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Barrett’s oesophagus: Diagnosis and management

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Barrett’s oesophagus is a benign condition where the normal (stratified squamous) lining of the oesophagus is replaced by abnormal cells (intestinal metaplasia). It affects up to  two per cent of the population in the Western world and although in itself it is not harmful, it is one of the most common premalignant conditions after colonic polyps.

 

At least 60 per cent develop following chronic indigestion and it has a lifetime risk of 3-5 per cent conversion to adenocarcinoma depending on the dysplasia grade.
Its incidence is increasing in the Western world and it is unclear as to whether this is a true rise or represents an increased awareness of the dangers of reflux disease and increased access to endoscopy.  However, a Dutch study has shown that the increase is even more pronounced when the prevalence is compared relative to the number of endoscopies.

Diagnosis
To make a diagnosis of Barrett’s oesophagus two criteria have to be satisfied: One endoscopic and one histological. The upper gastrointestinal endoscopy must demonstrate the squamo-columnar junction (Z-line) displaced beyond the gastro-oesophageal junction (GOJ). The Z-line normally corresponds with the GOJ, but in Barrett’s is displaced proximally.  Barrett’s oesophagus can then be graded according to the Prague endoscopic criteria measuring the height of circumferential Barrett’s (C-value) and the longest length of columnar mucosa (M-value).

Advanced imaging
While standard endoscopic imaging is adequate for grossly visible lesions – it is less so for subtle changes and newer imaging techniques may improve identification of Barrett’s oesophagus and dysplasia. Narrow Band Imaging (NBI) uses a blue light (which is absorbed by haemoglobin) which allows visualisation of the superficial vasculature which may be altered in intestinal metaplasia and irregular mucosa and abnormal blood vessels in dysplasia (Figure 1a and 1b).

Natural history
Although it is a recognised pre-malignant lesion, the lifetime risk of progression to oesophageal carcinoma is small (three-five per cent lifetime risk) with the majority of cases not progressing to adenocarcinoma. Known risk factors include age, male gender, white ethnicity, length of Barrett’s, cigarette smoking, and obesity as well as poor diet in vegetables and fruit, with the most important prognostic factors being the length of the abnormal mucosa and the degree of dysplasia.

Among patients without dysplasia, the risk of oesophageal adenocarcinoma is approximately 0.5 per cent  per year. In patients with low-grade dysplasia (LGD), the risk is approximately 0.6–1.7 per cent  per year, and in cases that progress to high-grade dysplasia (HGD), the risk of oesophageal cancer can vary from four per cent to more than 10 per cent  per patient year.

The management of Barrett’s oesophagus is focused on prevention of progression to adenocarcinoma. Proton pump inhibitors both heal oesophageal ulceration and improve symptoms; however, recent studies have mentioned links with deficiencies like osteoporosis, B12 and folate, which have to be taken into account, as do interactions affecting efficacy of other drugs such as clopidogrel.

Surgical correction of the oesophageal sphincter (fundoplication) has the added advantage of not just improving symptom control by preventing acid reflux, but also preventing any bile reflux which may play a role in neoplastic transformation.  It has been proven to be safe, cost effective and reliable; however, even though regression of Barrett’s oesophagus post-fundoplication has been reported, two Swedish database studies have suggested that anti-reflux surgery may not protect against progression to cancer. The development of cancer in these cases was found to occur early postoperatively.  A group from the Mayo Clinic in the US showed that no patient developed carcinoma after 39 months, suggesting that the cellular alterations may have taken place prior to the fundoplication and may represent the appearance of occult adenocarcinoma present prior to fundoplication.

Patients who are enrolled in surveillance programmes generally have cancer detected at an earlier stage, which should be more amenable to cure.  However, some patients with Barrett’s may not have any reflux symptoms and surveillance is dependent on the adherence to international guidelines. Recommendations for surveillance vary but most centres do endoscopies every two years, with four quadrant biopsies at 2cm intervals along the length of the Barrett’s mucosa.

Treatment

If there is dysplasia, endoscopy and biopsies are done more often, usually three-six months apart.  In the presence of high-grade dysplasia, occult carcinoma has been reported in up to 40 per cent of resected specimens. This, however, includes intramucosal carcinoma, and the rate of sub mucosalinvasive carcinoma is closer to 12 per cent  when applying strict pathological criteria.

Endoscopic mucosal resection (EMR) uses a cautery snare technique, which can remove visible or raised lesions for diagnostic and therapeutic benefit. It allows for complete histopathological assessment of the removed mucosa, and if this is superficial they can have further ablative techniques or if it is deep they can be referred for surgical therapy.

Long-term results are becoming available for EMR showing complete response rates of >96 per cent and five year survival of 84 per cent. If there is any mucosal irregularity EMR is recommended, with operative intervention if there is deep invasion present and ablative therapy for the remaining flat mucosa if resection is complete.

With ablative therapies the abnormal epithelium is destroyed, using methods including thermal radiofrequency or photochemical therapy.  The most common used are photodynamic therapy (PDT) and more commonly now radiofrequency ablation (RFA). RFA appears to have higher eradication rates of dysplasia (up to 98 per cent  as opposed to <80 per cent ) with fewer strictures (0-six per cent  as opposed to 30-40 per cent at five years) and no photosensitivity complications. It is rapidly becoming the ablative procedure of choice, however long-term data is not yet available and patients will require close follow-up surveillance.

Argon Plasma Coagulation may be used for small segments of abnormal mucosa or for bridges of abnormal mucosa following EMR or RFA.

While ablative techniques in combination with EMR may be suitable for intramucosal carcinoma, once the tumour breaches the submucosa the current recommendation is surgical therapy if the patient is suitable for surgery, although some authors report success with endoscopic submucosal resection. With surgery becoming more centralised and with specialist centres reporting low mortality and morbidity rates, oesophagectomy for high-grade dysplasia or intra-mucosal carcinoma can be carried out safely and should be offered to suitable patients.

Completely laparoscopic approaches have significant potential for reducing pulmonary morbidity; however, to date no significant difference between open and laparoscopic surgery has been shown.  Vagal sparing approaches have potentially interesting advantages in quality of life, but they have not been adequately evaluated to date.

Future
One of the difficulties with Barrett’s oesophagus is making the diagnosis, with 40 per cent  of patients being asymptomatic.  In our unit in Cambridge there are ongoing clinical trials (BEST and BEST2) using a sponge capsule that patients swallow with some water. The capsule has a string attached, which dissolves in the stomach and expands into a sponge-like mesh 3cm wide that is pulled out five minutes later.

The cells removed on the surface of the sponge are collected for analysis and stained with a molecular marker allowing the identification of Barrett’s cells, if present, under the microscope. This test had a sensitivity and specificity of 90 per cent and 93 per cent, respectively, for clinically relevant Barrett’s segment, and has enormous potential for population screening.

Minimally invasive surgical approaches may further reduce morbidity and mortality in patients who do require surgical resection, and robotics may have a role to play in increasing the extent of the surgery while keeping the morbidity low.

Further work is being done in molecular imaging using various panels of biomarkers to predict probability of progression from Barrett’s to adenocarcinoma.  This work has significant potential; however currently the prohibitive costs of these bio-markers make them non-viable for routine clinical use.

Significant collaboration between large groups such as Esophageal Adenocarcinoma Genetic Linkage (EAGLE) in Europe and the Oesophageal Cancer Clinical and Molecular Stratification Study (OCCAMS) in Cambridge are working on genome-wide studies to improve understanding of the disease.

Conclusion
Barrett’s oesophagus affects an increasing number of people each year and 40 per cent  of people are symptomatic. Identifying the patients and determining those who are at-risk of progression is currently the most difficult problem. Future approaches using molecular analysis and genomic studies may help to more accurately stratify the patient risks. Endoscopic resections are helpful in early mucosal carcinoma as both a staging and therapeutic tool. Further surgical advances may make surgical resection safer with less morbidity. 


Mr Chris Collins, Consultant Oesophago-Gastric Surgeon, Addenbrookes’s Hospital, Cambridge, UK

For information on Lollipop Day visit www.lollipopday.ie

 

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