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Targeting surveillance in Barrett's esophagus

Barrett’s esophagus is a condition where the squamous lining of the lower esophagus is replaced by metaplastic columnar epithelium secondary to severe prolonged gastroesophageal reflux. The metaplastic epithelium is inherently unstable and, especially in the presence of ongoing reflux, can lead to neoplastic change. While Barrett’s esophagus predisposes to dysplasia and carcinoma, the risk of adenocarcinoma may have been exaggerated. It is likely that the real risk of developing cancer is less than one in 200 patient years of follow up. Although it is accepted practice to enrol fit patients into a surveillance program to detect the development of dysplasia or carcinoma at an earlier stage, it has been argued that the cost-effectiveness and efficacy of surveillance have not been adequately established. Modelling of surveillance programs based on current estimates of risk shows that they will not have an impact on mortality from esophageal adenocarcinoma, as most patients with cancer present at the initial endoscopy and only a fraction of patients with Barrett’s esophagus go on to develop cancer. To be effective, surveillance programs need to target individuals with Barrett’s esophagus who are at high risk of progression to malignancy. What markers are there which could potentially identify highrisk individuals? Looking at demographic characteristics, the major risk group is male Caucasians especially if they are older and are smokers. Severe, long-standing gastroesophageal reflux understandably increases the risk in this reflux-associated disorder, as does obesity. Accordingly, limiting surveillance to males who have other risk factors may be one strategy to improve the effectiveness of surveillance. At endoscopy it has been shown that macroscopic markers such as stricture, nodularity, ulcers and severe esophagitis on entry into a surveillance program indicate a high-risk group for the subsequent development of dysplasia and adenocarcinoma. An Australian series followed 353 patients and again found that most cancers developed in males. As well, all but one patient developing adenocarcinoma had an endoscopic marker at the first endoscopy. Endoscopic markers also predicted progression to HGD, with a hazard ratio of 14 if more than one marker was present. If surveillance had been restricted to patients with endoscopic markers or dysplasia at index endoscopy, the incidence of cancer would have been one in 89 years instead of one per 176 years, increasing the efficiency of the surveillance program. In this issue of the Journal of Gastroenterology and Hepatology, a retrospective series from New Zealand is reported analyzing 13 years of surveillance for 212 patients with long-segment (>3 cm) Barrett’s esophagus. The incidence of adenocarcinoma was one per 100 years of follow up, a relatively high rate consistent with the smaller number studied and the exclusion of short segments (<3 cm). The authors point out that nearly all cancers developed in a small subset of patients. All patients developing cancer were male and all but one had ulceration or dysplasia at entry. Longer segments of Barrett’s esophagus also increased the risk of cancer. This study confirms the previous finding that male patients with macroscopic markers are at higher risk for developing adenocarcinoma. If macroscopic markers can denote a subset of patients at higher risk of developing malignancy, are these reliably present at index endoscopy? Our group has shown that this is not the case if proton pump inhibitors (PPI) are routinely used prior to endoscopy. Patients who entered without prior PPI therapy were 3.4-fold more likely to have a macroscopic marker or low-grade dysplasia (LGD) than those patients already on a PPI. Accordingly, it is possible that widespread use of PPI will confound surveillance strategies for patients based on entry characteristics of macroscopic markers. Another problem is that it isn’t easy for an endoscopist without a special interest in Barrett’s esophagus to report reliably on endoscopy findings. Assessing endoscopic landmarks and subtle mucosal abnormalities requires considerable experience, while following an appropriate biopsy protocol needs education and a surveillance coordinator to ensure adherence to guidelines. The development of chromoendoscopy and optical biopsy techniques may enhance the reliability of endoscopic sampling in the future. What about histological criteria to predict malignant progression in Barrett’s esophagus? A rigorous biopsy protocol increases the detection of early cancer in Barrett’s esophagus. Ideally, the ‘Seattle Protocol’ should be followed whereby biopsies are obtained at 1-cm intervals from all four quadrants over the entire length of the Barrett’s segment to provide adequate sampling of the tissue. However, this is time-consuming during a routine endoscopy list and best practice is often not followed. Also, in the presence of inflammation, the interpretation of dysplasia is notoriously unreliable. Hence, patients need to have reflux well controlled on PPI before any relevant histopathological criteria can be assessed. Interobserver variation is also a problem, and involvement of a specialist pathologist well versed in the interpretation of dysplasia in Barrett’s epithelium is mandatory. LGD is not a reliable marker for disease progression, but a recent metaanalysis showed that the presence of high-grade dysplasia (HGD) has a weighted incidence rate of adenocarcinoma of six per 100 patient years during the first few years of follow up. Thus, if HGD is present, intensive surveillance is indicated. Ideally, objective biomarkers would be used to stratify patients according to their risk of developing cancer. The Seattle group have used flow cytometry to predict patients at risk. In the absence of HGD, those patients with neither aneuploidy nor increased 4N fractions had a zero 5-year cumulative cancer incidence whereas all patients who developed cancer within 5 years had aneuploidy, increased 4N fractions or HGD at entry. The same group have also reported on p53 mutations and 17p loss of heterogeneity to identify patients at risk of malignant progression. However, the widespread application of such techniques will need to await the development of appropriate bio-arrays. So, is there a group of patients with Barrett’s esophagus who can be identified as being at high risk for the development of adenocarcinoma, and who should be targeted for surveillance? At Accepted for publication 22 May 2008.