advancement in the endoscopictreatment of HGD and mucosal adenocarcinoma,114 132 it is nolonger appropriate to restrict surveillance to patients who aret, and willing, to undergo oesophagectomy. In addition, radio-therapy and/or chemo-radiotherapy may be treatment options inpatients with more advanced disease who are deemed not t forsurgery.133 However, the patient should be t for repeatedendoscopy procedures and endoscopic therapy if HGD or earlycancer is detected. Very few studies have used the performance

status (PS) to correlate patient tness with the outcome of endo-scopic therapy for GI early cancers.134 135 Endoscopic therapy

Figure 3 Surveillance ow chart for non-dysplastic Barretts oesophagus. The endoscopicpathological correlation is required for the appropriateclinical management of patients with Barretts oesophagus. The presence of intestinal metaplasia and the length of the Barretts segment inuencethe timing of the endoscopic surveillance. OGD, oesophagogastroduodenoscopy.


Guidelines
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can be safely performed in patients with Eastern CooperativeOncology Group PS 02.136 Therefore it is reasonable to con-sider endoscopic surveillance in patients with PS 02, providedthat the estimated patient life expectancy is sufciently long forthe individual to benet from surveillance if dysplasia or earlycancer were detected.

If surveillance is thought to be clinically indicated, then theclinician should discuss with the patient the possible benets ofsurveillance in detecting early-stage tumours and improvingcancer survival. However, this discussion should also mentionthe lack of randomised controlled data to prove the benets ofsurveillance, and clinicians must also emphasise to the patientthat the actual risk of death from oesophageal cancer is small.Furthermore, the disadvantages of endoscopy surveillanceshould also be discussed, including the small risks of the proced-ure26 and the associated psychological morbidity.137 Forexample, in an American study conducted in a population ofVeterans with a diagnosis of Barretts, more than half of thepatients missed their follow-up endoscopy, suggesting that notall patients are willing to adhere to surveillance programmes.138

Clinicians should also emphasise that, as with any monitoringprogramme, there is a failure rate, in that surveillance cannotguarantee to detect every tumour that may develop. There areno clear data to support how best to impart this complex infor-mation, and more work in this area is warranted.

Patients should have early access to an outpatient clinic to beinformed about a new diagnosis of Barretts oesophagus and to

have an initial discussion about the pros and cons of surveillancewith written information provided (Recommendation grade C).

For a given patient, whether or not surveillance is indicatedshould be determined on the basis of an estimate of the likeli-hood of cancer progression and patient tness for repeat endosco-

pies, as well as patient preference (Recommendation grade C).

Endoscopic assessmentTechnological advancement with new-generation charge coupleddevices has allowed the routine use of high-resolution endos-copy (HRE), which produces images with resolutions rangingfrom 850 000 to more than one million pixels. HRE allows nedenition of the mucosal layer for the recognition of subtle

supercial abnormalities, with theoretical advantage in the rec-ognition of dysplasia and Barretts oesophagus-related early

neoplasia. It is the opinion of the experts that HRE, in conjunc-tion with careful cleaning of the mucosal surface of mucus,saliva and food debris, is the minimum standard for the evalu-ation of patients with known Barretts oesophagus4; however, todate, there is no randomised trial comparing conventionalendoscopy with HRE in Barretts oesophagus dysplasia detec-tion (Evidence grade IV). In an RCT, HRE performed equallycompared with chromoendoscopy and narrow band imaging(NBI) in the overall diagnosis of dysplasia139 (Evidence gradeIb). Mucolytic agents (eg, 410%N-acetylcysteine) or antifoam-ing agents (eg, simethicone) can be used to disperse excessmucus and bubbles. There is also evidence that longer inspec-tion times during assessment with white light endoscopy is asso-ciated with an increased detection rate for HGD and earlycancer140 (Evidence grade III). This should be taken intoaccount when planning how much time to allocate for endo-scopic surveillance of very long segments of Barretts, particu-larly those longer than 10 cm.

Although transnasal endoscopy has been shown to be accuratein the diagnosis of Barretts oesophagus (Evidence grade Ib), therandomised studies performed so far either included a smallnumber of patients,14 or were performed in a low-risk popula-tion.13 Furthermore, it should be noted that the biopsy speci-mens taken with these endoscopes are signicantly smaller,13

and this may increase sampling bias and hamper the interpret-ation of dysplasia. Therefore there is currently a lack of robustdata to recommend transnasal endoscopy in routine Barretts

oesophagus surveillance.HRE should be used in Barretts oesophagus surveillance

(Recommendation grade C).There is insufcient evidence to recommend transnasal endos-

copy as a replacement for transoral endoscopy (Recommendationgrade C).

Use of chromoendoscopy and advanced endoscopic imagingAdvanced endoscopic imaging has been investigated to increasethe detection of both IM and dysplasia in Barretts oesophaguswith the aim to help target biopsies (table 7).

Chromoendoscopy uses dyes to enhance endoscopic detec-tion. Methylene blue (MB) is a vital dye actively absorbed by

columnar intestinal-type cells141

and has been used to improvethe yield of IM in Barretts oesophagus142144 (Evidence grade

Table 6 Studies investigating correlation of abnormal p53 expression by immunohistochemistry and cancer risk in Barretts oesophagus

Study Finding Sample size EDRN stageGrade ofevidence

Weston et al2001359 KaplanMeier curves differed significantly between p53-positive and-negative patients for outcome defined as progression of LGD

Progressors n=5,non-progressors n=43

Prospectivephase 4

IIa

Murray et al2006196 OAC/HGD end point: OR 8.42 (95% CI 2.37 to 30.0) Progressors n=35, controlsn=175

Phase 3:retrospective

IIa

SIkkemaet al2009198

HR 6.5 (95% CI 2.5 to 17.1) Remained a risk factor on multivariableanalysis


Prospectivephase 4

IIa

Youneset al1997370 Progression from LGD to HGD/OAC, p=0.0108. p53 accumulation has asensitivity of 100%, specificity of 93%, and a predictive value of a positivetest of 0.56



IIa

Skacelet al2002130 Progression from LGD to HGD/OAC. A correlation with clinical progressionwas seen, p=0.017 (88% sensitivity and 75% specificity for progression)



IIa

Bani-Hani 2000197 OR=2.99 (95% CI=0.57 to 15.76; p=0.197). Nested casecontrol(unmatched), n=12 cases


IIa

Kastelein 2012131 RR=6.2 (95% CI=3.6 to 10.9) Progressors n=49,non-progressors n=586


IIa

HGD, high-grade dysplasia; HR, hazard ratio; LGD, low-grade dysplasia; OAC, oesophageal adenocarcinoma; OR, odds ratio.


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III). In a historical cohort, Sharma and coworkers found signi-cant enrichment of IM in MB-targeted biopsy samples com-pared with random samples145 (Evidence grade III). Thedetection rate of IM and dysplasia during MB chromoendo-scopy has been investigated in a number of randomised andcohort studies with conicting data14151 (table 7). A recentmeta-analysis has found no incremental yield of both IM anddysplasia with MB chromoendoscopy compared with standardendoscopy with random samples152 (Evidence grade Ia). Itshould also be noted that MB may damage DNA, which,

coupled with the lack of evidence for efcacy, suggests that itsuse cannot be recommended153 (Evidence grade III).

Indigo carmine (IC) is a contrast agent that allows detailedinspection of the mucosal pattern in combination with magni-cation endoscopy.154 A prospective multicentre study found thatthe ridged/villous pattern had a 71% sensitivity for IM, whilethe irregular/distorted pattern had an 83% sensitivity and an88% specicity for HGD/early cancer155 (Evidence grade III).The limitation of IC chromoendoscopy is the need for highmagnication with consequent narrow eld of view. Only onerandomised trial has evaluated IC chromoendoscopy for detec-tion of dysplasia in Barretts, but failed to nd an increased rateof dysplasia compared with high-resolution white light endos-copy139 (Evidence grade Ib).

The value of acetic acid (AA) to improve the diagnostic yieldof surveillance endoscopy has also been studied. AA inducesintracellular protein denaturation, with swelling of the mucosalsurface and enhancement of the architecture. Randomised cross-over studies have produced contradictory results on the diagnos-tic yield of AA-enhanced magnication endoscopy for IM156 157

(Evidence grade Ib). AA-enhanced magnication endoscopy hasbeen shown to have a higher dysplasia yield in Barrettsoesophagus surveillance, with 24% of patients having histo-logical upgrade compared with a previous standard endoscopywith random biopsies performed in a non-specialist centre158

(Evidence grade III). In a large single-centre prospective study,Pohlet al159 found that AA-targeted biopsies had a sensitivity of

96.7% and a specicity of 66.5% for a diagnosis of HGD/earlycancer. A single-centre retrospective cohort study has showed

signicantly increased dysplasia yield (p=0.001) compared withstandard endoscopy with random biopsies160 (Evidence gradeIII). The same group showed that histology on AA-targetedbiopsies was more cost-effective than the Seattle protocol in ahigh-risk population.161 More data are needed to decide on theusefulness of this technique.

With recent technological advancements, virtual chromoendo-scopy has become available, which allows chromoendoscopywithout the use of dyes. This is based on light lters (NBI,Olympus) or post-image acquisition processing (i-scan, Pentax

and FICE, Fujinon). The most extensively studied virtual chro-moendoscopy technique in Barretts oesophagus is NBI, whichhighlights the mucosal pattern and the supercial vasculature.

A number of different classications have been proposed todescribe mucosal pits in non-dysplastic and dysplastic Barretts,which yielded high diagnostic accuracy162164 (Evidence gradeIII). When NBI was compared with standard imaging techniques,one prospective tandem study showed an incremental diagnosticyield for dysplasia in the per-patient analysis165 (Evidence gradeIIa), and two additional studies reported an increased dysplasiadetection only in the per-biopsy analysis139 166 (Evidence gradeIb). A meta-analysis of eight studies has found that NBI has a sen-sitivity and specicity of 96% and 94%, respectively, for the diag-nosis of HGD, and 95% and 65%, respectively, for the diagnosisof IM.167 However, the interobserver agreement for the inter-pretation of the NBI images is only moderate. 168 Overall, despitethe nding that NBI performed by an expert endoscopist mayincrease the targeted yield of dysplasia, it also transpires thathigh-resolution endoscopy alone is sufcient to maximise dyspla-sia detection on a per-patient basis.

Autouorescence imaging (AFI), which exploits endogenousuorophores excited by short wavelengths, has been studied inthe context of Barretts oesophagus.169 170 Initial single-centrecohort studies showed that AFI can improve the diagnostic yieldof dysplasia compared with standard endoscopy, but with afalse-positive rate as high as 80%171 172 (Evidence grade III). Toovercome this, AFI has been incorporated into an HRE-NBI

scope with magnication, also known as endoscopic trimodalimaging (ETMI). Although an initial multicentre non-

Table 7 Comparative studies between standard and advanced imaging techniques for the diagnosis of IM and dysplasia in Barrettsoesophagus

Study Year Technique Study designNo ofpatients

Increased detectionof IM

Increased detectionof dysplasia

Grade ofevidence

Sharmaet al145 2001 MB Cohort 158 p=0.024 N/A IIb

Cantoet al147 2000 MB Randomised MB vs WLE 43 p=0.0001 p=0.03 Ib

Ragunathet al150 2003 MB Randomised cross-over 57 p=0.032 p=ns Ib

Woet al151 2001 MB Randomised cross-over 47 p=ns p=ns Ib

Horwhatet al149 2008 MB Randomised cross-over 48 p=ns p=ns Ib

Gossneret al146 2006 MB Cohort cross-over 86 N/A p=0.053 IIa

Limet al148 2006 MB Randomised cross-over 30 N/A p=0.02* Ib

Ngamruengphong et al152 2009 MB Meta-analysis 450 p=ns p=ns Ia

Karaet al139 2005 IC/NBI Randomised cross-over 28 N/A p=ns Ib

Hoffman et al156 2006 AA Randomised cross-over 31 p


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randomised feasibility study showed that ETMI increased thediagnostic yield for dysplasia from 63% to 90% compared withstandard endoscopy with random biopsies173 (Evidence gradeIII), this was not conrmed in two subsequent multicentre ran-domised studies, where ETMI only improved the diagnosticyield of dysplasia in the per-biopsy analysis174 175 (Evidencegrade Ib). Overall, these studies showed that, in selected high-risk cohorts of patients, ETMI does not allow the requirement

for random biopsies to be abandoned. Further studies inlow-risk patients will inform whether AFI can have a role inreducing the number of biopsies without loss of diagnosticaccuracy.

Other imaging techniques that have showed some value

bsg barretts 13

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