British Society of Gastroenterology Guideline on the Diagnosis and Management of Barrett’s oesophagus Author list, expertise and affiliations · Rebecca Fitzgerald (Editor), Cambridge University Hospitals, MRC Cancer Cell Unit (BSG Oesophageal committee member) · Massimiliano di Pietro (Editor), Cambridge University Hospitals, MRC Cancer Cell Unit (Gastroenterologist with special interest in Barrett’s) · Krish Ragunath (Editor) Queens medical Centre, Nottingham University Hospitals (BSG Oesophageal Committee member), · Yeng Ang, GI Science Centre, University of Manchester, Salford Royal NHS Foundation Trust (BSG Oesophageal Committee member) · Jin-Yong Kang, St George’s Hospital, London (BSG Oesophageal Committee member) · Peter Watson, Royal Victoria Hospital, Belfast (BSG Oesophageal Committee member) · John de Caestecker, Leicester University Hospitals (BSG Oesophageal Committee secretary) · Nigel Trudgill, Sandwell and West Birmingham Hospitals (BSG Oesophageal Committee member) · Praful Patel, Southampton University Hospitals (BSG Oesophageal and Endoscopy Committee member) · Philip Kaye, Queens Medical Centre, Nottingham University Hospitals (Barrett’s Pathology expert and BSG Pathology Committee member) · Scott Sanders, South Warwickshire NHS Foundation trust (Barrett’s Pathology expert) · Maria O’Donovan, Cambridge University Hospitals (Barrett’s Pathology expert) · Elizabeth Bird-Lieberman, Cambridge University Hospitals, MRC Cancer Cell Unit (Gastroenterologist with special interest in Barrett’s biomarkers) · Pradeep Bhandari, Queen Alexandra Hospital, Portsmouth (BSG Endoscopy and Oesophageal committee member) · Janusz Jankowski, Leicester University Hospitals (BADCAT chair, NICE GI Advisory Group chair, BSG Clinical Studies Group: Cancer Prevention and Early Diagnosis chair) · Stephen Attwood, Northumbria Healthcare and Durham University (Association of Upper GI Surgeons, Committee member of BSG Surgical and Oesophageal sections) · Simon Parsons, Queens Medical Centre, Nottingham University Hospitals (Association of Upper GI Surgeons) · Duncan Loft, University Hospital, Coventry (Chairman, BSG Clinical Services and Standards Committee) · Jesper Lagergren, King’s College, London (Epidemiological and Barrett’s expert) · Paul Moayyedi, McMaster University, Hamilton, Ontario (Public Health and Cost-effectiveness expert) · Georgios Lyratzopoulos, University of Cambridge (Public Health and Cost-effectiveness expert) · Mimi McCord, Peter Benest (Patient representatives) AGREE II instrument appraisers Krish Ragunath, John de Caestecker, Yeng Ang External reviewers sought by the authors Laurence Lovat (University College Hospital London) Jacques Bergman (Academic Medical Centre, Amsterdam) Sponsor The development of these guidelines was sponsored by the Oesophageal section of the British Society of Gastroenterology (BSG) after commissioning by the clinical standards committee. Approval was also sought from the Association of Upper GI Surgeons (AUGIS) clinical standards committee. Abbreviations AA: acetic acid; AGA: American Gastroenterology Association; AGREE: Appraisal of Guidelines for Research and Evaluation; AFI: autofluorescence imaging; ALA: aminolaevulinic acid; APC: argon plasma coagulation; AspECT: Aspirin Esomeprazole Chemoprevention Trial; AUGIS: Association of Upper GI Surgeons; BAD CAT : Barrett's Dysplasia and Cancer Taskforce; Barrett’s: Barrett’s oesophagus; BEST: Barrett’s esophagus screening trial; BMI: body mass index; BOSS: Barrett’s oesophagus surveillance study; BSG: British Society of Gastroenterology; CCD: charge coupled devices; CE: capsule endoscopy CI: confidence intervals; CIM: cardia intestinal metaplasia; CT: computerized tomography; ER: endoscopic resection; ETMI: endoscopic trimodal imaging; EUS: endoscopy ultra-sound; FACS: fluorescence-activate cell sorting; FISH: fluorescent in-situ hybridization; FNA: fine needle aspiration; GI: gastro-intestinal; GOJ: gastro-oesophageal junction; GORD: gastro-oesophageal reflux disease; GWAS: genome-wide association study HGD: high grade dysplasia; H2RA: histamine-2 receptor antagonists; HR: hazard ration; HRE: high resolution endoscopy; IC: indigo carmine; IHC: immunohistochemistry; IM: intestinal metaplasia; IWGCO: International Working Group for Classification of Oesophagitis; LGD: low grade dysplasia; LSBO: long segment Barrett’s oesophagus; LVI: lymphovascular invasion; MB: methylene blue; MIO minimally invasive oesophagectomy; MDT: multi-disciplinary meeting; NBI: narrow band imaging; NDBO: non-dysplastic Barrett’s oesophagus; NERD: non-erosive reflux disease; NICE: National Institute for Health and Clinical Excellence ; NSAIDs: non-steroidal anti-inflammatory drugs; OAC: oesophageal adenocarcinoma; OGD: oesophagus-gastro-duodenoscopy; OR: odds ratio; PCR: polymerase chain reaction; PDT: photodynamic therapy ; PET: positron emission tomography; PPI: proton pump inhibitor; PS: performance status; QALY: quality-adjusted life year; QOL: quality of life; PSA: probabilistic sensitivity analyses; RCT: randomized controlled study; RFA: radiofrequency ablation; RR: relative risk; Sens: sensitivity; SIR: standardized incidence ratio; Sm: submucosal; Spec: specificity; SSBO: short segment Barrett’s oesophagus; TNE: transnasal endoscopy; WLE: white light endoscopy; WHO: world health organization CONTENTS 1. PURPOSE AND METHODS……………………………………………………………………………… 7 2. DISSEMINATION AND IMPLEMENTATION OF THE GUIDELINES………………………. 12 3. EXECUTIVE SUMMARY OF KEY RECOMMENDATIONS…………………………………….. 13 4. INTRODUCTION AND HISTORICAL PERSPECTIVE …………………………………………….. 22 5. DIAGNOSIS…………………………………………………………………………………………………….. 23 · Definition summary · Endoscopic diagnosis of Barrett’s oesophagus and irregular Z-line · Defining the gastro-oesophageal junction · Documentation of Endoscopic Findings · Biopsy protocol and site mapping · Histopathological diagnosis · Histological features indicative of oesophageal origin of the biopsies · The relevance of intestinal metaplasia · Distinguishing between true Barrett’s oesophagus, an irregular z-line and IM of the cardia · Minimum dataset for histopathology diagnosis and clinico-pathological correlation 6. SCREENING FOR BARRETT’S OESOPHAGUS…………………………………………………….. 32 · Prevalence of Barrett’s oesophagus · Risk factors for Barrett’s oesophagus · Diagnostic technologies 7. SURVEILLANCE……………………………………………………………………………………………….. 34 · Rationale for endoscopic surveillance · Clinical and demographic risk factors associated with malignant progression · Correlation of histopathological grade of dysplasia and tissue molecular markers with risk of malignant progression 8. PRACTICALITIES OF SURVEILLANCE…………………………………………………………………. 40 - Patient selection and informed consent - Endoscopic assessment - Use of chromoendoscopy and advanced endoscopic imaging - Biopsy protocol - Frequency of surveillance for non-dysplastic Barrett’s oesophagus - Histological diagnosis of dysplasia · Pathological features and reporting of dysplasia · Dysplasia subtypes · Distinguishing between LGD, HGD and carcinoma · Dysplasia reporting and reproducibility · Aids to histological diagnosis of dysplasia and p53 staining 9. MANAGEMENT OF DYSPLASIA AND EARLY CANCER……………………………………….. 56 · Indefinite for dysplasia, a controversial entity · Low grade dysplasia: surveillance or ablation · HGD and intramucosal cancer: getting the diagnosis right · Role of specialist teams and decision making · Endoscopic therapy for Barrett’s related neoplasia associated to visible lesions · Endoscopic Resection(ER) · ER techniques · Pathology reporting of ER specimens · Imaging for HGD and T1 carcinoma: role of EUS and CT-PET · Ablative therapy for flat HGD and residual Barrett’s oesophagus post-ER · Follow-up after endoscopic therapy · Pathological reporting of biopsies post ablation therapy · Surgical management for early Barrett’s neoplasia · Efficacy and safety · Volume effect in specialist surgical centres · Type of surgery Transhiatal oesophagectomy Vagal sparing oesophagectomy for HGD Merendino segmental oesophagectomy Minimally invasive laparoscopic or thoracoscopic oesophagectomy · Quality of life · Follow-up after surgical treatment of HGD or early carcinoma · Documentation and audit 10. ECONOMIC CONSIDERATIONS……………………………………………………………………….. 78 11. STRATEGIES FOR CHEMOPREVENTION AND SYMPTOM CONTROL………………….. 81 · Acid-suppression therapy · Proton pump inhibitors · Anti-reflux therapy · Non-steroidal anti-inflammatory drugs 12. PATIENT PERSPECTIVE……………………………………………………………………………………. 84 13. FUTURE DEVELOPMENTS………………………………………………………………………………… 85 14. ACKNOWLEDGEMENTS…………………………………………………………………………………… 86 15. WORKING GROUPS………………………………………………………………………………………… 86 16. BIBLIOGRAPHY……………………………………………………………………………………………….. 87 1. PURPOSE AND METHODS The purpose of this guideline is to provide a practical and evidence based resource for the management of patients with Barrett’s oesophagus and Barrett’s oesophagus related early neoplasia. This document is therefore aimed at gastroenterologists, physicians and nurse practitioners, as well as members of multidisciplinary teams (surgeons, radiologists, pathologists), who take decisions on the management of such patients. The population covered by these guidelines includes: patients with gastro-oesophageal reflux disease or other risk factors for Barrett’s (obesity, family history for Barrett’s and oesophageal adenocarcinoma); every patient with incident or prevalent Barrett’s oesophagus regardless of their age, sex or comorbidities; patients with early oesophageal adenocarcinoma and patients with intestinal metaplasia at the gastro-oesophageal junction with no endoscopic evidence of Barrett’s oesophagus. The previous British Society of Gastroenterology guidelines were published in 2005 and since then there have been advances in the diagnostic and management tools available. Within these guidelines we have systematically reviewed the literature in order to address controversial issues in Barrett’s oesophagus and to formulate practical recommendations to guide patient management. In particular we have covered the following key questions: 1. How should Barrett’s oesophagus be defined and which patients should undergo regular surveillance; 2. Are there clinical features associated with increased cancer risk in Barrett’s oesophagus, which should influence the frequency of endoscopic surveillance; 3. Are there diagnostic tools which should be utilized to screen the population at risk for Barrett’s oesophagus; 4. Which imaging modality should be used for the endoscopic diagnosis and surveillance of Barrett’s oesophagus; 5. How should we best manage dysplasia in Barrett’s oesophagus; 6. Which staging modality is preferred for Barrett’s related early oesophageal adenocarcinoma; 7. What are the indications for endoscopic and/or surgical therapy in Barrett’s related adenocarcinoma; 8. Are there minimum standards for training and maintenance of skills in the field of endoscopic therapy; 9. How should patients be followed up after endoscopic therapy 10. Are there chemopreventive interventions recommended to reduce the likelihood for the progression of Barrett’s oesophagus; 11. What are the priorities for research and development in the field of Barrett’s carcinogenesis The AGREE II instrument(1) was used to provide a methodological strategy for the development of the guidelines and to aid assessment of the quality of the guidelines. Three appraisers within the author list have assessed the compliance of the guidelines to the AGREE II domains. As part of the AGREE II criteria, external review of this manuscript was also performed by two internationally renowned experts in the field (Dr L Lovat and Prof J Bergman). The authors comprised gastroenterologists, endoscopists, surgeons, pathologists, economists, public health physicians and patient representatives. Individuals were selected based on their current membership of the relevant British Society of Gastroenterology committees or on the basis of their expertise in the field in order to ensure representation across all the relevant disciplines. A working group was formed for each topic (working groups listed in section 15) and the authors of that group were then responsible for conducting a comprehensive literature search to indentify references relevant to individual topics. Studies were divided according to their methodologies (systematic reviews and meta-analyses, randomised controlled trials, cohort studies, diagnostic studies and economic studies) and the rigour and quality of the study was evaluated using the SIGN checklist system (www.sign.ac.uk/methodology/checklists.html). The authors included as many studies as possible to support the evidence; however studies with sub-optimal quality were excluded or included if they represented the only evidence to address particular clinical questions. Cohort studies with very small patient groups, feasibility studies, systematic reviews without meta-analysis, biomarker pilot discovery studies were excluded from evidence generating literature, as well as studies with methodological flaws that were considered unacceptable after careful review. Evidence was finally scored using the North of England evidence based guidelines(2) as follows: · Ia: Evidence obtained from meta-analysis of randomised controlled trials. · Ib: Evidence obtained from at least one randomised controlled trial · IIa: Evidence obtained from at least one well-designed controlled 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 studies such as comparative studies, correlative studies and case studies. · IV: Evidence obtained from expert committee reports, or opinions or clinical experience of respected authorities. The literature search was performed for Nursing and Allied Health Literature (CINAHL) for English language articles published through December 2012. We performed additional searches of MEDLINE using the Ovid database, including Ovid MEDLINE 1948 to present and Ovid MEDLINE (R) in-process and other non-indexed citations. The principal search terms were Barrett’s (o)esophagus, dysplasia, screening, surveillance, high grade dysplasia, intramucosal carcinoma, radiofrequency ablation, endoscopic mucosal resection, photodynamic therapy, argon plasma coagulation, (o)esophagectomy, biomarkers, P53, model, economic and Markov. The panel graded each of the recommendations based on the strength of the evidence, taking into consideration limitations of the studies and weighing the difference between the estimated benefits and risks of the intervention. Therefore recommendations were graded as follows: · Grade A requires at least one randomised controlled trial 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 absence of directly applicable clinical studies. Recommendations were scored by each individual author on the basis of a 5-tier system comprising the following agreement categories: A+, strong agreement; A, agree with reservation; U, undecided; D, disagree, D+ strongly disagree. Statements that failed to reach substantial agreement among authors, defined as > 80% agreement (A or A+), on the first round of voting were revisited and modified according to authors’ comments. Further rounds of voting were then continued until substantial agreement (>80%) was reached. Appendix 1 shows the percentage of authors’ agreement on individual statements and the number voting required to meet the minimum threshold of 80%. Detailed attention has been paid to other published guidelines, in particular the AGA Medical position Statement(3), a recent systematic review with consensus statements (BADCAT)(4) and NICE guidelines for management of dysplastic Barrett’s(5, 6), in order to try to align International practices and to aid useful comparisons of clinical outcomes for audit and research. In formulating these guidelines we took into consideration benefits and risks for the population and national health system as well as side effects. For example we considered the benefits to the population derived from the reduction of the incidence and mortality for oesophageal adenocarcinoma achievable through screening, endoscopic surveillance for Barrett’s and endoscopic therapy for dysplasia. We considered risks inherent in invasive interventions, such as endoscopic surveillance and therapy. We also took into account implications for the health care system, which can arise from expensive interventions, such as endoscopic screening or surveillance, and economic considerations using existing data in the field. We considered psychological morbidity and reduction of quality of life due to repeated interventions (surveillance and endotherapy for dysplasia as a preventive measure for cancer development). Patient perspectives were taken into consideration by consulting with two patient representatives. These lay members were consulted from the outset to ensure that patient perspectives were taken into account during the literature review process and in deciding which topics should be addressed prior to the literature review process. Draft guidelines were then re-submitted to the lay members and modifications made in accordance with their comments. Following completion of the guidelines they underwent appraisal and external review in accordance with the AGREE II instrument, as discussed above. The recommendations were then posted on the BSG website for open consultation and reviewed by BSG and AUGIS Clinical Services Committee reviewers prior to publication. It is anticipated that a thorough review of these guidelines will be required in about 5 years and specific sections may need reviewing in the interim as new data emerge when results from the ongoing trials such as AspECT (UKCRN ID 1339), BEST (UKCRN ID 9461), BOSS (UKCRN ID 4943) and SURF (NTR1198) are available. 2. DISSEMINATION AND IMPLEMENTATION OF THE GUIDELINES These guidelines have been written to be as practical as possible and it is intended that this will be supplemented by endoscopic and histopathological images for educational purposes. Dissemination will be achieved through publication in the peer-reviewed journal Gut and through presentations at National BSG conferences as well as at relevant training courses. Some of the statements in these guidelines, particularly those concerning endoscopic therapy, are in line with NICE recommendations(6, 7), which represent an additional source of guidance for the management of this disease. In this manuscript we have provided tables, which should help guide practitioners to acquire the minimum dataset of clinical information in order to optimise patient management (endoscopy and pathology proforma) and ensure consistency between hospitals. There is also a patient information leaflet explaining the diagnosis of Barrett’s oesophagus and the latest surveillance recommendations. These can be easily adapted to individual clinical settings. Audit and monitoring of these guidelines will be carried out through users’ feedbacks on the BSG website forum (http://www.bsg.org.uk/forum). This is a list of elements in clinical practice that can be subject of monitoring and auditing activity: · Adherence of endoscopists to Seattle protocol · Use of minimum dataset for endoscopy reporting · Use of minimum dataset for pathology reporting · Revision of diagnoses of dysplasia by second GI pathologist · Adherence to recommendations for endoscopic surveillance · Volume of case of endoscopic therapy to assess fitness of service provision · Safety and efficacy of endoscopic therapy for Barrett’s dysplasia and early neoplasia · MDT discussion of cases with high grade dysplasia and Barrett’s early cancer 3. EXECUTIVE SUMMARY OF KEY RECOMMENDATIONS Diagnosis: - Barrett’s oesophagus is defined as an oesophagus in which any portion of the normal distal squamous epithelial lining has been replaced by metaplastic columnar epithelium, which is clearly visible endoscopically above the gastro-oesophageal junction and confirmed histopathologically from oesophageal biopsies. (Recommendation Grade C) -The proximal limit of the longitudinal gastric folds with minimal air insufflation is the easiest landmark to delineate the GOJ and is the suggested minimum requirement. (Recommendation grade B) - Endoscopic reporting should be done using a minimum dataset including a record of the length using the Prague criteria (circumferential extent (C) , maximum extent (M) of endoscopically visible columnar-lined oesophagus in centimetres 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 discussion between experts the use of a minimum dataset is recommended to report histopathological findings (Recommendation grade C). Screening for Barrett’s oesophagus: - Screening with endoscopy is not feasible or justified for an unselected population with gastro-oesophageal reflux symptoms. (Recommendation Grade B). - Endoscopic screening can be considered in patients chronic GORD symptoms and multiple risk factors (at least three of age 50 years or older, white race, male sex, obesity). However, the threshold should be lowered in the presence of family history including at least one first degree relative with Barrett’s or oesophageal adenocarcinoma (Recommendation grade C) Surveillance: - Although randomised controlled trial data are lacking, given the evidence from the published studies that surveillance correlates with earlier stage and improved survival from cancer, surveillance is generally recommended. (Recommendation grade B) - Endoscopic monitoring with histopathological assessment of dysplasia is the only current method of surveillance with sufficient evidence to be recommended. (Recommendation grade B) - Surveillance regimens should take into account the presence of IM and length of the Barrett’s segment (Recommendation grade B) - Dysplasia confirmed 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 biomarker panels 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 Barrett’s oesophagus and to have an initial discussion about the pros and cons of surveillance with written information provided. (Recommendation grade C) - For a given patient whether or not surveillance is indicated should be determined on the basis of an estimate of the likelihood for cancer progression and patient fitness for repeat endoscopies. (Recommendation grade C) - High-resolution endoscopy should be used in Barrett’s oesophagus surveillance. (Recommendation grade C) - Standard trans-oral endoscopy should be preferred to trans-nasal endoscopy for surveillance of Barrett’s oesophagus. (Recommendation grade C) - There is not sufficient evidence to recommend routine use of advanced imaging modalities, such as chromoendoscopy or “virtual chromoendoscopy”, in Barrett’s oesophagus surveillance. (Recommendation grade A) - Adherence to a quadrantic, 2cm biopsy protocol in addition to sampling any visible lesions is recommended for all patients undergoing surveillance. This should also apply to long segments. (Recommendation grade B) - Surveillance is generally not recommended in patients with intestinal metaplasia at the cardia or in those with an irregular Z-line regardless of the presence of intestinal metaplasia. (Recommendation grade C) - For patients with Barrett’s oesophagus shorter than 3 cm without intestinal metaplasia or dysplasia a repeat endoscopy with quadrantic biopsies is recommended to confirm the diagnosis. If repeat endoscopy confirms the absence of intestinal metaplasia discharge from surveillance is encouraged as the risks for endoscopy likely outweigh the benefits. (Recommendation grade C) - Patients with Barrett’s oesophagus shorter than 3 cm, with intestinal metaplasia, should receive endoscopic surveillance every 3-5 years. (Recommendation grade C) - Patients with segments of 3 cm or longer should receive surveillance every 2-3 years. (Recommendation grade C) Histopathological diagnosis of dysplasia - Given the important management implications for a diagnosis of dysplasia, we recommend that all cases of suspected dysplasia are reviewed by a second GI pathologist, with review in a cancer centre if intervention is being considered. (Recommendation grade C) - Given the difficulties associated with the management of the “indefinite for dysplasia” category, all such cases should also be reviewed by a second GI pathologist and the reasons for use of the “indefinite for dysplasia” category should be given in the histology report in order to aid patient management. (Recommendation grade C) - The addition of a p53 immunostain to the histopathological assessment may improve the diagnostic reproducibility of a diagnosis of dysplasia in Barrett’s oesophagus and should be considered as an adjunct to routine clinical diagnosis. (Recommendation grade B) Management of Dysplasia and Early Cancer - Patients with a diagnosis of indefinite for dysplasia should be managed with optimization of anti-reflux medication and repeat endoscopy in 6 months. If no definite dysplasia is found on subsequent biopsies then the surveillance strategy should follow the recommendation for non-dysplastic Barrett’s oesophagus. (Recommendation grade C) - Management of low grade dysplasia (LGD) is unclear in view of limited data about the natural history. It is essential that the diagnosis is confirmed by two pathologists and patients should be surveyed endoscopically at 6 monthly intervals. Currently ablation therapy cannot be recommended routinely until more data are available. (Recommendation grade C) - Expert high resolution endoscopy (HRE) should be carried out in all Barrett’s patients with biopsy-detected high grade dysplasia in order to detect visible abnormalities suitable for endoscopic resection (ER). (Recommendation grade B) - Visible lesions should be considered malignant until proven otherwise. (Recommendation grade C) - Description of lesion morphology using the Paris classification gives an indication of the likelihood of invasive cancer and aids communication between clinicians. This should therefore be used for all visible lesions but cannot at present be used to predict prognosis. (Recommendation grade C) - All patients with dysplasia or early cancer, for whom therapy is considered, should be discussed at the specialist MDT for oesophago-gastric cancer. This team should include an Interventional Endoscopist, Upper GI cancer Surgeon, Radiologist and a GI Pathologist (Minimum standard). (Recommendation grade C) - Patients with dysplasia or early cancer should be informed of treatment options and have access to consultation with all specialists as required. (Recommendation grade C) Endoscopic therapy for Barrett’s related neoplasia - For high grade dysplasia and Barrett’s-related adenocarcinoma confined to the mucosa endoscopic therapy is preferred over oesophagectomy or endoscopic surveillance. (Recommendation grade B) - Endoscopic therapy of Barrett's neoplasia should be performed at centres where endoscopic and surgical options can be offered to patients. (Recommendation grade C) - A minimum of 30 supervised cases of Endoscopic Resection (ER) and 30 cases of endoscopic ablation should be performed to acquire competence in technical skills, management pathways and complications. (Recommendation grade C) - Endoscopic Resection should be performed in high volume tertiary referral centres. RFA should be performed in centres equipped with ER facilities and expertise. (Recommendation grade C) Endoscopic resection (ER) for Barrett’s related neoplasia associated with visible lesions - Endoscopic assessment will usually identify the area with the most advanced neoplasia. ER should aim to resect all visible abnormalities. (Recommendation grade C) - ER is recommended as the most accurate staging intervention for Barrett’s early neoplasia. (Recommendation grade B) - ER should be considered the therapy of choice for dysplasia associated with visible lesions and T1a adenocarcinoma. (Recommendation grade B) - For patients at high surgical risk endoscopic therapy can be offered as an alternative to surgery for treatment of good prognosis T1b adenocarcinomas (T1b sm1, well differentiated and without lymph vascular invasion). (Recommendation grade C) - For T1b adenocarcinomas with involvement of the second sub-mucosal layer or beyond (T1b sm2-sm3) endoscopic therapy should not be considered curative. (Recommendation grade B) - The cap and snare technique with sub-mucosal injection and the band ligation technique without sub-mucosal injection are considered to be equally effective. (Recommendation grade A) Pathology reporting of ER - Use of a minimum data set for the reporting of endoscopic resection specimens is recommended to ensure all prognostic information is included in reports. (Recommendation grade C) - The presence of tumour cells at deep margin indicates incomplete resection and warrants further treatment. (Recommendation grade C) Imaging for HGD and T1 carcinoma: Role of CT-PET and EUS - Prior to ER neither CT nor PET-CT have a clear role in the staging of patients with Barrett’s HGD or suspected T1 cancer and neither is routinely required. (Recommendation grade B). - CT and PET-CT should be performed in cases with submucosal disease being considered for surgery. (Recommendation grade C) - Since EUS can both overstage and understage T1 lesions, its routine use cannot be recommended for staging prior to ER for suspected early lesions. (Recommendation grade B) - In selected cases where the endoscopist cannot exclude advanced stage on the basis of the endoscopic appearance of nodular lesions, EUS +/- FNA is recommended to inform the therapeutic decision. (Recommendation grade C) - EUS +/- FNA of visible lymph nodes is recommended in selected cases with T1b (sm1) disease on staging ER for which endoscopic therapy is selected, due to the significant risk of lymph nodal involvment. (Recommendation grade C) Ablative therapy for flat HGD and residual Barrett’s post-ER - In the presence of HGD without visible lesions (flat HGD), dysplasia should be 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 profile and comparable efficacy. (Recommendation grade C) - Eradication of residual Barrett’s oesophagus after focal ER reduces the risk of metachronous neoplasia and is recommended. (Recommendation grade B) - Endoscopic follow up is recommended following endoscopic therapy of Barrett’s neoplasia with biopsies taken from the GOJ and within the extent of the previous Barrett’s oesophagus. (Recommendation grade B). Surgical management of early Barrett’s neoplasia - Surgical therapy is considered the treatment of choice for early adenocarcinoma that has extended into submucosa due to the significant risk of lymph node metastasis. (Recommendation grade B) - Oesophagectomy should be performed in high volume centres as these are associated with lower in hospital mortality than low volume centres. (Recommendation grade B) - There is currently no evidence to support one technique of oesophago-gastrectomy over another. It is recommended that the procedure is tailored to the particular case and the expertise available in that centre. (Recommendation grade C) - There is not sufficient data to recommend endoscopic surveillance after oesophagectomy for HGD or T1 adenocarcinoma provided that surgery has removed all Barrett’s mucosa. Until further evidence endoscopy should 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 insufficient data to indicate that endoscopic screening and surveillance for Barrett’s oesophagus are cost-effective. Further studies on non-endoscopic diagnostic methods are awaited. (Recommendation grade C) - Endoscopic therapy for dysplastic Barrett’s oesophagus and early OAC is cost-effective compared to oesophagectomy. (Recommendation grade B) Strategies for chemoprevention and symptom control - There is not yet sufficient evidence to advocate acid suppression drugs as chemopreventive agents. (Recommendation grade C) - Use of medication to suppress gastric acid production is recommended for symptom control. (Recommendation grade A) - PPIs have the best clinical profile for symptomatic management. (Recommendation grade A) - There is not sufficient evidence to recommend anti-reflux surgery to prevent progression to cancer. (Recommendation grade C) - Anti-reflux surgery should be considered in patients with Barrett’s oesophagus with poor or partial symptomatic response to PPIs. (Recommendation grade A) - There is currently insufficient evidence to support the use of aspirin, NSAIDs or other chemopreventive agents in patients with Barrett’s 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 endoscopist as well as a surgeon. (Recommendation grade C) Future developments The following developments would revolutionise the care of individuals with Barrett’s oesophagus and should be priorities for policy makers and funders: · A non-endoscopic test(s) for diagnosis and surveillance · Better understanding of the impact of screening and surveillance on QOL · More research into the use of advanced imaging modalities to improve dysplasia detection and cost-effectiveness of surveillance · Better risk stratification biomarkers to augment or replace the reliance on a histopathological assessment of dysplasia and better inform the indication for endoscopic ablative therapy · More studies on the natural history of Barrett’s oesophagus, especially in the context of very short segments of columnar lined epithelium, low grade dysplasia and cases with particular molecular profiles · Evidence that endoscopic therapies are durable and do not require long-term endoscopic monitoring or replacement of long-term surveillance with a cost-effective non-endoscopic technique · 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 4. INTRODUCTION AND HISTORICAL PERSPECTIVE Since the original eponymous description in 1950 there have been numerous definitions of the condition Barrett’s oesophagus, which have led to difficulties in diagnosis and management as well as hampering comparison between research studies. Between 1950 and 1970 it was established that Barrett’s oesophagus was an acquired condition occurring in response to gastro-oesophageal reflux leading to a columnar lined distal oesophagus(8-10). It then became apparent that this entity embraced a spectrum of at least 3 different cellular types, which commonly occur as a mosaic. These are principally a gastric fundic-type (oxyntic) epithelium comprising mucus-secreting, parietal and chief cells; a cardiac-type (transitional) mucosa comprising almost entirely mucus secreting cells; and an intestinal type characterized by goblet cells(11). A multilayered columnar epithelium is also described, possibly specific for an early phase in the development of Barrett’s esophagus(12). The association with adenocarcinoma was established in the 1970’s and as a result of this endoscopic surveillance protocols have been introduced. However, there has been significant debate surrounding which features of Barrett’s oesophagus predispose to malignant conversion and hence which patients should be classified as having Barrett’s oesophagus and the frequency of follow-up advised. For example, the length of the Barrett’s segment (ultra-short, short and long) and the different cellular subtypes (gastric or intestinal) have been sub-classified over the years with differing recommendations emerging over time and between different countries and specialist societies. More recently there has been interest in whether the relative contribution of individual lifestyle, inherited factors and molecular alterations of the tissue might also alter the potential for malignant conversion. 5. DIAGNOSIS Definition summary In these guidelines, we have taken the view that the basic definition should be descriptive of the acquired metaplastic state and clearly separated from the question of malignant potential. The estimated likelihood of cancer development is an evolving area, which the working group felt should be assessed based on a synthesis of the endoscopic, histopathological and molecular features according to the current evidence in order to inform the precise follow-up or surveillance recommendations. Barrett’s oesophagus is defined as an oesophagus in which any portion of the normal distal squamous epithelial lining has been replaced by metaplastic columnar epithelium, which is clearly visible endoscopically above the gastro-oesophageal junction and confirmed histopathologically from oesophageal biopsies. (Recommendation grade C) Endoscopic diagnosis of Barrett’s oesophagus and irregular Z-line Defining the gastro-oesophageal junction (GOJ) At the current time the gold-standard diagnostic tool for Barrett’s oesophagus is endoscopy. The term endoscopy here refers to standard trans-oral endoscopy, however trans-nasal endoscopy has also been investigated and recently been proven to be an accurate and well tolerated alternative(13, 14). Trans-nasal endoscopy has been shown to have a sensitivity and specificity of 98 and 100%, respectively, for the endoscopic diagnosis of Barrett’s oesophagus when compared to standard endoscopy in the study from Shariff and co-workers (Evidence grade Ib). The role of trans-nasal endoscopy in Barrett’s oesophagus surveillance 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 essential to accurately delineate the gastro-oesophageal junction (GOJ). This can be done by visualising the distal end of the palisade vessels, which lie in the oesophageal mucosa but penetrate the submucosal layer at the level of the GOJ(15) or by delineating the proximal end of the gastric folds(16, 17), (Evidence grade III). Theoretically the two landmarks should coincide at the GOJ, however the presence of oesophagitis, the degree of insufflation, vascular anatomical variants of the oesophageal vessels, as well as respiration and peristalsis, can make the correspondence between these two landmarks inconsistent(3). In a study comparing these two diagnostic methods, the palisading criteria resulted in an overall poor diagnostic reproducibility with a kappa value of 0.14; endoscopic experience had no impact on the level of agreemen (18). After an explanation of the Prague C&M Criteria (see below) utilising the gastric folds there was a statistically significant improvement in diagnostic agreement. (Evidence grade III) Barrett’s oesophagus should be endoscopically distinguished from an irregular Z-line, whereby the squamo-columnar junction appears with tongues of columnar epithelium shorter than 1 cm and with no confluent columnar-lined segment. In a case-control study, an irregular Z-line has been found with higher frequency in patients with reflux disease(19) (Evidence grade IIa). Although one study found that about 40% of cases of irregular Z-line harboured IM on biopsies, the significance of this endoscopic finding is still unclear(20) (Evidence grade III). Appendix 2 shows examples of normal GOJ, irregular Z-lines in contrast to clearly visible Barrett’s. The proximal limit of the longitudinal gastric folds with minimal air insufflation is the easiest landmark to delineate the GOJ and is the suggested minimum requirement. (Recommendation grade B) Documentation of endoscopic findings (proforma of minimum dataset) It is important to measure the length and shape of the columnar-lined segment using a standardised methodology in order to aid communication between clinicians and to help determine the level of diagnostic confidence and the perceived risk for adenocarcinoma development, which can alter with segment length as discussed below (table 1). It is appreciated that distinguishing between an irregular Z-line within physiologically normal limits and a short tongue of columnar lined mucosa can be very difficult. Endoscopists need to ensure that they have carefully delineated the GOJ as discussed above and if uncertain about whether the appearance of an irregular Z-line is sufficient to support a confident endoscopic diagnosis of Barrett's oesophagus, then an endoscopic diagnosis of Barrett's oesophagus should not be made. As stated in the definition “columnar epithelium should be clearly visible endoscopically above the gastro-oesophageal junction”. Since the diagnosis of an irregular Z-line is subjective and there is no accepted length cut-off to distinguish between an irregular Z-line and Barrett’s oesophagus, we would suggest that 1 cm (M of Prague criteria) should be the minimum length for an endoscopic diagnosis of Barrett’s (Evidence grade IV).   According to the degree of suspicion, biopsies may be taken to aid the diagnosis. If the biopsies are taken within an irregular Z-line, with no clear endoscopic evidence of Barrett’s, they should be then labelled as GOJ and not oesophageal biopsies. Since the presence of pure fundic/oxyntic mucosa is a very rare finding in Barrett’s oesophagus, this pathological finding would suggest sampling of the GOJ, (see section on “Minimum dataset for histopathology diagnosis and clinico-pathological correlation”). The Prague C&M classification for Barrett’s length is based on validated, explicit, consensus-driven criteria(21). The International Working Group for Classification of Oesophagitis (IWGCO) developed criteria including assessment of the circumferential (C) and maximal (M) extent of the endoscopically visualized Barrett’s segment as well as endoscopic landmarks such as the diaphragmatic hiatal pinch and the proximal extent of the gastric folds. Video recordings were scored by an international panel of 29 endoscopists and the overall reliability coefficients for endoscopic recognition of Barrett’s >/=1 cm was 0.72, whereas for Barrett’s <1 cm, it was 0.22. The reliability coefficients for recognizing the location of the GOJ and the diaphragmatic pinch were 0.88 and 0.85, respectively (Evidence grade IIb). These findings have been reproduced in different patient populations(22, 23) and have been recently validated in a multicentre study(24) (Evidence grade III). The Prague classification includes recording as subtext the presence of Barrett’s islands, which are increasingly prevalent following endoscopic therapy. In future a modification of the Prague could provide an easier system for recording columnar lined epithelium that is not continuous with the squamo-columnar junction. The presence and the location of visible lesions should also be recorded according to the Paris classification(25) in order to improve lesion recognition at the time of endoscopic therapy. Information on the number of biopsies taken is necessary to assess quality of a surveillance endoscopy. Endoscopic reporting should be done using a minimum dataset including a record of the length using the Prague criteria (circumferential extent (C) , maximum extent (M) of endoscopically visible columnar-lined oesophagus in centimetres and any separate islands above the main columnar-lined segment noted). (Recommendation grade B) Biopsy protocol and site mapping The Seattle biopsy protocol, which entails 4-quadrant random biopsies every 2 cm in addition to targeted biopsies on macroscopically visible lesions, is recommended at the time of diagnosis and at subsequent surveillance(26), (Evidence grade III). If a patient is unable to tolerate this procedure at the initial diagnostic evaluation, often performed under local anaesthetic spray, then it is recommended that the patient is brought back at the earliest opportunity for further evaluation including the full biopsy protocol in order to inform further management. Targeted biopsies from visible lesions should be taken before random biopsies. Distal areas should be biopsied first commencing 1-2 cm above the GOJ and advancing proximally to minimize obscured view from bleeding. Histopathological diagnosis Histological features indicative of an oesophageal origin of the biopsies From a histopathological perspective it has been proposed that: ‘the true GOJ is distal to the end of the tubular oesophagus and proximal to rugal folds as shown by the presence of submucosal oesophageal glands in this region’. Hence, the distinction between columnar lined oesophagus and intestinal metaplasia at the gastric cardia (CIM) can only be made definitively histologically when columnar mucosa with or without IM is seen juxtaposed with native anatomical oesophageal structures such as submucosal glands and/or gland ducts(27-29). Reports also suggest that multilayered epithelium or squamous islands are helpful, as the former is reported as pathognomonic of Barrett’s, and the latter are almost always seen in continuity with the superficial portion of gland ducts(12, 28, 30). In large studies however native structures are seen in only 10-15% of biopsies and therefore are present in less than 1 in 6 diagnostic procedures; a definitive oesophageal or gastric origin can only therefore be determined in the minority of biopsies(27, 31, 32). The great majority of biopsies may include columnar mucosa of cardiac, oxyntic or intestinal type, often juxtaposed with squamous mucosa, but lacking native structures. The presence of IM in these biopsies is highly corroborative but not specific for a diagnosis of Barrett’s oesophagus, as CIM cannot be confidently ruled out (see below). Due to the relative paucity of native structures it is no longer considered helpful to classify these patients separately as in the previous guidelines. However, this information should be recorded and the diagnosis of Barrett’s oesophagus should take into account the degree of histopathological confidence based on a combined analysis of endoscopic and histopathological criteria. The relevance of intestinal metaplasia Intestinal metaplasia (IM) in Barrett’s is most frequently of an incomplete (type II or III) subtype comprising mucous cells and goblet cells, although a complete type (type I with absorptive cells) may also be seen(33, 34). There is a body of evidence to suggest that of the types of metaplastic columnar epithelium in the oesophagus, intestinal type is the most biologically unstable with the greatest risk for neoplastic progression through dysplasia to adenocarcinoma. This comes from early pathological studies(35, 36) and more recent population based studies(37), (Evidence grade III). It is this evidence that has led the AGA to conclude in their most recent guidelines that: “for the purposes of this statement the definition of Barrett’s esophagus is the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus. Presently intestinal metaplasia is required for the diagnosis of Barrett’s metaplasia because intestinal metaplasia is the only one of the three types of esophageal columnar epithelium that clearly predisposes to malignancy.”…“therefore we suggest that the term ‘Barrett’s oesophagus’ presently should be used only for patients who have intestinal metaplasia in the esophagus”. This AGA definition of Barrett’s oesophagus is at odds with the definition in previous BSG guidelines(38) (BSG 2005) due to concern that confirmation of the presence of IM can be limited by sampling error in mucosal biopsies. In a study by Harrison et al of 1646 biopsies from 125 patients with long segment Barrett's oesophagus, the optimum number of biopsies needed to demonstrate goblet cells in 67.9% of endoscopies was 8, but in contrast, if only 4 were obtained, only 34.7% of endoscopies yielded a positive result for identification of goblet cells(39). Thus there are some data to show that the chances of detecting goblet cells is maximized by taking a minimum of 8 biopsies throughout the Barrett's segment (Evidence grade III). In addition, Gatenby et al found that, although the rate of development of dysplasia and cancer in patients without IM at index biopsies (n=322) was equal to that of patients with IM (n=612), they also found that >50% of the patients without IM had evidence of IM at 5 years follow up and >90% were diagnosed with IM at 10y (Evidence grade III)(40). These two studies indicate that a single endoscopy with a low number of biopsies is not sufficient to exclude IM, particularly in a short segment of Barrett’s oesophagus. Two additional studies challenged the notion that IM is the most biological unstable type of columnar metaplasia in the oesophagus. Takubo et al carefully analysed the columnar mucosa adjacent to 141 early OACs resected endoscopically and found that less than half of them showed evidence of IM, concluding that cancer may also arise in a non-intestinalized columnar epithelium (Evidence grade III)(41). This study however does not indicate whether these patients had evidence of IM in the remainder of their Barrett’s segment and therefore one cannot exclude the possibility that cancer may be associated with loss of intestinal differentiation. In a retrospective study, Kelty and colleagues found that the cancer risk in a historical cohort of 379 patients with oesophageal IM was similar to a group of 319 patients with columnar lined oesophagus without IM (Evidence grade III)(42). This study however lacks information about endoscopic findings and whether patients without IM did go on to develop IM during later surveillance. In keeping with data from these studies, there is also evidence that the non-goblet columnar epithelium may harbour similar molecular abnormalities to goblet cell epithelium(43-46). On the other hand the recent population based study from the N Ireland register found that the annual incidence of HGD and cancer in patients with IM is significantly higher than in those without IM (0.38% vs 0.07 (37). Even though this study has some of the same limitations as the study from Kelty et al, it is a population study with over 8,000 patients, of which 40% had documented endoscopic evidence of Barrett’s oesophagus and 20% had information on the length of Barrett’s (Evidence grade III). In addition there was no significant difference in the cancer incidence between patients with and without endoscopic correlation suggesting that the absence of endoscopy data in 60% of the cohort is unlikely to impact the overall results. For these reasons even though the insistence of the identification of IM to define or confirm a diagnosis of Barrett’s oesophagus is problematic, it is recognised that the inclusion of gastric type mucosa in short tongues of columnar lined oesophagus is of lesser clinical importance in terms of the likelihood of malignant transformation and has the potential to greatly influence the frequency of diagnosis of Barrett’s oesophagus at index endoscopy and the number of patients entering into follow up and surveillance programmes. This may in turn profoundly influence our understanding of the natural history and biology of the condition. However, whether or not IM is present can be taken into consideration when determining the frequency and necessity for follow-up of patients. Hence, we suggest that the presence of IM is not a pre-requisite for the definition of Barrett’s oesophagus, but should be taken into account when deciding on the clinical management as discussed in the surveillance section. Distinguishing between true Barrett’s oesophagus and IM of the cardia Differentiation of oesophageal IM from IM of the proximal stomach ("cardia") in a mucosal biopsy from the GOJ region on morphological grounds is difficult in most circumstances, apart from when oesophageal native structures are seen. The different forms of IM may occur at both sites and, similarly, studies suggesting a distinctive type of cytokeratin 7 and 20 immunocytochemical staining in Barrett’s have not been sufficiently reproducible to apply in routine setting(27, 47-50). In view of the lack of reliable markers to distinguish between IM of the cardia and oesophagus, this distinction needs to be made endoscopically and the endoscopist is therefore required to carefully label the site from which biopsies were taken in reference to the endoscopic landmarks. Minimum dataset for histopathology diagnosis and clinico-pathological correlation The histopathological information needs to be integrated with the endoscopic findings in order to reach an accurate clinical diagnosis and determine the ramifications for follow-up. The pathologist should record the following elements in the histopathological report: · number of biopsies 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 standardize the histopathological reporting for Barrett’s oesophagus and to ensure that all the information required for the assessment of disease is included. This dataset can be incorporated into a proforma to facilitate the interpretation of the report, which is particularly encouraged in the presence of dysplasia. Examples of a short proforma (Table 2a) and a more comprehensive proforma (Table 2b) are given, which may be adapted to suit particular clinical settings and practice. We have taken the decision to abandon the previous nomenclature from the 2005 guidelines, since although academically appealing it was cumbersome and the distinction between "diagnostic", "corroborative of" and “in keeping with" are difficult to remember. In particular as discussed above, although native oesophageal structures do identify the oesophageal origin of the biopsies, these only occur in a minority of biopsies and hence cannot be relied upon to help reach a diagnosis. In the context of biopsies confidently labelled by the endoscopist as being taken within the tubular oesophagus the following diagnostic terms are advocated: 1) Barrett’s oesophagus with gastric metaplasia only (glandular epithelium with cardiac/fundic metaplasia) 2) Barrett’s oesophagus with intestinal metaplasia (glandular epithelium with intestinal metaplasia) 3) No evidence of Barrett’s oesophagus (squamous mucosa without glandular tissue). Appendix 3 shows histological examples of Barrett’s with gastric metaplasia and intestinal metaplasia. Particular attention to exclude sampling from the hiatus hernia or cardia should be given when fundic/oxyntic mucosa only is found, since pure fundic metaplasia is a rare finding in Barrett’s oesophagus(51) (evidence grade III). This can be useful when trying to distinguish between an irregular z-line and true Barrett’s oesophagus. The endoscopist should record whether the biopsies are taken at the gastro-oesophageal junction (irregular Z-line, without convincing endoscopic evidence of Barrett’s oesophagus), as this will lead to the distinct histopathological diagnosis of “Junctional mucosa with cardiac or oxyntic epithelium with/without intestinal metaplasia”  In order to improve the standard of care and to ease discussion between experts the use of a minimum dataset is recommended to report histopathological findings. (Recommendation grade C) 6. SCREENING FOR BARRETT’S OESOPHAGUS In order to determine the usefulness and potential feasibility of screening it is necessary to consider: the population prevalence; the identifiable risk factors which might focus screening on subgroups at higher risk; and the diagnostic tests available(52). Prevalence of Barrett’s oesophagus The prevalence of Barrett´s oesophagus in the population at large remains uncertain, which is due to the need for endoscopy to define this condition. Two studies have attempted to assess the prevalence in an endoscopy screening of the unselected adult population. An Italian study conducted endoscopies in 1033 individuals, showing a prevalence of Barrett’s oesophagus of 1.3%(53). A Swedish population study of 1000 people revealed a prevalence of 1.6%(54). However, the limited participation rate remained a concern in both these studies, since it introduced a risk of selection bias resulting in a possible over estimate of the prevalence. Risk factors for Barrett´s oesophagus Male gender(29-31), older age(55, 56) and history of reflux symptoms(55-59) are the main established predictors of increased risk of Barrett’s oesophagus (Evidence grade IIa). There is also an association with obesity, at least when assessed as waist to hip ratio(55, 60) and abdominal circumference(61) (Evidence grade IIa), while studies of BMI only have shown more contradictory results(60-63). A history of cigarette smoking is associated with Barrett’s oesophagus in some studies(55, 57, 58), but not all(63). Familial clustering for Barrett’s oesophagus is reported in about 7% of individuals with Barrett’s oesophagus or oesophageal adenocarcinoma(64). A positive family history for Barrett’s oesophagus or oesophageal adenocarcinoma is associated with an increased risk of Barrett’s oesophagus(64, 65) and in up to 28% of first degree relatives of patients with oesophageal adenocarcinoma or Barrett’s HGD also have Barrett’s oesophagus(66). (Evidence grade IIa). Studies on familial aggregation have implicated genetic factors in the development of Barrett’s(65) and a recent genome-wide association study has identified the first two loci associated with the disease(67). Studies on this topic are summarized in table 3. Diagnostic technologies The diagnostic technologies used for screening also impact the feasibility and cost-effectiveness of such a programme. For example, ultrathin transnasal endoscopy (TNE) may have advantages over standard endoscopy and non-endoscopic cytology devices may also be much more suitable for population based screening. The data on the sensitivity of these devices and associated assays is summarised in Table 4. The use of an immuno-based assay significantly enhances the sensitivity and specificity of a cytology collection device (CytospongeTM) device and this is promising, but results of further trials, such as the ongoing BEST2 trial, are required before such technologies can be recommended for screening outside of research. Screening with endoscopy is not feasible or justified for an unselected population with gastro-oesophageal reflux symptoms. (Recommendation grade B) Endoscopic screening can be considered in patients chronic GORD symptoms and multiple risk factors (at least three of age 50 years or older, white race, male sex, obesity). However, the threshold should be lowered in the presence of family history including at least one first degree relative with Barrett’s or oesophageal adenocarcinoma. (Recommendation grade C) 7. SURVEILLANCE Rationale for endoscopic surveillance Survival from invasive adenocarcinoma of the oesophagus is very poor with <13% overall survival at 5 years (68)(also available at: http://info.cancerresearchuk.org/cancerstats/). The aim of endoscopic surveillance is to detect cancer or pre-cancer at a stage when intervention may be curative. Specifically surveillance should detect cancer prior to invasion of the submucosa when the risk of lymph node metastases significantly increases and varies between 9 and 50% depending on the depth of invasion within the submucosa(69). The practice of surveillance is widespread among European and North American Gastroenterologists despite the lack of randomised controlled trial evidence to demonstrate its efficacy. The BOSS Trial which is a randomised controlled trial for systematic Barrett’s surveillance compared with endoscopy “at the time of need” is now in the follow-up phase and it is hoped that this will provide clear evidence one way or the other. In the meantime the current evidence base is from case-control cohorts and epidemiological retrospective cohort studies(70-77). (Evidence grade IIa) The first consideration with regards to the justification for Barrett’s surveillance is the annual cancer conversion rate. Historically, this has been quoted as 0.5% per annum based on a number of case series(78-84). These have tended to be small and subject to publication bias(85). However, two new population based studies have suggested that the true rate may be lower than this. In a N Ireland population based study the incidence of cancer and HGD was determined in 8,522 patients with an endoscopic diagnosis of Barrett’s with or without intestinal metaplasia with a mean follow-up of 7.0 years (59,784 patient years). The overall risk for HGD and OAC was 0.22% per year (or 0.16% per year for OAC only), which increased to 0.38% per year when the analysis was restricted to those with intestinal metaplasia(37). In a Danish study the ascertainment was through histopathology records only on the basis of a diagnosis of intestinal metaplasia. 11,028 patients were identified with a median follow-up of 5.2 years (58,547 patient years)(86). Here the annual risk for HGD and OAC was 0.26% per year (or 0.12% for OAC only). The risk in this Danish cohort is similar to that in individuals with short segments [(0.11% per annum for <3 cm in N Ireland cohort and 0.19% in a recent meta-analysis(87)],which is a group likely to be over-represented when ascertainment is based on histopathological criteria(88). Geographical differences in incidence between different countries should also be born in mind, as there is evidence of a higher incidence of oesophageal adenocarcinoma in the UK compared to other areas, including US and Northern Europe(89, 90). Meta-analyses are a useful calibrator and in the most recent published meta-analysis(87) 57 studies comprising 11,434 patients and 58,547 years of follow-up were selected from 3450 as meeting required criteria. Here the incidence of OAC in non-dysplastic Barrett’s was 0.33% (95% CI 0.28% to 0.38%) with no evidence of publication bias. When comparing the cancer risk in patients with Barrett’s oesophagus with other conditions, even taking the most conservative study, the standardized incidence ratio (SIR) of OAC was 11.3(86), which is: 4.7 fold higher than the colon cancer risk in ulcerative colitis(91); 3.9 fold higher than primary sclerosing cholangitis(92); 4.5 higher than the risk of any lymphoproliferative disorder/malignancy in coeliac disease(93); and roughly equal to the risk of breast cancer in first degree relatives of BRCA1/2 mutation carriers with breast cancer(94). Therefore, methods to detect individuals at increased risk merits careful consideration. If surveillance is worthwhile then it should detect earlier stage cancers and hence should be a reasonable predictor of longer survival. The published literature suggests that cancers detected during surveillance are generally earlier stage and associated with improved survival (Table 5) (Evidence grade IIa). However, although improved survival rates are the most desirable indicators of the effectiveness of any surveillance programme these data are often not available and when they are, are confounded by inherent lead-time bias and length bias. Although randomised controlled trial data are lacking, given the evidence from the published studies that surveillance correlates with earlier staging and improved survival from cancer, surveillance is generally recommended. (Recommendation grade B) Endoscopic monitoring with histopathological assessment of dysplasia is the only current method of surveillance with sufficient evidence to be recommended. (Recommendation grade B) Clinical and demographic factors associated with malignant progression As discussed above, there is evidence that the presence of IM correlates with greater biological instability. This has been confirmed in the population study on the N Irish cohort where the cancer risk in patients with IM was almost 3 times 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 for development of OAC compared with women and the median age peaks in 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 the studies concerning the association of male sex and the progression to cancer (Table 6) and hence different management for males is not currently indicated. The same group has examined the effect of lifestyle factors and has shown that current tobacco smoking was significantly associated with an increased risk of progression (HR = 2.03; 95% confidence interval, 1.29-3.17) compared with never smokers, and across all strata of smoking intensity(95), (Evidence grade III). Alcohol consumption was not related to risk of progression. Measures of body size were infrequently reported in studies, and body size was not associated with risk of progression. The majority of the recent studies (3 meta-analyses, 11 cohort studies and 2 case-control studies) reported a positive correlation between the length of Barrett’s segment and the risk for adenocarcinoma although this did not reach statistical significance in all of them(37, 57, 80, 96-109) (Evidence grade III) (Table 6). Traditionally 3 cm has been used as a cut-off to distinguish between long and short segments, and this has been reflected in the majority of the studies. Whilst this is arbitrary, data suggest that inter-observer agreement is reduced for very short segments especially once they are<1cm(21)). These studies are summarised in Table 6 (see recommendation below). Asides from segment length, the presence of ulcers, strictures and nodules are indicative of prevalent malignancy and should be re-assessed without delay including multiple targeted biopsies or diagnostic endoscopic resection (ER) if appropriate(82, 110). In the future surveillance intervals should take into account all the socio-demographic risk factors and characteristics of the Barrett’s segment; however such risk algorithms have not yet been developed and validated sufficiently. In the meantime the segment length seems the most striking discriminator and the low rate of progression in segments <3cm is sufficient to warrant differences in surveillance frequency (see Figure 1). Surveillance regimens should take into account the presence of IM and length of the Barrett’s segment. (Recommendation grade B) Intestinal metaplasia at the cardia and gastro-oesophageal junction The presence of IM in the gastric cardia or at the gastro-oesophageal junction is a common pathological finding at endoscopy and can occur in 5-18% of normal population(106, 111, 112). This appears to have a distinct epidemiological and clinical profile compared to Barrett’s oesophagus. IM at the cardia or GOJ has a higher prevalence in females and non-white races and according to some, but not all of the studies can be more frequently associated with H.pylori infection(106, 113, 114) (Evidence grade III). More importantly there is evidence that individuals with IM at the cardia or GOJ have a significantly lower cancer risk than Barrett’s patients(106, 115, 116). In particular one recent population study that followed up 86 patients with IM at the GOJ for a median interval of 8 years has found no incident cases of cancer(114). (Evidence grade III) Surveillance is generally not recommended in patients with intestinal metaplasia at the cardia or in those with an irregular Z-line regardless of the presence of intestinal metaplasia. (Recommendation grade C) Correlation of histopathological grade of dysplasia and tissue molecular markers with risk of malignant progression The risk of cancer in Barrett’s has been shown repeatedly to be higher in glandular mucosa harbouring intestinal metaplasia, as discussed earlier. The current biomarker is dysplasia which is based on morphological criteria and reflects the underlying complex array of molecular alterations leading to abnormal cell kinetics, differentiation status and epithelial polarity. During surveillance patients with non-dysplastic Barrett’s may be at least 10 times more likely to die from an unrelated cause than to develop OAC(87, 117-119). Furthermore, the risk appears to decrease over time since the initial diagnosis in non-dysplastic Barrett’s(120). In the Danish population study the risk for low grade dysplasia was 5 times higher than that for non-dysplastic Barrett’s(86) and in the N Ireland population the hazard ratio (HR) for development of HGD and OAC combined was 5.67 for LGD with no dysplasia as 1.00 as the referent(37) (Evidence grade III). In a Dutch study in which all cases of Barrett’s oesophagus with LGD were reviewed by expert histopathologists, the progression rate was 13.4% per annum for those that were confirmed compared to 0.49% per annum for the 85% of cases that were down-staged to non-dysplastic Barrett’s(121) (Evidence grade III). The impact of the consensus diagnosis on the progression rate was confirmed in a UK study(122). On the other hand in a US study with a similar design, the review by expert pathologists did not make any difference; however the kappa value for agreement for LGD was 0.18(99), highlighting the extreme practical limitations of this diagnosis. The extent of LGD, i.e. the number of biopsies with LGD, has also been suggested to correlate with risk for progression(123). However, a more recent study has not confirmed this finding(99). Overall, the natural history of low grade dysplasia is still unclear and is likely to be heavily influenced by the histopathological stringency of the diagnosis. Dysplasia confirmed by two GI pathologists is currently the best tissue biomarker for the assessment of cancer risk. (Recommendation grade B) A number of molecular abnormalities have been characterised during the progression to adenocarcinoma and several of these have been suggested as suitable for biomarkers to supplement or replace the current problematic assessment of dysplasia(124), (summarised in Supplementary table 1). Most of these have not been validated sufficiently to justify clinical use and technological considerations have also hampered application in routine histopathology laboratories. However, molecular methodologies are being increasingly introduced into routine clinical laboratories and more robust validation studies suggest that progress is being made(125). There is evidence that immunohistochemistry for p53 can improve inter-observer agreement for dysplasia and improve patient stratification(122, 126, 127) (Evidence grade III) (Table 7). This is discussed in more detail in the section on the histopathological diagnosis of dysplasia. Until randomised controlled evidence is available biomarker panels cannot yet be recommended as routine of care. (Recommendation grade C) 8. PRACTICALITIES OF ENDOSOPIC SURVEILLANCE Patient selection and informed consent When Barrett’s oesophagus is detected at endoscopy and confirmed by histopathological findings, this diagnosis should be discussed with the patient in the clinic. Patients should receive an early outpatient appointment (ideally within 4 to 6 weeks) to discuss the implications of this diagnosis with a physician with a clinical interest in Barrett’s. Discussion should include the low but significant cancer risk, possible life style changes, whether or not there is an indication for endoscopic surveillance and the therapeutic options if dysplasia is detected (endoscopic and surgical). Family history for Barrett’s oesophagus and oesophageal adenocarcinoma should also be recorded. If there is still uncertainty about a diagnosis of Barrett’s that requires further work up, this should be clearly explained to the patient to avoid confusion. Written information should be provided for the patient to take away using BSG (Appendix 4) or other approved materials such 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). Prior to seeking informed consent for surveillance, the diagnosis of Barrett’s oesophagus should have been confirmed on endoscopic and histopathological grounds based on the criteria above. Due to the recent advancement in the endoscopic treatment for HGD and mucosal adenocarcinoma(110, 128) it is no longer appropriate to restrict surveillance to patients who are fit, and willing, to undergo oesophagectomy. In addition, radiotherapy and/or chemo-radiotherapy may be treatment options in patients with more advanced disease who are deemed not fit for surgery(129). However, the patient should be fit for repeated endoscopy procedures and endoscopic therapy if HGD or early cancer is detected. Very few studies have used the performance status (PS) to correlate patient fitness with the outcome of endoscopic therapy for GI early cancers(130, 131). Endoscopic therapy can be safely performed in patients with ECOG PS 0-2 (132). Therefore it is reasonable to consider endoscopic surveillance in patients with PS 0-2, provided that the estimated patient life expectancy is sufficiently long for the individual to benefit from surveillance if dysplasia or early cancer were detected. If surveillance is thought to be clinically indicated then the clinician should discuss with the patient the possible benefits of surveillance in detecting early stage tumours and improving cancer survival. However, this discussion should also mention the lack of randomised controlled data to prove the benefits of surveillance and clinicians must also emphasise to the patient that the actual risk of death from oesophageal cancer is small. Furthermore, the disadvantages of endoscopy surveillance should also be discussed including the small risks of the procedure(26) and the associated psychological morbidity(133). For example, in an American study conducted in a population of Veterans with a diagnosis of Barrett’s more than half of the patients missed their follow up endoscopy, suggesting that not all patients are willing to adhere to surveillance programmes(134). Clinicians should also emphasise that, as with any monitoring programme, there is a failure rate, in that surveillance cannot guarantee to detect every tumour that may develop. There are no clear data to support how best to impart this complex information and more work in this area is warranted. Patients should have early access to an outpatient clinic to be informed about a new diagnosis of Barrett’s oesophagus and to have an initial discussion about the pros and cons of surveillance with written information provided. (Recommendation Grade C) For a given patient whether or not surveillance is indicated should be determined on the basis of an estimate of the likelihood of cancer progression and patient fitness for repeat endoscopies. (Recommendation Grade C) Endoscopic assessment Technological advancement with new generation charge coupled devices (CCDs) has allowed the routine use of high resolution endoscopes (HRE), which produce images with resolutions ranging from 850,000 to more than 1 million pixels. HRE allows fine definition of the mucosal layer for the recognition of subtle superficial abnormalities, with theoretical advantage in the recognition of dysplasia and Barrett’s oesophagus-related early neoplasia. It is the opinion of the experts that HRE, in conjunction with careful cleaning of the mucosal surface from mucus, saliva and food debris, is the minimum standard for the evaluation of patients with known Barrett’s oesophagus(4), however to date there is no randomized trial comparing conventional endoscopy with HRE in Barrett’s oesophagus dysplasia detection (Evidence grade IV). In an RCT, HRE performed equally compared with chromoendoscopy and NBI in the overall diagnosis of dysplasia(135) (Evidence grade Ib). Mucolytic agents (e.g. 4-10% N-acetylcysteine) or anti-foaming agents (e.g. simethicone) can be used to disperse excess of mucus and bubbles. There is also evidence that longer inspection times during assessment with white light endoscopy is associated with an increased detection rate for HGD and early cancer(136) (Evidence grade IIb). This should be taken into account when planning how much time to allocate for endoscopic surveillance of very long segments of Barrett’s, particularly those longer than 10cm. High-resolution endoscopy should be used in Barrett’s oesophagus surveillance. (Recommendation grade C) Although trans-nasal endoscopy has been showed to be accurate in the diagnosis of Barrett’s oesophagus (Evidence grade Ib), the randomized studies performed so far either included a small number of patients(14), or were performed in a low risk population(13). Furthermore, it should be noted that the biopsies taken with these endoscopes are significantly smaller(13) and this may increase sampling bias and hamper the interpretation of dysplasia. Therefore there is currently lack of robust data to recommend trans-nasal endoscopy in routine Barrett’s oesophagus surveillance. Standard high resolution trans-oral endoscopy should be preferred to trans-nasal endoscopy for surveillance of Barrett’s oesophagus. (Recommendation grade C) Use of chromoendoscopy and advanced endoscopic imaging Advanced endoscopic imaging has been investigated to increase the detection of both IM and dysplasia in Barrett’s oesophagus with the aim to help target biopsies (Table 8). Chromoendoscopy uses dyes to enhance endoscopic detection. Methylene blue (MB) is a vital dye actively absorbed by columnar intestinal-type cells(137) and has been used to improve the yield of IM in Barrett’s oesophagus(138-140) (Evidence grade III). In a historical cohort, Sharma and co-workers found a significant enrichment of IM in MB-targeted biopsies compared to random biopsies(141) (Evidence grade IIb). Detection rate of IM and dysplasia during MB chromoendoscopy has been investigated in a number of randomized and cohort studies with conflicting data(142-147) (Table 8). A recent meta-analysis has found no incremental yield of both IM and dysplasia with MB chromoendoscopy compared to standard endoscopy with random biopsies(148) (Evidence grade Ia). Indigo carmine (IC) is a contrast agent that allows detailed inspection of the mucosal pattern in combination with magnification endoscopy(149). A prospective multi-centre study found that the ridged/villous pattern had a 71% sensitivity for IM, while the irregular/distorted pattern had an 83% sensitivity and an 88% specificity for HGD/early cancer(150) (Evidence grade III). The limitation of IC chromoendoscopy is the need for high magnification with consequent narrow field of view. Only one randomized trial has evaluated IC chromoendoscopy for detection of dysplasia in Barrett’s, but failed to find an increased rate of dysplasia compared to high resolution white light endoscopy(135) (Evidence grade Ib). The value of acetic acid (AA) to improve the diagnostic yield of surveillance endoscopy has also been studied. AA induces intracellular protein denaturation, with swelling of the mucosal surface and enhancement of the architecture. Randomized cross-over studies have produced contradictory results on the diagnostic yield of AA-enhanced magnification endoscopy for IM(151, 152)) (Evidence grade Ib). AA-enhanced magnification endoscopy has been shown to have a higher dysplasia yield in Barrett’s oesophagus surveillance with 24% of patients having histological upgrade compared to a previous standard endoscopy with random biopsies performed in a non-specialist centre(153), (Evidence grade III). In a large single centre prospective study, Pohl et al found that AA targeted biopsies had a sensitivity of 96.7% and a specificity of 66.5% for a diagnosis of HGD/early cancer(154). A single centre retrospective cohort study has showed significantly increased dysplasia yield (p=0.001) compared to standard endoscopy with random biopsies(155) (Evidence grade III). The same group showed that histology on AA targeted biopsies was more cost-effective than the Seattle protocol in a high risk population(156). More data are needed to decide on the usefulness of this technique. With recent technological advancements “virtual chromoendoscopy” has become available, which allows chromoendoscopy without the use of dyes. This is based on light filters (narrow band imaging, Olympus) or post image acquisition processing (i-scan, Pentax and FICE, Fujinon). The most extensively studied “virtual chromoendoscopy” technique in Barrett’s oesophagus is narrow band imaging (NBI), which highlights the mucosal pattern and the superficial vasculature. A number of different classifications have been proposed to describe mucosal pits in non-dysplastic and dysplastic Barrett’s, which yielded high diagnostic accuracy(157-159), (Evidence III). When comparing NBI with standard imaging techniques, one prospective tandem study showed an incremental diagnostic yield for dysplasia in the per-patient analysis(160) (Evidence grade IIa) and two additional studies reported an increased dysplasia detection only in the per-biopsy analysis(135, 161) (Evidence grade Ib). A meta-analysis of 8 studies has found that NBI has a sensitivity and specificity of 96 and 94%, respectively, for the diagnosis of HGD, and 95 and 65%, respectively, for the diagnosis of IM(162). However, the inter-observer agreement for the interpretation of the NBI images is only moderate(163). Overall, despite the finding that NBI performed by an expert endoscopist may increase the targeted yield of dysplasia, it also transpires that high-resolution an endoscopy alone is sufficient to maximize dysplasia detection on a per-patient basis. Autofluorescence imaging (AFI), which exploits endogenous fluorophores excited by short wavelengths, has been studied in the context of Barrett’s oesophagus(164, 165). Initial single-centre cohort studies showed that AFI can improve the diagnostic yield of dysplasia compared to standard endoscopy, however with a false positive rate as high as 80%(166, 167) (Evidence grade III). To overcome this, AFI has been incorporated in a HRE-NBI scope with magnification, also known as endoscopic Trimodal Imaging (ETMI). Although an initial multi-centre non-randomized feasibility study showed that ETMI increased the diagnostic yield for dysplasia from 63 to 90% compared to standard endoscopy with random biopsies(168) (Evidence grade III), this was not confirmed in two subsequent multi-centre randomized studies, where ETMI only improved the diagnostic yield of dysplasia in the per-biopsy analysis(169, 170) (Evidence grade Ib). Overall, these studies showed that in selected high risk cohorts of patients, ETMI does not allow one to abandon the requirement for random biopsies. Further studies in low risk patients will inform whether AFI can have a role in reducing the number of biopsies without loss of diagnostic accuracy. Other imaging techniques that have showed some value in Barrett’s oesophagus include confocal laser endomicroscopy, spectroscopy and optical coherence tomography(165, 171-173), however further studies are needed to clarify whether they can improve diagnostic accuracy during Barrett’s oesophagus surveillance. In the future, molecular imaging may improve our imaging armamentarium to increase dysplasia detection. Molecular imaging exploits fluorescently labelled molecules that bind with different affinity to dysplastic compared to non-dysplastic cells. Two types of compound have been studied so far. In a proof of principle study, Li and colleagues identified a 7-aminoacid peptide that binds an oesophageal adenocarcinoma cell line more avidly than a non-dysplastic Barrett’s oesophagus cell line and they confirmed the differential binding in surgical specimens of oesophageal adenocarcinoma ex vivo(174). Similarly, Bird-Lieberman and co-workers identified a natural lectin (wheat germ agglutinin) that differentially binds surface glycoproteins of dysplastic and non-dysplastic cells and used an auto-fluorescence endoscope in surgically resected oesophagi to validate the ex vivo findings(175). In vivo studies are needed to validate these techniques. There is not sufficient evidence to recommend routine use of advanced imaging modalities, such as chromoendoscopy or “virtual chromoendoscopy”, in Barrett’s oesophagus surveillance. (Recommendation grade A) Biopsy protocol To find dysplasia endoscopists have generally relied on the directed sampling of any visible lesions, which may be aided by enhanced endoscopic visualisation tools as discussed above, together with systematic, 4-quadrant biopsies every 2 cm according to the so-called “Seattle protocol”(26) . A prospective study has demonstrated a significant increase in the detection of early lesions through the introduction of such a protocol(176) (Evidence grade III). However, adherence to this protocol is limited and ranges from 10% to 79% with poorer adherence for longer segments(177-179) and failure to adhere to the protocol has been shown to result in a significantly lower rate of dysplasia detection(180). Overall, although intense and time-consuming, the multiple biopsies involved in the Seattle protocol have been demonstrated to be safe when performed by experienced endoscopists (26). Another limitation of this technique is the high cost generated by processing multiple biopsies, but this still seems justified at the current time in the absence of an alternative. Future RCTs will need to compare cost-effectiveness of the standard practice with alternative techniques such as histology on targeted biopsies guided by conventional or virtual chromoendoscopy. Adherence to a quadrantic, 2cm biopsy protocol in addition to sampling any visible lesions is recommended for all patients undergoing surveillance. This should also apply to long segments. (Recommendation Grade B) Frequency of surveillance for non-dysplastic Barrett’s oesophagus (Figure 1) In the previous BSG guidelines published in 2005 the recommended surveillance interval for non-dysplastic Barrett’s was every 2 years. However, given the recent data suggesting that the overall risk for malignant conversion is lower than previously thought we recommend that the interval should be lengthened in line with other guidelines(3). We therefore advocate a new surveillance strategy whereby the managing clinician synthesizes the endoscopic and histopathological findings to tailor the surveillance interval on a more individual basis (Figure 1). A degree of variation in this interval is permitted which may be influenced by the presence of risk factors for the development of cancer. To summarise, in practical terms short segments of columnar epithelium with no intestinal metaplasia have an extremely low risk for malignant conversion (37, 87) (~0.05% per annum) (Evidence grade III). For these patients, it is recommended to repeat the endoscopy once in 3-5 years to confirm the findings and account for sampling and measurement error. If there is doubt, the endoscopy could be repeated sooner. If two good quality endoscopies, each with a minimum number of 4 oesophageal biopsies where possible, confirm a short segment (<3cm) with gastric metaplasia only, then discharge is encouraged as the risks for endoscopy likely outweigh the benefits. In selected cases with a strong personal risk profile for OAC (see recommendation on screening), continued endoscopic surveillance can be considered. For patients with Barrett’s oesophagus shorter than 3 cm without intestinal metaplasia or dysplasia a repeat endoscopy with quadrantic biopsies is recommended to confirm the diagnosis. If repeat endoscopy confirms the absence of intestinal metaplasia discharge from surveillance is encouraged as the risks for endoscopy likely outweigh the benefits. (Recommendation grade C) There is evidence that the risk for cancer progression correlates significantly with the length of the Barrett’s segment; such that segments shorter than 3 cm have a lower cancer incidence (Table 6). Therefore, in view of the recent evidence supporting a lower cancer risk in non-dysplastic Barrett’s oesophagus than previously thought, it is reasonable for patients with short segments containing IM to have a longer endoscopic surveillance interval than patients with long segments. We propose a range between 3 to 5 years to allow the clinician to tailor surveillance on the perceived individual cancer risk. Patients with Barrett’s oesophagus shorter than 3 cm, with intestinal metaplasia, should receive endoscopic surveillance every 3-5 years. (Recommendation grade C) For longer segments (>3cm) a shorter surveillance interval is more appropriate. This is regardless of the presence of IM, since it is noted that in long segments IM is almost always present but can be missed due to sampling error. We propose a range (between 2 and 3 years), which may be informed by the individual risk factors and patient and physician preference. Because of the poor adherence to the surveillance biopsy protocol for long segments of Barrett’s oesophagus, consideration should be given to refer patients with a very long segment (>10cm) to tertiary referral centres for endoscopic surveillance, as suggested also in the new Dutch guidelines (personal communication). Patients with segments of 3 cm or longer should receive surveillance every 2-3 years. (Recommendation grade C) Histopathological diagnosis of dysplasia Pathological features and reporting of dysplasia Appendix 3 shows histological examples of Barrett’s with different degrees of dysplasia. There are very few studies that investigated reporting of dysplasia in Barrett's oesophagus. Two studies examined the Vienna classification and found a degree of agreement among pathologists that was at best moderate for HGD, fair for LGD and poor for Indefinite for dysplasia(122, 181). The approach to reporting upper GI tract neoplasia differs significantly in certain parts of the world and this has led to inconsistency in the terminology used and hence inconsistent data on incidence and clinical progression outcomes. The most recent recommendations by the WHO state that dysplasia should be graded as either low or high grade(182). The revised Vienna Classification for gastrointestinal mucosal neoplasia attempts to standardise diagnostic terminology into biologically similar groupings with scores from 1-5(183) depending on the presence or absence of dysplasia or malignancy: 1. Negative for dysplasia This includes normal epithelium, metaplastic epithelium showing reactive or regenerative changes, and mucosa showing reactive/regenerative changes including nuclear enlargement, nuclear hyperchromasia, and prominent nucleoli. 2. Indefinite for dysplasia This category is used for cases where the morphological features between true dysplasia and regenerative/inflammatory atypia are blurred(184). It is important to appreciate that this diagnosis may in fact mean that the patient has features suspicious of high grade dysplasia but not enough certainty is present to warrant this call. This may be due to technical factors such as poor staining, poor orientation, cross cutting or denuded surface epithelium, or due to severe active inflammation or ulceration leading to marked atypia, precluding a confident diagnosis of dysplasia. In other cases, the epithelium appears abnormal but the features are not sufficiently well developed to justify a definite diagnosis of dysplasia. Features favouring dysplasia are the presence of an abrupt transition from normal to atypical epithelium, together with nuclear pleomorphism, atypical mitoses and loss of nuclear polarity(185). Evidence of ‘surface maturation’, i.e., loss of the cytological atypia seen in the deeper glands as the mucosa matures into the surface epithelium is often taken as the best marker to favour regeneration rather than dysplasia, although this is also not invariably true (e.g. crypt dysplasia described below). Explicit mention in the pathology report of the reason justifying this diagnosis can be useful to aid patient management. 3. Low grade dysplasia (LGD) In low grade dysplasia glandular architecture is relatively preserved and the diagnosis is made on the bases of cytological atypia. Morphological patterns of Low grade dysplasia · LGD generally shows an “adenomatous” cytological appearance, (resembling the dysplastic changes associated with adenomatous polyps of the colon) in which nuclei are elongated (pencil shaped), slightly enlarged and hyperchromatic with inconspicuous nucleoli. There may be mild pleomorphism, mucin depletion, mild loss of polarity, nuclear crowding and stratification of nuclei up to three-quarters of the height of the cell, but not touching the luminal surface. Mitoses and apoptotic debris may be seen on the surface or in the upper portions of the glands. Evidence of loss of ‘surface maturation’ i.e. presence of cytological atypia seen in the deeper glands into the surface epithelium is often taken as the best marker to distinguish true dysplasia from regenerative atypia, however in the presence of ulceration regenerative surface epithelium may also closely mimic LGD. · A non-adenomatous (foveolar) type composed of small round cells with abundant cytoplasm may occasionally be seen (186). Although this is less well characterised, cells with nuclear:cytoplasmic ratios <50% are probably best put into this low grade category. 4a. High grade dysplasia (HGD) (incorporating carcinoma in-situ) The distinction between HGD and LGD is largely based on the presence of architectural changes in conjunction with more marked nuclear atypia. These changes may be accompanied by complex architectural changes including a papillary or villous surface (although villiform change may also be seen in reactive epithelium), in conjunction with branching, complex budding or back to back ‘crowding’ arrangements. Intraluminal papillae, bridges or cribriform patterns are also seen. There are increased numbers of atypical mitoses on upper levels of crypts, together with mucin depletion and a loss of nuclear polarity. Of note, high grade dysplasia can be accompanied by acute inflammation and should not be downgraded in its presence(185). Morphological patterns of high grade dysplasia · “Adenomatous” cytological appearance: Nuclei are elongated, pencil shaped, enlarged, hyperchromatic and show crowding and stratification up to the luminal surface of the cells. The distinction between the upper end of “low grade” and “high grade” dysplasia can be subjective. · “Non adenomatous”, which includes the term foveolar dysplasia: Cells have a cytological appearance characterized by rounded nuclei showing marked nuclear enlargement and marked atypia with increased nuclear: cytoplasmic ratios, irregular nuclear membranes, including angular edges, coarse chromatin, prominent or irregular nucleoli. The foveolar type may have a more bland appearance, comprising small round nuclei with conspicuous nucleoli. The grading of this variant is less well characterised, however, nuclear: cytoplasmic ratio appears to be more important for grading, with high ratios (nuclei involving >50% of cell) being put into a high grade category. Crypt dysplasia Significant cytological atypia in the crypt bases with surface maturation has been reported in up to 7.3% of cases of Barrett’s(187). Previously this would have been regarded as either “negative for dysplasia” or “indefinite for dysplasia”, as the atypia does not reach the surface epithelium. It seems likely however that crypt dysplasia represents an early stage in the development of dysplasia and the atypia is highly likely to progress up to the surface over time and so warrants recognition(188). Crypt dysplasia stands out as a focus that is distinctly different from the surrounding crypts and can appear as low grade or high grade cytological atypia. Although the dysplasia can be of the “adenomatous” or “non adenomatous – round cell” type, the most common features are nuclear enlargement, loss of polarity, marked pleomorphism with irregular shapes and sizes, nuclear crowding, increased mitotic activity and goblet cell dystrophy. Crypt dysplasia should not be diagnosed purely on the basis of stratification and hyperchromasia in the absence of significant nuclear pleomorphism as these changes may frequently be seen in regenerative cryptal epithelium. P53 immunohistochemistry may be a helpful adjunct for the assessment of crypt dysplasia. Crypt dysplasia should be reported according to the degree of dysplasia present. If there is uncertainty, then the “indefinite” category may be appropriate. Some pathologists favour putting cases with high grade features in to an “at least low grade” category in view of the likely early nature of the lesion and the implications of a high grade diagnosis, however cases of isolated crypt dysplasia are probably best managed as low grade until further data becomes available(188). 4b. Intramucosal carcinoma (including suspicious for invasive carcinoma) Intramucosal carcinoma is a lesion in which neoplastic cells have penetrated the basement membrane and invaded the lamina propria or muscularis mucosae, but without invasion into the submucosa. However, histological recognition of lamina propria invasion may be difficult, due to the absence of objective criteria. Patterns of lamina propria invasion that are utilized by gastrointestinal pathologists include sheets of neoplastic cells, abortive angulated glands, a never-ending/anastomosing gland pattern, a highly complex cribriform arrangement of glands, tightly packed small tubular glandular arrays, and single cell infiltration. Recognition of each of these patterns is somewhat subjective, with kappa statistics varying between 0.21 and 0.47 suggesting poor or at best fair agreement(122, 181). If definitive lamina propria or submucosal invasion is in question the term suspicious of invasive carcinoma can be used. Distinguishing between LGD, HGD and carcinoma Distinguishing these categories can be problematic especially when the changes are focal or mixed. With regards to distinguishing HGD from intramucosal adenocarcinoma; the widely accepted definition of intramucosal c