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Barrett’s esophagus (BE) represents the morphological premalignant manifestation of gastroesophageal reflux disease (GERD), which develops as a consequence of the dysfunction and failure of the antireflux mechanism38. BE involves the formation of intestinal metaplasia (IM) from the squamous epithelium of the esophagus, which is a reparative response to reflux-induced damage37. Although the prevalence in Western countries is about 1-2% in the general population and about 10% in population who report acid reflux symptoms, the accurate prevalence of BE in the general population is difficult to determine as the majority of individuals with BE are not diagnosed40,42. Epidemiological and histopathological evidence indicate that many cases of esophageal adenocarcinoma (EAC) arise in individuals with BE by the progression of IM (nondysplastic Barrett’s esophagus [NDBE]) and indefinite for dysplasia (IND) to dysplasia (including low-grade dysplasia [LGD] and high-grade dysplasia [HGD]) and finally to neoplasia46. To date, dysplasia remains the best available marker of cancer risk in patients with BE.
Since BE is considered a complication of chronic GERD, it is perhaps not surprising that risk factors for gastric reflux are also strongly associated with BE30,54. Reflux-induced injury has been linked to cellular and molecular changes in the esophagus12,39. Symptoms of heartburn and regurgitation are strongly associated with the presence of BE, and duration of GERD symptoms may also be a risk factor for BE7. Although GERD is a strong risk factor for both BE and EAC, 40-50% of patients with these disorders do not report chronic reflux symptoms, suggesting that silent reflux or other risk factors such as male sex57, age 50 or older43, white race58, central obesity28, and cigarette smoking9 also likely play a role in the pathogenesis of BE and EAC.
Although BE is well-established precursor for EAC, the assumption that all patients who develop EAC go through the same reflux-induced response leading to adenocarcinoma was challenged by a retrospective analysis that found that only 46% of patients with EAC presented with endoscopic confirmation of BE and histopathological evidence of IM45. Furthermore, comparison of patients with EAC who had confirmed BE at presentation to those without BE suggested the existence of two EAC phenotypes with different tumor behavior and response to therapy45. These findings raise the question of whether EAC always develops through the IM-dysplasia-EAC sequence.
Accepting that a controversy exists, the natural course of progression to dysplasia and cancer in BE in the majority of patients is thought to be stepwise from NDBE to LGD to HGD and cancer. The annual cancer risk depends on the degree of dysplasia, such as 0.33% if there is no dysplasia, 0.54% with LGD, and 7% with HGD47. Thus, the management is based on disease stages.
Proton-pump inhibitor (PPI) therapy is recommended to control reflux symptoms in patients with NDBE. The American College of Gastroenterology (ACG)47, American Gastroenterological Association (AGA)52, and American Society for Gastrointestinal Endoscopy (ASGE)46 all recommend that surveillance endoscopy with four-quadrant biopsies at 2-cm intervals every 3-5 years for NDBE. PPI therapy is associated with a 71% decrease in the risk of developing HGD and EAC in patients with BE50. Long-term therapy (>2-3 years) has a higher protective effect50. Chemoprevention to inhibit the progression to cancer in patients with BE is currently being assessed. Various medications such as aspirin, metformin, and statins have been studied. A randomized controlled trial indicated that the combination of high-dose esomeprazole plus aspirin had the strongest protective effect compared with low-dose esomeprazole without aspirin at a median follow-up of 8.9 years25. However, the ACG guidelines do not currently recommend chemoprevention for all patients with BE, but suggest it should be considered in patients with BE who are appropriate candidates for aspirin use for cardioprotection47.
In BE IND, either the epithelial abnormalities are insufficient for a diagnosis of dysplasia, or the nature of the epithelial abnormalities is uncertain due to inflammation or technical difficulties with specimen processing. The risk of HGD or cancer within 1 year of the diagnosis of IND varies between 1.9% and 15%55. The recommendation from ACG47 for management is to optimize acid suppressive therapy for 3-6 months and then to repeat esophagogastroduodenoscopy (EGD). If indefinite dysplasia is noted again, repeat endoscopy in 12 months is recommended59.
Most patients with an initial diagnosis of LGD (73%) are downstaged to NDBE or to IND after review by expert gastrointestinal pathologists10. Patients with confirmed and persistent LGD are at higher risk of progression11. Once LGD is confirmed by a second gastrointestinal pathologist, the patient should be considered for endoscopic ablation. A landmark study demonstrated the benefit of radiofrequency ablation in achieving complete eradication of dysplasia (90.5% vs. 22.7% for a sham procedure) and complete eradication of IM (77.4% vs. 2.3% for a sham procedure)49. Patients with confirmed LGD who do not undergo eradication therapy should have surveillance endoscopy every 6-12 months.
As with LGD, the diagnosis of HGD needs to be confirmed by a second pathologist with gastrointestinal expertise. In the past, the treatment was esophagectomy, but due to demonstrated lower morbidity and equivalent efficacy of radiofrequency ablation, the current treatment of choice is endoscopic mucosal resection (EMR) of raised lesions, followed by radiofrequency ablation of the entire affected segment23. Pathology is best assessed by EMR, especially in areas of nodularity and ulceration. A randomized controlled study of 42 patients with HGD was randomized between radiofrequency ablation and sham procedure. Complete eradication of dysplasia was achieved in 81% of ablation patients versus 19% with the sham procedure49. Eradication of IM was achieved in 77% of ablation patients versus 2% of patients with the sham therapy49. Results of 3-year follow-up from the same cohort showed complete eradication of dysplasia in 98% and of IM in 91%48. Endoscopic eradication therapy is recommended for all patients with BE and HGD without the potential comorbidity and side effects associated with esophageal resection. Short segment Barrett’s (<3 cm) with HGD can also be assessed for complete ablation with EMR alone. Alternatively, surveillance every 3 months is an option if the patient does not wish to undergo eradication therapy48.
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