Chronic gastro-oesophageal reflux disease can induce a metaplastic change of the distal oesophagus called Barrett’s oesophagus whereby the normal squamous epithelium is substituted by a columnar epithelium. Patients with Barrett’s oesophagus are at increased risk of oesophageal adenocarcinoma which occurs through dysplastic stages with increasing degree of cellular and architectural disorganization. Barrett’s oesophagus represents an ideal model to study the genetic events supporting the onset of an invasive tumour since patients with this condition are surveilled with endoscopic tissue sampling until high grade dysplasia or intramucosal carcinoma develop. However, due to the relatively low incidence of this disease compared to other cancers, i.e. colon and breast, it is only recently that researchers have concentrated on understanding the genetic events supporting the onset of Barrett’s and its transformation to cancer. Here, we review the knowledge acquired so far on the genetic and molecular alterations along the oesophageal metaplasia–dysplasia-carcinoma sequence.

Barrett’s esophagus (BE) is a condition in which the normal stratified squamous epithelium of the esophagus is replaced by a metaplastic columnar mucosa as a complication of chronic gastroesophageal reflux disease (GERD) (1,2). BE is the only known precursor to esophageal adenocarcinoma, which has greater than 90% mortality unless detected early (2–4).

About 60 years ago, (1950) found instances in which the lower esophagus was lined by columnar epithelium, and reported this as a congenital anomaly. He inferred that the segment lined by columnar epithelium represented the stomach which was situated in the mediastinum, in association with a congenitally short esophagus. (1953) regarded the columnar epithelium- lined segment as part of the esophagus, however, and Barrett later changed his view and concluded that the condition might be acquired (Mangla).

Chapter Overview

Barrett’s esophagus is an acquired condition in which specialized metaplastic intestinal epithelium with goblet cells replaces the normal strati-fied squamous epithelium anywhere in the esophagus. The relationship between long-standing gastroesophageal reflux disease (GERD), the development of specialized intestinal metaplasia in the distal esophagus, and subsequent progression to adenocarcinoma has been clearly established. Once Barrett’s esophagus is diagnosed, it is critical to extensively biopsy the segment of Barrett’s epithelium to exclude dysplasia and cancer. Management of Barrett’s esophagus should focus on relieving symptoms of GERD and performing endoscopic surveillance at appropriate intervals. The timing of surveillance endoscopy is governed by the presence of mucosal dsyplasia and its pathologic grade. Recommendations about endoscopic surveillance intervals will undoubtedly be modified as the natural history of Barrett’s esophagus becomes better understood. Studies to validate existing biomarkers of cancer risk in patients with Barrett’s esophagus have the potential to permit stratification of patients into low-risk and high-risk groups and to eventually guide surveillance intervals. High-grade dysplasia within Barrett’s esophagus continues to be managed with esophagectomy; however, the advent of endoscopic ablative techniques has provided alternative management strategies for use in patients who are not optimal candidates for surgery and patients treated in the setting of clinical trials.

Barrett’s metaplasia-associated esophageal adenocarcinoma is one of the most rapidly increasing cancers in Western countries. Whereas early detection remains the cornerstone of prevention, chemoprevention is emerging as a complementary strategy. Carcinogenesis in Barrett’s mucosa is a multistep process in which cellular growth becomes progressively dysregulated. Fortunately, the process of carcinogenesis is a protracted one, which provides ample opportunity for intervention. In this review, we will discuss various potential chemoprevention targets and rationale behind their use to prevent Barrett’s related esophageal adenocarcinoma. We will also critically appraise the emerging preclinical and clinical literature regarding prevention of neoplasia in Barrett’s esophagus.

Objectives Lifestyle and demographic risk factors for the development of oesophageal adenocarcinoma developing from columnar-lined oesophagus are not well defined. Methods Demographic and lifestyle factors, endoscopy and histology reports were extracted from 1,761 subjects from seven UK centres. The associations of columnar-lined oesophagus with demographic and lifestyle factors and the development of adenocarcinoma were examined. Results 5.5% of patients had prevalent adenocarcinoma (more common in males, older patients, patients diagnosed earlier in the cohort and current or recent smokers). Adenocarcinoma incidence was 23 patients in 3,912 years or 0.59% per annum. Only increased age at diagnosis correlated with an increased risk of incident adenocarcinoma. There was no association with obesity or alcohol history. Conclusions Oesophageal adenocarcinoma occurs more commonly in older patients and is more frequent in males than females. Once columnar-lined oesophagus had been diagnosed, there were no other demographic or lifestyle factors which were predictive of the development of incident adenocarcinoma in this cohort.

Summary

Decision making in endoscopic ablation therapy involves assessment of the disease, the patient, and institutional factors. A lesion in the Barrett’s esophagus can be classified as “low risk” if the diameter is less than 2 cm, if it is well or moderately differentiated, and if it is limited to the mucosa. The patient’s life expectancy, comorbidity, adherence to endoscopy, and attitude toward cancer risk all have to be considered. Finally, the local expertise in histologic assessment, staging, and surgery needs to be taken into account in an extensive discussion of therapeutic options with the patient.

Barrett's esophagus (i.e. columnar epithelial metaplasia in the distal esophagus) is an acquired condition that in most patients results from chronic gastroesophageal reflux. It is a disorder of the white male in the Western world with a prevalence of about 1/400 population. Due to the decreased sensitivity of the columnar epithelium to symptoms, Barrett's esophagus remains undiagnosed in the majority of patients. Gastroesophageal reflux disease in patients with Barrett's esophagus has a more severe character and is more frequently associated with complications as compared with reflux patients without columnar mucosa. This appears to be due to a combination of a mechanically defective lower esophageal sphincter, inefficient esophageal clearance function, and gastric acid hypersecretion. Excessive reflux of alkaline duodenal contents may be responsible for the development of complications (i.e., stricture, ulcer, and dysplasia). Therapy of benign Barrett's esophagus is directed towards treatment of the underlying reflux disease. Barrett's esophagus is associated with a 30- to 125-fold increased risk for adenocarcinoma of the esophagus. The reasons for the dramatic rise in the incidence of esophageal adenocarcinoma, which occurred during the past years, are unknown. High grade dysplasia in a patient with columnar mucosa is an ominous sign for malignant degeneration. Whether an esophagectomy should be performed in patients with high grade dysplasia remains controversial. Complete resection of the tumor and its lymphatic drainage is the procedure of choice in all patients with a resectable carcinoma who are fit for surgery. In patients with tumors located in the distal esophagus, this can be achieved by a transhiatal en-bloc esophagectomy and proximal gastrectomy. Early adenocarcinoma can be cured by this approach. The value of multimodality therapy in patients with advanced tumors needs to be shown in randomized prospective trials.