Endoscopic management of Barrett’s esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement

Abstract

Current practices for the management of Barrett’s esophagus (BE) vary across Europe, as several national European guidelines exist. This Position Statement from the European Society of Gastrointestinal Endoscopy (ESGE) is an attempt to homogenize recommendations and, hence, patient management according to the best scientific evidence and other considerations (e.g. health policy). A Working Group developed consensus statements, using the existing national guidelines as a starting point and considering new evidence in the literature. The Position Statement wishes to contribute to a more cost-effective approach to the care of patients with BE by reducing the number of surveillance endoscopies for patients with a low risk of malignant progression and centralizing care in expert centers for those with high progression rates.

Main statements

MS1 The diagnosis of BE is made if the distal esophagus is lined with columnar epithelium with a minimum length of 1 cm (tongues or circular) containing specialized intestinal metaplasia at histopathological examination.

MS2 The ESGE recommends varying surveillance intervals for different BE lengths. For patients with an irregular Z-line/columnar-lined esophagus of < 1 cm, no routine biopsies or endoscopic surveillance is advised. For BE ≥ 1 cm and < 3 cm, BE surveillance should be repeated every 5 years. For BE ≥ 3 cm and < 10 cm, the interval for endoscopic surveillance should be 3 years. Patients with BE with a maximum extent ≥ 10 cm should be referred to a BE expert center for surveillance endoscopies. Patients with limited life expectancy and advanced age should be discharged from endoscopic surveillance.

MS3 The diagnosis of any degree of dysplasia (including “indefinite for dysplasia”) in BE requires confirmation by an expert gastrointestinal pathologist.

MS4 Patients with visible lesions in BE diagnosed as dysplasia or early cancer should be referred to a BE expert center. All visible abnormalities, regardless of the degree of dysplasia, should be removed by means of endoscopic resection techniques in order to obtain optimal histopathological staging

MS5 All patients with a BE ≥ 10 cm, a confirmed diagnosis of low grade dysplasia, high grade dysplasia (HGD), or early cancer should be referred to a BE expert center for surveillance and/or treatment. BE expert centers should meet the following criteria: annual case load of ≥10 new patients undergoing endoscopic treatment for HGD or early carcinoma per BE expert endoscopist; endoscopic and histological care provided by endoscopists and pathologists who have followed additional training; at least 30 supervised endoscopic resection and 30 endoscopic ablation procedures to acquire competence in technical skills, management pathways, and complications; multidisciplinary meetings with gastroenterologists, surgeons, oncologists, and pathologists to discuss patients with Barrett’s neoplasia; access to experienced esophageal surgery; and all BE patients registered prospectively in a database.

Abbreviations

BE: Barrett’s esophagus

BSG: British Society of Gastroenterology

DGVS: Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (German Society of Gastroenterology, Digestive and Metabolic Diseases)

EAC: esophageal adenocarcinoma

EMR: endoscopic mucosal resection

ESD: endoscopic submucosal dissection

ESGE: European Society of Gastrointestinal Endoscopy

GERD: gastroesophageal reflux disease

GI: gastrointestinal

HGD: high grade dysplasia

IM: intestinal metaplasia

LGD: low grade dysplasia

RFA: radiofrequency ablation

SIED: La Società Italiana di Endoscopia Digestiva (Italian Society of Digestive Endoscopy)

SKMS: Stichting Kwaliteitsgelden Medisch Specialisten (Dutch Quality Fund for Medical Specialists)

Introduction

Barrett’s esophagus (BE) is a premalignant condition predisposing to esophageal adenocarcinoma (EAC). Although the risk of cancer progression is low (estimated at about 0.3 % per year [1]), in most countries patients with BE are managed with endoscopic surveillance at regular intervals. However, current practices for the management of BE and EAC vary across Europe, as several national European guidelines exist. The current Position Statement from the European Society of Gastrointestinal Endoscopy (ESGE) is an attempt to homogenize recommendations and, hence, patient management according to the best scientific evidence as well as other considerations (e. g. health policy). The aim of this document, therefore, is to deliver a very practical guide, in the form of a Position Statement, even when supporting evidence is weak [2].

A secondary aim of the current Position Statement is to contribute to a more cost-effective approach to the care of patients with BE, through reduction of the number of surveillance endoscopies for patients with a low risk of malignant transformation, and centralization of care for those with higher progression rates. This was felt necessary because, although several recent reports indicate that the outcome of BE-associated EAC is improved with endoscopic surveillance of BE [3] [4], the annual incidence of EAC among patients with BE is relatively low. The burden on gastrointestinal (GI) endoscopy facilities and health care resources might therefore be reduced.

In developing this Statement, we focused on issues that were directly relevant to endoscopy practice. Hence, other issues, such as chemoprevention for progression of BE or the use of biomarkers for prediction of progression in BE, are not part of this Position Statement.

Methodology

Recently, several national guidelines have been issued in Europe for the management of BE, either in international scientific journals or as consensus statements distributed locally by national societies. These existing guidelines served as the starting point for the current Position Statement in order to take advantage of the discussions of the scientific literature performed by the respective national BE guideline committees.

In order to retrieve as many national European guidelines as possible, an inquiry was sent to all national gastrointestinal endoscopy society members of the ESGE. Questions in the survey were:

1. Has your national society ever produced their own national guideline on BE? If so, when was it written or published?

2. Is there a particular guideline on BE that your society recommends endoscopists follow?

3. Which currently available guideline on BE do you think is mostly used by endoscopists in your country?

4. Are you currently considering writing a national guideline on BE, or are you planning to revise your current guideline?

The results of this inquiry are summarized in Supplementary Material 1.

Using the results of this inquiry, four recent national guidelines were selected based on year of publication and robustness of methodology: the British Society of Gastroenterology (BSG) guidelines on the diagnosis and management of Barrett’s esophagus [5], the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) guideline on gastroesophageal reflux disease (GERD), which includes recommendations for BE [6], the Italian Society of Digestive Endoscopy (SIED) consensus meeting on the diagnosis and management of BE (see Supplementary Material 2), and the Dutch Guideline on BE funded by the Dutch Quality Fund for Medical Specialists (SKMS; http://www.mdl.nl/richtlijnen2?noCache=214;1484584659. See Supplementary Material 3, in Dutch only).

Members of the Working Group on the ESGE Position Statement on the endoscopic management of BE were selected based on their contribution to the included national guidelines, complemented by recognized experts on BE from other European countries. All Working Group members are listed as contributing authors on this paper.

A list of topics to be covered by the current Position Statement was derived from the existing guidelines, and agreed on during a teleconference of the Working Group members (see Supplementary Material 4). Subsequently, all relevant statements of the four selected national guidelines were sorted into a table, according to this list of topics. All Working Group members where then asked to complete three additional columns containing the following questions:

1. Are all recommendations from the four merging guidelines in agreement (Yes/No, explain)?

2. If Yes, do you personally agree (Yes/No, explain)?

3. Are you aware of any new studies relevant for this issue (Yes/No, explain)?

In order to cover the gap between the time period covered by the literature searches of the selected national guidelines and the ESGE Position Statement, a Medline search was performed through PubMed for the period January 2013 – November 2015.

During a consensus meeting, the statements of the existing national guidelines were discussed. In the case of discrepancy between recommendations of the national guidelines, new statements were generated based on a consensus agreement among the Working Group members, supported by new literature if available. Comments were added to the statements, if necessary, in order to: mention or discuss additional evidence arising from new literature; clarify the statement in case of partial agreement or disagreement among the four national guidelines; highlight additional important insights of the working group members; or a combination thereof. The manuscript was then sent to the ESGE Governing Board, member societies, and individual members for comment.

As the current ESGE Position Statement on the endoscopic management of BE was largely formed by merging the four existing national guidelines, the reader is referred to these publications for full lists of references.

Statements

Each statement is followed by information on:

• Extent of agreement between the four constituent guidelines

• Availability of new evidence

• Whether there is consensus between the Working Group members on the current statement.

This may be followed by additional Comments, as described above in the Methodology section.

• Partial agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

Comments

In patients with columnar epithelium extending less than 1 cm above the upper end of the gastric folds (tongues or circular), obtaining random biopsies (i. e. biopsies from columnar epithelium in the absence of a visible abnormality) is not recommended. Targeted biopsies from this region should only be obtained in cases where a visible abnormality is detected. Endoscopic surveillance of patients with these short segments of columnar-lined esophagus (tongues or circular columnar epithelium extending less than 1 cm above the gastric folds) is not recommended, irrespective of presence of intestinal metaplasia (IM).

For BE ≥ 1 cm, IM is a prerequisite to justify surveillance. In cases where random biopsies are obtained according to guidelines (see Statement 6 below), absence of IM more likely reflects a misinterpretation of a hiatal hernia ([Fig. 1]) than actual sampling error. For larger segments of BE, absence of IM (provided that random biopsies are obtained according to guidelines) is rare, and the management of these cases does not justify detailed instructions by guidelines.

Fig. 1 Example of a patient with a small hiatal hernia. a The esophagogastric junction in desufflation. The squamocolumnar junction coincides with the location of the top of the gastric folds. b The esophagus and hiatal hernia are overinflated leading to the misinterpretation of the hiatal hernia as circular Barrett’s epithelium.

• Agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

• Agreement between merged guidelines

• New evidence available on this statement

• Consensus on current statement between Working Group members

Comments

Currently, randomized controlled trials on surveillance in patients with BE are lacking. However, studies in patients with BE suggest that adequate endoscopic surveillance correlates with detection of cancer at an earlier stage, and with improved survival from EAC [3] [4].

• Agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

Comments

For the detection of dysplasia in BE, currently available data do not provide sufficient proof of additional value from the abovementioned advanced imaging techniques over high definition white-light endoscopy. Despite the lack of solid proof, optical chromoendoscopy techniques (narrow-band imaging, flexible spectral imaging color enhancement, I-SCAN) are nowadays widely available and do not impose additional costs; they are used by many experts for the detection and characterization of lesions in BE. Therefore, in high volume centers, the use of advanced imaging modalities can be advantageous during the work-up of patients with early neoplasia to delineate the margins of the lesions and inform endoscopic therapy [7].

• Agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

Comments

BE surveillance endoscopy should ideally be performed within specifically allocated time slots, preferably in sedated patients. Before inspection of the BE for any visible lesions, the esophagus should be properly cleaned from mucus by rinsing. Careful attention should be paid to inspection of the cardia, using a retroflexed position ([Video 1]).

Video 1: Example of surveillance endoscopy for Barrett’s esophagus. The various steps of an appropriate surveillance endoscopy are illustrated, such as cleaning the esophagus to remove mucus, and inspection of the cardia using a retroflexed endoscope position.

• Agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

• Disagreement between merged guidelines

• New evidence available on this statement

• Consensus on current statement between Working Group members

Comments

The extent of BE is an accepted risk factor for malignant progression [8]. The suggested cutoff levels are arbitrary.

The cutoff of 10 cm for referral to a BE expert center is based on the finding that the risk for progression in these patients might reach a level comparable to that of patients with a confirmed diagnosis of low grade dysplasia (LGD) (see Statement 12 below) for which referral to an expert center is also advised (see Statement 17 below).

The age cutoff is also arbitrary, and is based on average life expectancy; hence, surveillance extension up to 80 years can be considered in individual cases.

Contrary to earlier guidelines, the Working Group does not recommend a standard follow-up endoscopy at 1 year after the first diagnosis of BE, provided that the initial (diagnostic) endoscopy is performed according to the standards as described in this Position Statement (e. g. high definition endoscopy, adequate setting, sufficient number of random biopsies).

• Disagreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

Comments

The average risk of cancer progression in patients with nondysplastic BE is low, estimated at about 0.3 % per year [1]. This leads to a high number-needed-to-treat for the prevention of a single case of cancer, and consequently to unfavorable cost – effectiveness. In addition, uncertainty exists on the need for long-term follow-up in patients with nondysplastic BE post ablation.

• Agreement between merged guidelines

• New evidence available on this statement

• Consensus on current statement between Working Group members

Comments

An accepted definition of the term “expert GI pathologist” is lacking. The Working Group suggests the following description: “an expert GI pathologist is a pathologist with special interest in GI pathology recognized as such by his/her peers.” When considering endoscopic treatment, confirmation by an independent pathologist from an independent institution is preferable in order to increase robustness of the diagnosis.

The addition of p53 immunostaining to the histopathological assessment may improve the diagnostic reproducibility of a diagnosis of dysplasia in BE and should be considered as an adjunct to routine clinical diagnosis.

The importance of expert histopathology review is underscored by studies showing that the majority of patients with a community diagnosis of LGD are downstaged to nondysplastic BE by expert GI pathologists. In patients with confirmed LGD, however, progression rates to high grade dysplasia (HGD) and cancer are considerable [9] [10].

• Recommendation only present in one guideline

• No new evidence available on this statement

• Consensus on current statement between Working Group members

• Agreement between merged guidelines

• New evidence available on this statement

• Consensus on current statement between Working Group members

Comments

For Barrett’s lesions containing dysplasia or early cancer, endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) are both highly effective. ESD was not shown to provide improved overall patient outcome compared with EMR, yet it is considered to be technically more difficult and is associated with a higher rate of complications [11] [12]. Therefore, EMR is the preferred resection technique for early Barrett’s neoplasia. ESD may be indicated for removal of lesions with a significant luminal component (“bulky lesions”) that cannot be removed by cap-based techniques, and for lesions where submucosal invasion is suspected.

• Partial agreement between merged guidelines

• New evidence available on this statement

• Consensus on current statement between Working Group members

Comments

In 30 % of patients with a single endoscopy diagnosis of confirmed LGD, the diagnosis will not be reproduced on subsequent endoscopies [9]. A single diagnosis of confirmed LGD therefore does not justify endoscopic ablation therapy.

Confirmed LGD, especially if it is repeated over time, and/or if it is documented at multiple esophageal levels, is a strong risk factor for progression to HGD and EAC [10].

Based on the currently available literature, radiofrequency ablation (RFA) has the best efficacy and safety profile, hence it is recommended as the technique of choice for ablation of BE [13].

• Partial agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

Comments

True flat HGD without endoscopically visible lesions is rare and accounts for less than 20 % of patients with HGD. The absence of visible abnormalities in a patient with HGD is most often the result of an overlooked lesion, or over-staging of the histopathology. Flat HGD (as for flat LGD) therefore requires a confirmed diagnosis on two separate time points before treatment is initiated.

• Agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

Comment

A diagnosis of esophageal adenocarcinoma is virtually always associated with an endoscopically visible abnormality, which requires endoscopic resection for staging and treatment.

In the absence of a visible lesion, a diagnosis of esophageal adenocarcinoma should be followed by a second imaging endoscopy to find the area of interest instead of performing ablation therapy for flat “invisible” cancer.

• Partial agreement between merged guidelines

• New evidence available on this statement

• Consensus on current statement between Working Group members

Comments

The choice between endoscopic therapy and surgical resection should be based on a careful assessment of the risk of lymph node metastasis, surgical mortality and morbidity, and patient preferences. Tumors fulfilling all of the abovementioned criteria are considered as low-risk T1b cancers; the risk of lymph node metastasis appears to be low ( < 2 %) [14].

• Partial agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

Comment

After endoscopic resection of visible abnormalities, recurrence rates between 15 % in 5 years and 30 % in 3 years have been reported for patients in whom the remaining BE is left untreated.

• Partial agreement between merged guidelines

• No new evidence available on this statement

• Consensus on current statement between Working Group members

Supplementary Material 1 Results of inquiry of European guidelines on the management of Barrett’s esophagus.

Response to inquiry.

Question 1: Has your national society ever produced their own national guideline on BE? If so, when was it written or published?

Question 2: Is there a particular guideline on BE that your society recommends endoscopists follow?

Question 3: Which currently available guideline on BE do you think is mostly used by endoscopists in your country?

Question 4: Are you currently considering writing a national guideline on BE, or are you planning to revise your current guideline?

Supplementary Material 2 Report of the Italian Society of Digestive Endoscopy (SIED) consensus meeting on the diagnosis and management of Barrett's esophagus.

Supplementary Material 3 The Dutch Guideline on Barrett’s esophagus.http://www.mdl.nl/richtlijnen2?noCache=214;1484584659.

Supplementary Material 4 Topics identified by the Working Group. 

List of topics to be covered by the working group

1. Diagnosis:

   • Endoscopy: minimum length

   • Endoscopy: minimum dataset (Prague and Paris Classification)

   • Pathology: IM required?

   • Pathology: double reporting for dysplasia by expert GI pathologist

2. Screening

   • Yes/no/selected population

3. Surveillance

   • Yes/no?

   • Biopsy protocol

   • Advanced imaging

   • The case of IM at the cardia: surveillance yes/no?

4. Management of nondysplastic Barrett’s

   • Intervals for nondysplastic Barrett’s, including stopping criteria

   • Stratification according to the length

5. Management of dysplastic Barrett’s

   • Indefinite for dysplasia: surveillance intervals

   • Low grade dysplasia: treatment or surveillance

   • High grade dysplasia

   • Intramucosal cancer

   • Submucosal cancer

6. Training and service provision

   • Logistics of training

   • Minimum number of procedures to acquire competence

   • High volume tertiary referral centers for endoscopic therapy

Competing interests

R. Bisschops has received: speaker’s fees from Covidien (2009 – 2014) and Fujifilm (2013); speaker’s fee and hands-on training sponsorship from Olympus Europe (2013 – 2014); speaker’s fee and research support from Pentax Europe; and an editorial fee from Thieme Verlag as co-editor of Endoscopy. E. Coron has provided paid consultancies to Mauna Kea Technologies (2011 – 2015), Fujifilm (2016 –), and Medtronic (2015 –); his department has received training sessions in ESD from Fujifilm (2014–2016). M. di Pietro has received sponsorship for educational events (2015 – 2016). B. Weusten’s department has received research support for IRB-approved studies from C2 Therapeutics (2012–), Boston Scientific (2015 –), and Medtronic (2013 –). M. Dinis-Ribeiro, J.-M. Dumonceau, J.-M. Esteban, C. Hassan, O. Pech, and A. Repici have no competing interests.

Acknowledgment

The working group thank Prof. H. Messmann for his valuable comments on the manuscript.

• References

• 1 Desai TK, Krishnan K, Samala N. et al. The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett’s oesophagus: a meta-analysis. Gut 2012; 61: 970-976
• 2 Dumonceau J-M, Hassan C, Riphaus A, Ponchon T. European Society of Gastrointestinal Endoscopy (ESGE) guideline development policy. Endoscopy 2012; 44: 626-629
• 3 Verbeek RE, Leenders M, Ten Kate FJW. et al. Surveillance of Barrett’s esophagus and mortality from esophageal adenocarcinoma: a population-based cohort study. Am J Gastroenterol 2014; 109: 1215-1222
• 4 Kastelein F, van Olphen SH, Steyerberg EW. et al. Impact of surveillance for Barrett’s oesophagus on tumour stage and survival of patients with neoplastic progression. Gut 2016; 65: 548-554
• 5 Fitzgerald RC, di Pietro M, Ragunath K. et al. British Society of Gastroenterology (BSG) guidelines on the diagnosis and management of Barrett’s oesophagus. Gut 2014; 63: 7-42 Available from: http://gut.bmj.com/content/63/1/7.full.pdf+html
• 6 Koop H, Fuchs KH, Labenz J. et al. (S2k Guideline: Gastroesophageal Reflux Disease Guided by the German Society of Gastroenterology AWMF Register No. 021-013). Z Gastroenterol 2014; 52: 1299-1346 Available from: https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0034-1385202.pdf
• 7 Sharma P, Bergman JJ, Goda K. et al. Development and validation of a classification system to identify high-grade dysplasia and esophageal adenocarcinoma in Barrett’s esophagus using narrow-band imaging. Gastroenterology 2016; 150: 591-598
• 8 Pohl H, Pech O, Arash H. et al. Length of Barrett’s oesophagus and cancer risk: implications from a large sample of patients with early oesophageal adenocarcinoma. Gut 2016; 65: 196-201
• 9 Phoa KN, van Vilsteren FGI, Weusten BLAM. et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia. JAMA 2014; 311: 1209-1217
• 10 Duits LC, Phoa KN, Curvers WL. et al. Barrett’s oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel. Gut 2015; 64: 700-706
• 11 Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T. et al. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy 2015; 47: 829-854
• 12 Terheggen G, Horn EM, Vieth M. et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut 2016; 1-11 Available from: http://gut.bmj.com/lookup/doi/10.1136/gutjnl-2015-310126
• 13 Small AJ, Araujo JL, Leggett CL. et al. Radiofrequency ablation is associated with decreased neoplastic progression in patients with Barrett’s esophagus and confirmed low-grade dysplasia. Gastroenterology 2015; 149: 567-576.e3
• 14 Manner H, Pech O, Heldmann Y. et al. The frequency of lymph node metastasis in early-stage adenocarcinoma of the esophagus with incipient submucosal invasion (pT1b sm1) depending on histological risk patterns. Surg Endosc 2015; 29: 1888-1896