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Consensus Guideline – Management of Barrett’s Esophagus

Benign Barrett’s and Cancer Taskforce (BOB CAT): a Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia

 

Barrett’s esophagus (BE) is a premalignant lesion of metaplastic columnar epithelium of any histological subtype. Even though guidelines for the management of BE exist, its endoscopic and histopathologic classification, and management is highly variable among and within countries. Given the impact of a diagnosis of nondysplastic BE on the patient, the cost, risk of endoscopic surveillance, and the consequences of progression to invasive esophageal adenocarcinoma (EA), the international consensus group has produced an evidence-based guideline focused on the management of nondysplastic BE and low-grade dysplasia (LGD). The consensus group agreed on a new international definition of Barrett’s esophagus. A number of other clinical recommendations were made such as:
  • Population screening with endoscopy is not recommended
  • Endoscopic resection is recommended for visible, nodular disease
  • Surveillance is not needed when life expectancy is <5 years
The Benign Barrett’s and Cancer Taskforce (BOB CAT) has established a definition of BE:
  • BE is defined by the presence of columnar mucosa in the esophagus;
    • It should be stated whether intestinal metaplasia (IM) is present above the gastroesophageal junction.
    • This definition combines the divergent European (non-IM allowed) and the US (IM only allowed) systems.
Consensus exists on a new bidirectional pathway to de-escalate or escalate the management of patients with lower-risk BE compared with those with potentially higher-risk BE such as indefinite for dysplasia (IND), or LGD with persistence over two endoscopies, multifocality, and long-segment BE. In the case of LGD found on a single occasion (if not treated), follow-up should be close (a more intensive 6–12-month surveillance interval) with strict biopsy protocols, as many may also have or go on to develop high-grade dysplasia (HGD). The diagnosis of IND should be considered a temporary diagnosis only and should prompt further close follow-up with adequate biopsy sampling.
Patients with persistent and confirmed LGD should be treated with ablative therapy, which decreases progression to neoplasia, and not just followed up.

 

Recommendations for the management of nondysplastic Barrett’s esophagus (BE) and/or low-grade dysplasia (LGD)

 

Risk factors
  • Population screening: The Benign Barrett’s and Cancer Taskforce suggests against screening the general population for BE endoscopically or with non-endoscopic methods.
  • High-risk individuals: The Benign Barrett’s and Cancer Taskforce suggests screening in men over 60 years old with GERD symptoms for 10 years, to detect BE and for the investigation of dyspepsia.
  • Accepted risk factors for cancer: men, length of BE, central obesity (waist to hip ratio), smoking, aberrant p16 and p53
Diagnosis
  • Adoption of internationally accepted pathology criteria for both benign and dysplastic BE.
  • Consensus pathology reporting for any grade of dysplasia LGD and Indefinite for dysplasia in BE (at least 2 upper GI specialist pathologists).
  • A single specialist histopathologist report is acceptable for non-dysplastic BE.
  • A proforma to report non-dysplastic BE is good practice,
  • Number of biopsies: The Benign Barrett’s and Cancer Taskforce suggests research to determine the optimum number of biopsies for surveillance.
  • Endoscopic criteria: using a proforma is good practice.
  • Measure the length of BE by reference to the proximal margin of the gastric folds.
  • High-resolution endoscopy with targeted biopsy.
  • Advanced endoscopic imaging techniques is not recommended for routine use.
  • Biomarkers: The Benign Barrett’s and Cancer Taskforce suggests research to test their utility in the histological assessment of dysplasia, and as methods of risk stratification
Management
  • The Benign Barrett’s and Cancer Taskforce suggests research into the optimal pathways of management in, and setting for, BE surveillance.
  • Surveillance in non-dysplastic BE, if undertaken, should be targeted at high risk groups with factors including but not limited to: age 50 years or older, white race, male sex, obesity, and symptoms.
  • Surveillance in non-dysplastic BE in low-risk groups to decrease mortality rates and differential management for short and long segment BE is not recommended. Surveillance intervals are unproven for non-dysplastic BE.
  • Surveillance cycle should stop if life expectancy is less than 5 years.
  • IND is an interim diagnosis only and should be intensively followed up.
  • LGD on a single occasion is to be managed with continued more frequent (6 to 12 months) surveillance (providing the patient is fit for endoscopy and not already undergoing therapy).
  • Absence of LGD after 2 consecutive endoscopic evaluations is to be managed with routine BE surveillance.
  • Chemoprevention with aspirin, statins or diet is not recommended. Current evidence does not support modification of standard guidelines for the management of Helicobacter pylori in patients with BE. In patients with BE, the Benign Barrett’s and Cancer Taskforce suggests against using aspirin.
Surgery, endoscopic, and ablative therapies
  • PPI over surgery is recommended for symptom control.
  • Surgery generally is not superior to PPIs in prevention of progression of BE.
  • ER (endoscopic resection) or ablation is not recommended in benign BE.
  • LGD and higher-risk features (multifocality, segment length, persistence) should be offered treatment options including ablative therapies. Ablative therapy with follow-up decreases the progression to neoplasia.
  • ER: in patients with non-dysplastic BE, LGD, and IND, and a visible lesion, the Benign Barrett’s and Cancer Taskforce suggests ER (followed by ablation if HGD or cancer detected) over simple biopsies.
  • Expertise level for competency in ER unknown
Consensus Guideline Statement Summary

 

Definition of BE 
  • BE is a combined endoscopic and pathological diagnosis; BE is defined by the endoscopic presence of columnar mucosa of the esophagus, and the pathology report should state whether IM is present or absent in the tissue samples taken from the above gastroesophageal junction.
  • Good practice includes the adoption of internationally accepted pathology criteria for both benign and dysplastic BE.
    • Three caveats should be considered to ensure that this new global definition of BE is clinically meaningful:
      • The gastroesophageal junction is irregular and tongues of ≤1 cm may be a natural phenomenon (even if IM is present, it can occur in the cardia of the stomach).
      • In >80–90% of cases of BE a hiatal hernia (HH) also coexists.
      • The diagnosis must be an agreed clinicopathological definition.
      • There are cases in which either the pathologist or the endoscopist may be able to overrule the other (i.e. long segments of BE >3 cm (most HH are ≤3 cm) or micrometaplasia, missed endoscopically but picked up by the pathologist).
  • The optimal definition of LGD in BE includes the use of an agreed upon internationally recognized criteria including increased nuclear/cytoplasmic ratio and hyperchromatic and heterochromic nuclei.
    • The criteria for unequivocal low-grade intraepithelial neoplasia typically include preserved nuclear polarity, nuclear heterogeneity and margination, few mitoses, no atypical mitoses, and decreased numbers of transition to adjacent glandular epithelium. Architectural changes are absent or minimal in LGD but may include irregular growth patterns, parallel tubules, minimal gland distortions, no single cell budding, no significant branching of glands, no solid or cribriform patterns, and normal lamina propria. There are intraobserver variations in the diagnosis and grading of LGD and in differentiating it from reactive changes.
Diagnosis
  • The evaluation of routine biopsies by a single specialist (in BE) histopathologist, i.e. single reporting, for the diagnosis of BE is satisfactory.
  • In BE, the diagnosis of IND can be used for a variety of histopathological appearances and requires consensus agreement between at least two specialist GI pathologists.
    • When there are features of the epithelium and glands which are suspicious for dysplasia the term ‘indefinite for dysplasia’ may be useful.
      • The epithelium may possesse cytological features of dysplasia (nuclear pleomorphism, hyperchromasia, loss of polarity), but the features are present only in the base of crypts and not in the surface epithelium.
      • Lack of surface maturation has been required for the diagnosis of dysplasia.
      • Regenerative changes may mimic dysplasia, whereby there is a constellation of cytological atypical features, evidenced by an often marked increase in mitotic figures, nuclear pleomorphism, and loss of cell polarity, associated with inflammation, but a retained architecture and no sharp cutoff between normal and abnormal epithelium.
      • Technical factors may make a definitive assessment of the tissue impossible.
      • Reproducibility of a diagnosis of IND is poor and there is no evidence pointing to an optimal number of pathologists required for an IND diagnosis, but all cases of dysplasia require consensus review by at least 2 specialist GI pathologists.
  • A consensus between at least two specialist gastrointestinal (GI) pathologists is required for the diagnosis of any dysplasia (IND, LGD, HGD).
  • A proforma (standardized reporting form) should be used to report BE.
    • The use of a proforma report is strongly recommended in the setting of BE, at least for the reporting of biopsies from the index endoscopy to improve completeness, accuracy, and reproducibly of recording and reporting the morphological features of BE.
    • Proposed data set/data items that could be included in a draft proforma may include the following:
      • the number of biopsies per cm (including levels)
      • mucosal subtypes—e.g., squamous, columnar, mosaic, presence or absence of reflux esophagitis
      • IM presence or absence
      • active or chronic inflammation, with grading into mild/moderate/severe
      • presence of native structures
      • Vienna neoplasia category (1: no dysplasia, 2: IND, 3: LGD, 4: HGD, 5: invasive EA)
      • p53 immunostaining.
Screening to detect BE
  • Endoscopic screening for BE is not justified in the general population.
  • Endoscopic screening for BE is recommended to decrease the risk of death from esophageal adenocarcinoma in men >60 years old with GERD symptoms for 10 years.
Risk factors for progression to EA
  • The risk of progression of BE metaplasia to HGD or EA is related to central obesity (measured by waist circumference, waist–hip ratio, or visceral abdominal fat area).
  • The risk of nondysplastic BE progressing to dysplasia or EA is greater among men than among women.
  • The risk of progression of BE metaplasia is related to the (longer) length of BE.
Endoscopic methods in confirmed BE
  • Endoscopic reporting should be carried out using a minimum data set including a record of the length using the Prague criteria, and the presence and size of a HH below and esophagitis above the BE segment.
    • The Prague criteria provide a uniform set of criteria for describing BE. Objective landmarks should be formally recorded during BE surveillance. It is vital to identify the size of the HH in order to avoid false classification of the BE where no BE or a much smaller BE segment exists.
  • Surveillance and biopsy of BE should be performed by experienced endoscopists, with the availability of and training in appropriate techniques and tools, used according to standard protocols and with sufficient time allowed for careful inspection.
    • Further studies are needed on the optimal pathways of management in BE using risk factors and biomarkers to test systematic protocols for biopsy collection, in particular the optimum number and the optimal setting for BE surveillance (e.g., dedicated lists, specialist centers).
    • Use of high-definition endoscopy and narrow band imaging is recommended.
    • It is not clear whether examination time has an influence on findings.
    • Surveillance of BE should be done in a careful and systematic manner, although there is no clear evidence to recommend specialized referral units or clinics for BE.
  • High-resolution endoscopy with targeted biopsies in experienced hands is an effective tool for the diagnosis of BE neoplasia.
    • Endoscopic surveillance of BE should be performed using high-resolution white-light endoscopy. High-resolution endoscopes (HREs) – 1,000,000 pixel resolution – have greatly improved the ability to visualize subtle mucosal abnormalities in BE and appear to have higher sensitivity for detecting progression to early neoplastic lesions in BE.
    • The use of high-resolution endoscopy with targeted biopsies is only suggested in expert centers.

Surveillance and surveillance intervals

  • For the purposes of reducing mortality from EA in nondysplastic BE patients, routine surveillance (vs. no surveillance) is not supported.
    • In the absence of agreement on surveillance vs. no surveillance for reduction of mortality from EA, consensus on statements examining intervals for surveillance was not achieved
  • If surveillance of nondysplastic BE is undertaken, it should be targeted at high-risk groups (defined using composite risk factors including, but not limited to, age ≥50 years, white race, male sex, obesity, and symptoms).
    • There are currently no tightly defined and accepted criteria to differentiate those with nondysplastic BE and a higher risk of progression from those at lower risk.
    • The decision to carry out surveillance should be based on risk of progression of BE and include evaluation of factors known to place patients at higher risk of progression.
      • Age
      • Sex
      • Length of the segment
      • Central obesity
      • Symptom duration, frequency, and severity
    • Due to the lack of definitive evidence conclusive surveillance strategies can not be made.
  • Among patients with nondysplastic BE who have <5-year life expectancy, endoscopic surveillance is not recommended.
  • There are almost no data on different surveillance intervals or its effects among individuals with only LGD. There was no agreement for surveillance intervals in LGD in BE.

Management strategies

  • Endoscopic ablation therapy should not be offered routinely to patients with nondysplastic BE.
    • Studies indicate that no ablation technique can achieve 100% BE ablation and neosquamous epithelium after ablative treatment may still contain buried glands  that could be associated with progression to cancer. Prophylactic BE ablation does not appear to be cost effective.
  • Patients with BE with LGD on a single occasion (confirmed by at least two specialist GI pathologists), without higher risk features (including multifocality, long segment), should be managed with continued more frequent (6–12 months) surveillance (provided the patient is fit for endoscopy and is not already undergoing therapy).
    • The majority of patients diagnosed with LGD do not progress to HGD/EA.
    • The rate of progression from LGD to EA was reported as 0.44% per year; 1.83% per year progression from LGD  to HGD or EA combined.
    • LGD is subject to a high degree of inter observer variability and may be overcalled.
  • Absence of dysplasia in two subsequent consecutive endoscopic evaluations, after an initial diagnosis of LGD in BE, identifies a cohort of patients who are at low risk to progress to dysplasia or EA and can continue routine surveillance rather than intensive surveillance.
    • If patients are diagnosed with dysplasia (confirmed by at least 2 specialist GI pathologists), they should have a repeat endoscopy to confirm the findings (i.e., 8 weeks to 12 months). If the repeat endoscopy shows that dysplasia is absent after two further endoscopies (at 6–12-month intervals), the patients appear to be at lower risk of developing EA comparable to patients who have not been diagnosed with LGD. Intervention in these patients can be de-escalated to continued routine surveillance rather than intensive BE surveillance.
  • Patients with BE with multifocal LGD (confirmed by at least two specialist GI pathologists) have an increased risk for progression of neoplasia compared with those with focal LGD.
  • Patients with BE with LGD (confirmed by at least two specialist GI pathologists) that persists have an increased risk for progression of neoplasia compared with those with LGD at a single endoscopy.
    • The absolute risk of neoplastic progression (to HGD or EA) in BE patients with LGD has been controversial.
    • Phenotypic characteristics of LGD in BE (e.g., focal vs. multifocal, short segment vs. long segment, persistent over time vs. intermittent (i.e., found at a second confirmatory endoscopy at a surveillance interval of 6–12 months), consensus pathological agreement, have variably been described as important in predicting progression.
    • Patients with persistent, multifocal LGD in a longer segment of BE are more likely to progress to EA.
  • Patients with BE with LGD (confirmed by at least two specialist GI pathologists) and higher-risk features (multifocality, segment length, persistence) should be offered treatment options including ablative therapies.
  • Ablative therapy (with scheduled follow-up) decreases the progression of neoplasia in BE with LGD (confirmed by at least two specialist GI pathologists) and with risk factors (persistence, long BE segment, multifocality).
    • Ablation of BE in patients with LGD remains controversial due to the lack of reproducible data on cancer risk or clarity as to the clinical features that confer increased risk in BE patients with LGD. However, ablation therapy has improved outcomes by reducing neoplastic progression (to EA). Indirect evidence would suggest that in high-risk patients with LGD (multifocality, segment length, persistence) escalating intervention to ablative therapy to decrease the risk of progression to EA should be considered. There is evidence from RCTs and case studies that the durability of LGD eradication is long lasting.
  • Management of IND in BE should require an agreed consensus diagnosis by at least 2 specialist GI pathologists. Follow up with intense sampling by endoscopic biopsies within 12 months should be undertaken, after increased acid suppressive therapy, to downgrade or upgrade the lesion.
    • Note that the diagnosis of IND should be considered as an interim diagnosis only. Further endoscopic surveillance (after acid-suppressive therapy and within 1 year or sooner) is required to up- or downgrade the dysplasia after careful biopsy sampling/endoscopic resection (ER) (endoscopic mucosal resection).
    • Follow-up is recommended because of uncertainty about the nature of the lesions classified as IND. Some follow-up studies have shown increased likelihood of progression to higher grades of neoplasia. The risk appears higher in patients with multifocal IND.
    • It has been suggested that patients with “regenerative” changes and inflammatory infiltration require increased acid suppression with PPI therapy before rebiopsy
  • ER should not be offered routinely to patients with nondysplastic BE and no visible lesion (harms outweigh benefits).
  • BE patients with visible lesions in the BE segment should undergo ER to stage the lesion.
  • ER of visible endoscopic lesions in diagnosed LGD should be carried out to enable accurate histological assessment.
    • Patients with a visible lesion in nondysplastic BE (as well as visible lesions in BE with LGD or IND) should undergo ER (followed by ablation if HGD or intramucosal cancer is detected) over simple biopsies.
    • A biopsy finding of LGD in BE, especially if multifocal, carries a higher risk of progression to HGD or cancer compared with benign BE. Hence, the finding of endoscopically visible lesions is especially significant in the setting of biopsy-detected LGD as they may contain HGD or invasive cancer. ER of visible lesions (nodules and irregularities visualized by conventional endoscopy, without obvious signs of invasion) in previously confirmed LGD with the diagnosis confirmed by at least two specialist GI pathologists should be carried out to enable accurate histological assessment, as ER may result in a change in the diagnosis of LGD.

Molecular markers of dysplasia and progression

  • Aberrant p16, p16 methylation, or p16 loss in nondysplastic BE is associated with an increased risk of progression to LGD.
  • Aberrant p53, p53 mutation, or p53 loss in nondysplastic BE is associated with an increased risk of developing dysplasia.

Prevention of progression

  • Chemoprevention with aspirin (acetylsalicylic acid; ASA), statins, or diet was not agreed upon.
  • The use of PPIs (compared with no therapy or histamine receptor type 2 antagonists) is not associated with a decrease in progression from benign BE metaplasia to BE neoplasia (dysplasia and EA).
    • There is no evidence from high-quality prospective trials (RCTs) that PPI use prevents progression of BE to neoplasia, but there is scientific plausibility (prevention of injury leading to mutational events and neoplasia).
      • Cohort studies demonstrate that the use of PPIs decreased neoplasia development.
      • Systematic reviews have reported a strong inverse association between PPI use and the risk of EA or HGD in patients with BE.

Surgical therapies for prevention of progression

  • Antireflux surgery offers an alternative to PPIs in the treatment of GERD: it corrects lower esophageal sphincter failure and associated HH and controls abnormal gastric and duodenal reflux in 80–90% of patients.
  • Rates of progression to dysplasia or cancer in patients with BE are similar when comparing medical management with fundoplication.
    • Surgical management of reflux (fundoplication) in GERD patients, with or without BE, can provide long-term control of symptoms and esophageal pH.
    • Some cohort studies suggest that effective antireflux surgery may reduce the risk of progression.
  • The Benign Barrett’s and Cancer Taskforce suggests against antireflux surgery beyond establishing reflux control in patients with BE and suggests using medical therapies over surgical therapies for preventing progression to dysplasia or cancer in patients with BE. Patients who place a lower value on potential complications from surgery and a higher value on avoiding daily medications may opt for surgical approaches. Patients should be counselled that acid suppression medications may need to be used on a long-term basis after surgery.

 

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