Barrett’s Oesophagus: Diagnosis and Management

Introduction: Oesophageal cancer is the seventh leading cause of cancer mortality worldwide.1 Two major pathological subtypes exist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Oesophageal adenocarcinoma is the predominant subtype in Europe, North America and Oceania with epidemiological studies in the last decade showing a gradual increase in incidence.2 The focus of this article is Barrett’s oesophagus, an established risk factor for the development of oesophageal adenocarcinoma.

Background

Barrett’s oesophagus (BE), first identified by N. R. Bennett in 1950, is defined as the replacement of squamous epithelium of the distal oesophagus by metaplastic (intestinal-type) epithelium.3 A recent systematic review of risk factors for BE found a prevalence of 0.8% in those without GORD symptoms.4 Prevalence was higher in individuals with known risk factors for BE including family history, male sex, increasing age, GORD and obesity. A positive linear relationship was shown between BE prevalence and the number of risk factors identified, with an increased in prevalence of 1.2 % for each additional risk factor.4

Diagnosis and Surveillance

The diagnosis of Barrett’s oesophagus involves recognition during endoscopy, appropriately targeted biopsies, and histologic confirmation. The Prague criteria are a well-validated and widely accepted system used to diagnose and classify Barrett’s oesophagus at endoscopy. The gold-standard for tissue sampling is the Seattle Protocol, first described in 1993, which consists of four-quadrant biopsies at intervals of every 1–2 cm and separate samples of areas identified by mucosal irregularity along the entire involved segment.

The stepwise progression of Barrett’s metaplasia to high-grade dysplasia and invasive cancer provides an excellent opportunity for screening and surveillance. Screening for BE or oesophageal adenocarcinoma in an unselected population is not currently recommended, however, because of the relatively low risk in the general population.5 The estimated prevalence of BE in a general population is 1-2%, is with an annual risk of progression to high grade dysplasia (HGD) or oesophageal adenocarcinoma of 0.3–0.8%.6, 7 The European Society of Gastrointestinal Endoscopy (ESGE) suggests that, if screening is considered, it should be limited to a select, higher risk population. Similarly, the American College of Gastroenterology (ACG) advocate a single screening endoscopy for individuals with GORD symptoms and three or more risk factors for BE.8

ESGE does advocate for the use of the non-endoscopic cell collection device, Cytosponge by Medtronic, as an alternative to endoscopy for case finding. A recent UK randomised control trial, the Barrett Esophagus Screening Trial 3 (BEST3) showed that the offer of a Cytosponge test was associated with a 10-fold higher rate of diagnosis of BE compared with usual care among a screening population reporting symptoms of reflux disease and taking a PPI.9

Surveillance intervals

Current surveillance intervals for those with confirmed BE are stratified by BE length and dysplasia, as these are both accepted risk factors for disease progression.

For those without dysplasia, ESGE currently recommends a 5 year surveillance gastroscopy for BE with a maximum extent of >1cm and <3cm and a 3 year gastroscopy for BE with a maximum extent of >3cm and <10cm. For patients with an irregular Z-line of < 1 cm, no routine biopsies or endoscopic surveillance are advised.5 Surveillance in those with dysplasia depends on the degree of dysplasia and response to / need for endoscopic eradication therapy. ESGE suggests that, if a patient has reached 75 years of age at the time of the last surveillance endoscopy and/or the patient’s life expectancy is less than 5 years, the discontinuation of further surveillance endoscopies can be considered.5

Treatment

Chemoprevention

In patients with BE, PPIs are primarily indicated for control of reflux symptoms. There is however increasing evidence that PPIs may have a chemopreventive effect. In one large meta-analysis which included 12 observational studies with over 150,000 patients, PPI use was associated with a two-fold risk reduction of BE progression to HGD or oesophageal adenocarcinoma.10

Of note, long-term PPI usage has recently garnered interest with regards to potential side effects, including interference in absorption of B12, magnesium and calcium, and enteric infections. These associations have recently been studied in a randomized trial of almost 20,000 patients who received either PPI or placebo and were followed for three years. This trial demonstrated no adverse events associated with three year PPI use, except for a possible increase in risk of enteric infection.11

Based on the available evidence, no recommendation can be made on the optimal PPI dose. ESGE currently recommends double-dose PPI (equivalent to Omeprazole 40 mg twice daily) when undergoing endoscopic treatment, with dose adjustment after this as tolerated.5

Endoscopic therapy

Endoscopic therapy is not currently recommended for those with BE without dysplastic changes.5

For patients with low grade dysplasia (LGD), the risk of progression to high grade dysplasia (HGD) or oesophageal adenocarcinoma is between 9.2 % and 13.4 % per patient per year. A repeat gastroscopy is currently recommended six months after initial confirmation of LGD. If no dysplasia at this six month gastroscopy, the interval can be broadened to one year. ESGE recommends offering endoscopic eradication therapy (EET) to those who have LGD on at least two separate endoscopies. ESGE also recommends EET for BE with confirmed HGD without visible lesions, to prevent progression to invasive cancer. Radiofrequency ablation (RFA) is the ablation method most extensively studied. RFA has proven to be safe and effective in several large prospective randomized and non-randomized studies.12

ESGE recommends the use of endoscopic mucosal resection (EMR) for visible lesions <20mm with low probability of submucosal invasion (Paris type 0-IIa, 0-IIb) and for larger or multifocal benign (dysplastic) lesions. ESGE suggests the use of endoscopic submucosal dissection (ESD) for lesions suspicious for submucosal invasion (Paris type 0-Is, 0-IIc), for malignant lesions of >20mm, and for lesions in scarred/fibrotic areas. ESGE recommends endoscopic resection as curative treatment for T1a Barrett’s cancer with well/moderate differentiation and no signs of lymphovascular invasion.

It has been shown that the rate of recurrence or metachronous HGD and/ or oesophageal cancer is up to 20–35 % after successful endoscopic resection of focal lesions. As a result of this, most centres follow the two-step strategy of endoscopic resection of all visible lesions, followed by ablation of the remaining BE.

Artificial Intelligence

The ultimate goal of gastroscopy for BE is the detection of early neoplastic changes that are suitable for endoscopic intervention. Guidelines recommend surveillance with high-definition white light endoscopy, virtual and dye-assisted chromoendoscopy and a labour intensive biopsy protocol. Despite well established guidance, a recent meta-analysis of missed oesophageal adenocarcinoma after a diagnosis of BE showed that still about 20% of HGD and oesophageal adenocarcinoma in those with known BE were detected within 1 year from initial diagnosis.13 The use of artificial intelligence as an auxiliary tool has shown potential in detecting oesophageal precancerous lesions and several computer-assisted diagnostic (CADe) systems have been developed to date.14-16 In one pilot study, a convoluted neural network algorithm analysed 458 images and correctly detected early neoplasia with a sensitivity of 96.4%, specificity of 94.2% and accuracy of 94.2% (16). Areas where AI will likely play a role in the diagnosis and management of BE include improving the quality of upper GI endoscopy performed, identifying individuals at risk/ appropriate for screening and as an adjunctive tool for pathologists where great intra-observer variability exists.17

Conclusion

BE remains an important clinical diagnosis as the only recognised precursor for the development of oesophageal adenocarcinoma. In the coming years, a focus on nonendoscopic diagnostic tools and AI systems will likely have a significant impact on BE diagnosis and management.

References available on Request

Written by E Gibbons, Consultant Gastroenterologist, Letterkenny University Hospital

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