Management of Barrett's Esophagus
Management of Barrett's Esophagus
Barrett's esophagus represents replacement of normal distal esophageal squamous epithelium with specialized columnar epithelium containing goblet cells. Typically arising in the setting of chronic gastroesophageal reflux disease, the presence of Barrett's esophagus carries a 50- to 100-fold increased risk of developing esophageal cancer. Risk factors include male sex, smoking history, obesity, Caucasian ethnicity, age > 50 and > 5-year history of reflux symptoms. Aggressive medical or surgical antireflux therapy may ameliorate symptoms, but have not yet been proven to affect the risk of developing esophageal adenocarcinoma in randomized trials. Although dysplasia is an imperfect biomarker for the development of subsequent malignancy, random sampling of esophageal tissue for dysplasia remains the clinical standard. There have been no studies to establish that endoscopic screening/surveillance programs decrease the rates of death from cancer. Fit patients with Barrett's esophagus and high-grade dysplasia should undergo esophagectomy to prevent the risk of developing esophageal adenocarcinoma. For non–operative candidates, endoscopic ablative approaches may represent a reasonable therapeutic alternative.
The columnar-lined esophagus was first described in 1906 by the pathologist Tileston, who identified a series of patients with "peptic ulcer of the esophagus." He described a mucus membrane around the ulcer "similar to that found in the stomach." In 1950, Norman Barrett published his treatise on the columnar-lined segment of tissue located within the distal esophagus that now bears his name. Boscher and Taylor were the first to recognize that this specialized epithelium contains the hallmark feature of intestinal-type goblet cells. In 1959, Moersch and associates were the first to suggest that this columnar lining might be a sequela of chronic reflux esophagitis. Over the past 50 years, the association between gastroesophageal reflux, Barrett's esophagus, dysplasia, and adenocarcinoma has been well-established.
Great advances have been made in our understanding and treatment of Barrett's esophagus. Herein we review current concepts in the management of the syndrome.
Barrett's esophagus is defined as the replacement (metaplasia) of the normal esophageal squamous mucosa with columnar epithelium containing goblet cells. This condition is most commonly diagnosed in the setting of chronic gastroesophageal reflux disease (GERD). Repeated mucosal injury in this setting predisposes patients to the development of mucosal dysplasia and, ultimately, adenocarcinoma. It should therefore be considered a premalignant condition carrying a 50- to 100-fold increased risk of cancer compared with the general population. The risk of developing adenocarcinoma in patients with Barrett's esophagus has been estimated to be 0.5% per year. The incidence of Barrett's esophagus has increased dramatically over the past few decades in conjunction with the associated surge in the frequency of GERD. It remains unproven, however, whether the rising incidence of esophageal adenocarcinoma is caused by an increasing frequency of GERD in the general population.
Risk factors for the development of Barrett's esophagus include male sex, smoking history, obesity, Caucasian ethnicity, age greater than 50 years, and a greater-than-5-year history of reflux symptoms.[7,8] Most patients with Barrett's esophagus have a history of heartburn and acid regurgitation. Less frequent symptoms include dysphagia, chest pain, hematemesis, and melena. Symptoms, however, are unreliable predictors of which patients have Barrett's esophagus, or of who will develop the condition.
Barrett's epithelium typically arises in the setting of chronic gastroesophageal reflux. Although acid exposure is believed to play an important role in Barrett's metaplasia, bile reflux may be more closely associated with the development of this condition. Chronic distal esophageal acid inflammation leads to a variety of cellular changes including loss of disaccharidase activity, low mucosal glutaminase levels, and altered levels of mucosal protein synthesis. In addition, a variety of intracellular pathways have been shown to be altered by reflux in the setting of Barrett's metaplasia, including MAP kinase activation and upregulation of COX-2 expression. Bile acids have also been demonstrated to have significant carcinogenic potential. In high concentrations, bile acids have been shown to induce cell membrane and mitochondrial membrane damage, release of reactive oxygen species, and mutation of tumor-suppressor genes such as p53.
Evidence suggests that Barrett's epithelium may progress through a metaplasia-dysplasia-carcinoma sequence. Metaplastic and dysplastic epithelium are frequently found adjacent to each other within pathologic specimens. In addition, progression from metaplasia to low-grade dysplasia, to high-grade dysplasia, and ultimately to adenocarcinoma has been observed in individual patients.
The molecular pathogenesis of Barrett's esophagus and esophageal adenocarcinoma has been shown to include the accumulation of multiple genetic alterations over time. In Barrett's esophagus, loss of heterozygosity of tumor-suppressor genes such as p53, the adenomatous polyposis coli gene (APC), the gene deleted in colorectal cancer (DCC), and MTS1 (p16) has been demonstrated to correlate with progression from metaplasia to dysplasia to cancer. Extensive ongoing work is aimed at determining whether such tumor markers can help clinicians distinguish those patients with Barrett's esophagus who are more likely to progress to adenocarcinoma. Currently available data are insufficient to support the use of these markers during routine clinical practice.
The diagnosis of Barrett's esophagus is achieved at endoscopy (Figure 1), revealing abnormal salmon-colored columnar epithelium extending proximally within the esophagus. The hallmark histologic finding within these specimens is the presence of columnar epithelial metaplasia with mucin-producing goblet cells (Figure 2).
For decades, the diagnosis of Barrett's esophagus was based on the finding of long segments (≥ 3 cm) of columnar epithelium. More recently, intestinal metaplasia has been identified from biopsy specimens of short segments (< 3 cm) of Barrett's esophagus, even in patients with no evidence of GERD. Investigators now recognize that shorter segments of Barrett's esophagus can be associated with the development of adenocarcinoma. Although it would seem logical that the risk of cancer would correlate with the extent of esophageal metaplasia, this notion remains unproven. Currently, patients with long- and short-segment Barrett's esophagus are managed similarly.
Treatment of GERD
Antireflux therapy is designed to eliminate the signs and symptoms of GERD and to prevent its complications. Both antisecretory therapy (H2 blockers, proton pump inhibitors [PPIs]) and surgical fundoplication have been shown to be effective in reducing or eliminating reflux symptoms (> 90% symptomatic improvement). Despite excellent control of symptoms, no antireflux therapy (medical or surgical) has been definitively proven to promote the regression and/or prevent the progression of Barrett's metaplasia or to decrease the risk of esophageal adenocarcinoma.
Antisecretory therapy is directed at acid suppression and is prescribed according to the intensity of GERD symptoms, or based on the severity of the associated esophagitis. Though symptomatic relief can be achieved in the majority of patients, many continue to demonstrate continued acid reflux during pH studies. In fact, up to 80% of patients treated with twice-daily PPIs continue to demonstrate nocturnal gastric acid reflux. Combination regimens employing PPIs and H2 blockers can achieve gastric achlorhydria, leading investigators to speculate whether such medical therapy might have a favorable impact on the natural history of Barrett's esophagus.
A few retrospective studies have been published suggesting that PPIs can promote partial regression of specialized intestinal metaplasia. In a study of 68 patients with acid reflux and proven Barrett's esophagus, profound acid suppression with omeprazole, 40 mg twice daily, was compared with milder acid suppression using ranitidine, 150 mg twice daily. The twice-daily omeprazole regimen reduced reflux symptoms in 99% of patients, and a small but statistically significant regression of Barrett's esophagus was achieved, both in length (6.4%) and in area (7.9%). Malesci and associates similarly demonstrated excellent control of acid exposure with 60 mg of omeprazole every morning, and an associated 53% reduction in length of Barrett's epithelium at endoscopy at 1 year.
Although these studies suggest that aggressive control of acid reflux might be beneficial, such findings do not necessarily translate into a decreased risk of cancer. Therefore, the need for continued surveillance is unchanged. If a patient with no symptoms or esophagitis is found incidentally to have Barrett's esophagus, the decision to prescribe a PPI or other regimen remains controversial.
Emerging data suggest that chronic antisecretory medical therapy might actually enhance the development of cancer. Achlorhydria is a known risk factor for developing adenocarcinoma of the stomach, and is felt to promote the propagation of bacteria that produce carcinogenic nitroso compounds. Acid suppression also increases serum gastrin levels that have been shown to be associated with increased proliferative markers and mucosal hyperplasia in patients with Barrett's esophagus. These findings have yet to be corroborated with clinical trials in humans. In other human studies evaluating the impact of chronic H2-receptor blockade and PPI usage, there was no apparent impact on the risk of developing esophageal adenocarcinoma.
Gastric fundoplication has been postulated to provide a more effective form of antireflux therapy, providing a mechanical barrier to both acid and bile reflux in patients with Barrett's esophagus. Randomized trials to date have not definitively proven this contention, however, with no significant difference reported between medical and surgical antireflux therapy regimens in the prevention of esophageal adenocarcinoma.[26,27] A large case-control study from Sweden and a recent meta-analysis similarly demonstrated no protective effect of antireflux surgery on the development of esophageal adenocarcinoma.
Though not substantiated by prospective, randomized studies to date, several larger nonrandomized series have documented a reduction in the overall risk of cancer progression in patients undergoing fundoplication.[30,31] In a longitudinal analysis of 102 patients with Barrett's esophagus treated medically and/or surgically, 19 patients ultimately developed low-grade dysplasia, 4 developed high-grade dysplasia, and 4 patients progressed to adenocarcinoma with medical treatment alone. None of the patients from this cohort (n = 15) who underwent Nissen fundoplication developed dysplasia or adenocarcinoma.
In a comprehensive review of the outcomes in 97 patients with Barrett's esophagus treated with fundoplication during a median follow-up of 5 years, regression of low-grade dysplasia to a nondysplastic Barrett's epithelium occurred in 44% of patients. No patient developed high-grade dysplasia or cancer in 410 patient-years of follow-up.
In another small randomized study of 59 patients with Barrett's esophagus comparing medical therapy (H2 blockers or omeprazole, n = 27) and surgical therapy (n = 32), a decrease in length of Barrett's esophagus was noted in the surgical arm. Six patients developed dysplasia (five low-grade, one high-grade with early carcinoma) in the medical arm, compared to only one (high-grade with early carcinoma) in the surgical arm. Interestingly, the patient with disease progression in the surgical arm had evidence of failure of the antireflux procedure documented by 24-hour pH analysis. Patients with successful antireflux surgery documented by 24-hour pH studies demonstrated no dysplastic changes or progression to adenocarcinoma.
This principle is further underscored by reports of regression of low-grade dysplasia after successful antireflux procedures, not typically seen with maximal medical therapy regimens. Gurski et al evaluated 91 consecutive patients with Barrett's esophagus receiving either surgical (fundoplication, n = 77) or medical (PPIs, n = 14) therapy. In this series, apparent regression was reported in 28 (36.4%) of 77 patients in the surgical arm vs 1 (7.1%) of 14 in the medical arm. Regression of low-grade dysplasia (17 of 25 patients) to no dysplasia was noted, as well as regression of Barrett's to no Barrett's (11 of 52 patients) in the surgical arm. The median time to regression was 18.5 months. Independent predictors of regression were the presence of a short-segment of Barrett's and antireflux surgery.
In another study, Oelschlager and associates studied the endoscopic outcomes of 106 patients undergoing antireflux surgery in the setting of Barrett's esophagus. Approximately 55% of patients with short-segment Barrett's esophagus were reported to attain complete regression, with only one patient developing cancer in a median 40-month follow-up.
Though such studies are certainly provocative, the concept of regression of Barrett's esophagus remains highly controversial and has not been substantiated by controlled clinical trials. Whether fundoplication ultimately reduces the risk of cancer development also remains unproven. Fundoplication is safe and effective, and can be performed with durable results using minimally invasive techniques. We strongly consider this approach in patients with symptomatic Barrett's esophagus.