Barrett Esophagus

Harlan G. Rich, M.D.

Basic Information

Definition

Barrett esophagus occurs when the squamocolumnar junction is displaced proximal to the gastroesophageal junction and the squamous lining of the lower esophagus is replaced by metaplastic columnar epithelium, which predisposes to the development of esophageal adenocarcinoma. While cardia-type epithelium has been shown to predispose to esophageal cancer, the presence of intestinalized epithelium is still considered essential for the diagnosis. Recent data show that the absolute annual risk for esophageal carcinoma in Barrett esophagus is 0.12%, which is much lower than the assumed risk of 0.5% that is the basis for current surveillance guidelines.

Synonyms

Barrett’s esophagus
Esophagus, Barrett
Esophagus, columnar-lined
Ulcer, Barrett’s

ICD-10CM CODES
K22.70	Barrett esophagus without dysplasia
K22.710	Barrett’s esophagus with low grade dysplasia
K22.711	Barrett’s esophagus with high grade dysplasia
K22.719	Barrett’s esophagus with dysplasia, unspecified

Epidemiology & Demographics

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Male/female ratio of 4:1.
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Mean age of onset is 40 yr, with a mean age range of diagnosis of 55 to 60 yr.
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Occurs more frequently in white and Hispanic individuals than in African American individuals, with a ratio of 10 to 20:1.
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Mean prevalence of 5% to 15% in patients undergoing endoscopy (EGD) for symptoms of gastroesophageal reflux disease (GERD).
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Independent risk factors include chronic reflux (>5 years), hiatal hernia, age >50 years, male gender, white ethnicity, smoking history, and intraabdominal obesity. A family history with at least one first-degree relative with Barrett esophagus or adenocarcinoma of the esophagus may also be a risk factor.
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It is estimated that 5.6% of adults in the United States have Barrett esophagus. Prevalence rate in asymptomatic cohorts ranges from 5% to 25%.

Physical Findings & Clinical Presentation

Symptoms

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Chronic heartburn
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Dysphagia with solid food
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May be an incidental finding on EGD in patients without reflux symptoms
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Less frequent: chest pain, hematemesis, melena
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Patients may be asymptomatic.

Physical Findings

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Nonspecific; can be completely normal
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Epigastric tenderness on palpation

Etiology

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Metaplasia is thought to result from reepithelialization of esophageal tissue injured as a result of chronic GERD.

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Patients with Barrett esophagus tend to have more severe esophageal motility disturbances (decreased lower esophageal sphincter pressure, ineffective peristalsis) and greater esophageal acid exposure on 24-hour pH monitoring. Table 1 lists some physiologic abnormalities that have been reported in Barrett patients and suggests how these abnormalities may contribute to GERD severity.

TABLE1 Proposed Physiologic Abnormalities Contributing to Gastroesophageal Reflux Disease in Patients With Barrett EsophagusFrom Feldman M, et al.: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.

Abnormality	Potential Consequences
Extreme hypotension of the lower esophageal sphincter	Gastroesophageal reflux
Ineffective esophageal motility	Defective clearance of refluxed material
Gastric acid hypersecretion	Reflux of highly acidic gastric juice
Duodenogastric reflux	Esophageal injury caused by reflux of bile acids and pancreatic enzymes
Decreased salivary secretion of EGF	Delayed healing of reflux-damaged esophageal mucosa
Decreased esophageal pain sensitivity to refluxed caustic material	Failure to initiate therapy
EGF, Epidermal growth factor.

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Intraesophageal bile reflux may also play a role in the pathogenesis.
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Familial clustering of GERD and Barrett esophagus suggests a genetic predisposition, but no gene has yet been identified. Early data suggest that patients who develop Barrett are genetically predisposed to a severe inflammatory response to GERD. Candidate susceptibility loci include CRTC1, BARX1, and FOXP1.
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Progression from metaplasia to carcinoma is associated with changes in gene structure and expression, including the caudal-related homeobox family of transcription factors (CDX1 and CDX2) and the tumor suppressors p16 (CDKN2A) and TP53.

Diagnosis

Differential Diagnosis

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GERD, uncomplicated
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Erosive esophagitis
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Gastritis
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Peptic ulcer disease
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Angina
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Malignancy
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Stricture or Schatzki’s ring

Workup

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The American Gastroenterological Association Medical Position Panel gave a weak recommendation for screening patients with multiple risk factors, including age over 50, male sex, white race, chronic GERD, hiatal hernia, elevated body mass index, and intraabdominal distribution of body fat. An international consensus group suggested screening men over 60 with GERD symptoms for more than 10 years. An American College of Gastroenterology (ACG) Clinical Guideline suggested screening men with >5 years and/or frequent symptoms of GERD and two or more risk factors including age >50, Caucasian race, presence of central obesity, current or past history of smoking, and a confirmed family history of Barrett or esophageal adenocarcinoma. General population screening is not currently recommended. Although screening has become standard of practice in some communities, the effectiveness of screening using current techniques is controversial because it may not improve mortality rates from adenocarcinoma.
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EGD with biopsy is necessary for diagnosis. Ideally, this should be done via high-resolution white-light endoscopy with at least four biopsies for every 2-cm segment. If erosive esophagitis is present, patients should be treated to heal esophagitis with repeat endoscopy and biopsies 8-12 weeks later to determine if underlying Barrett esophagus is present.
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Unsedated transnasal endoscopy and an esophageal cytology device called a Cytosponge may be acceptable alternatives to conventional endoscopy. Wireless esophageal capsule endoscopy may detect Barrett esophagus but with too low a sensitivity and specificity to be recommended. Imaging studies are not useful.
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Diagnosis requires the presence of metaplastic columnar epithelium at least 1 cm proximal to the gastroesophageal junction (Figs. 1 and E2). Longer-segment (≥3 cm) Barrett esophagus is more readily diagnosed. Barrett esophagus may be described using the Prague criteria, documenting the circumferential and maximal length via a C and M score. At least two expert gastrointestinal pathologists should concur if any grade of dysplasia is diagnosed.

FIG.1

Anatomic landmarks of the normal LES region (A) and of Barrett esophagus (B).

Note that gastric mucosa is very common and normal in the LES region and that in Barrett esophagus, the squamocolumnar junction is not only proximally displaced within the tubular esophagus, but that the intervening mucosa is composed of intestinalized Barrett’s metaplastic epithelium. HH, Hiatal hernia.

From Silverburg SG: Principles of practice of surgical pathology and cytopathology, ed 4, New York, 2006, Churchill Livingstone.

FIG.E2

Images of nondysplastic Barrett esophagus using a high-resolution endoscope without (A) and with (B) narrow band imaging. In the lower panels (C, D) an area of early intramucosal cancer in the background of high-grade dysplasia associated with Barrett esophagus is shown. Note the irregular and distorted pit and vascular pattern in the area of high-grade dysplasia or intramucosal cancer compared with the nondysplastic Barrett esophagus (A, B), which has a regular pit and vascular pattern.

From Feldman M, et al.: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.
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Intestinal metaplasia of the gastric cardia is not Barrett esophagus and does not have the same risk for malignancy.
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Biomarkers and advanced imaging techniques such as chromoendoscopy, narrow band imaging, autofluorescence imaging, white light postprocessing algorithms, confocal laser endomicroscopy, and optical coherence tomography are being evaluated to assist with diagnosis and to better understand progression of disease, prediction of response to therapy, or prognosis.
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Screening for Helicobacter pylori infection in patients with GERD and Barrett esophagus is not recommended.

Treatment

The goal is to control GERD symptoms and maintain healed mucosa.

Nonpharmacologic Therapy

Nonpharmacologic therapy includes lifestyle modifications; elevating head of bed; and avoiding chocolate, tobacco, caffeine, mints, and certain drugs (see “Gastroesophageal Reflux Disease”).

Acute General Rx

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Proton pump inhibitors are the most effective treatment for GERD. Therapy should be titrated to control symptoms and/or to promote healing of endoscopic signs of disease.
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If patient is asymptomatic and incidentally found to have Barrett esophagus, once-daily proton pump inhibitors should be prescribed, as they may reduce the risk of neoplastic progression.

Chronic Rx

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Chronic acid suppression is recommended to control symptoms, maintain healing, and reduce neoplastic progression. For patients with Barrett esophagus, the benefits of the use of proton-pump inhibitors is thought to outweigh the potential risks.
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Antireflux surgery may be considered for management of GERD and associated sequelae, but it has not been proven to be superior to medical therapy. Patients continue to require endoscopic surveillance of their esophagus.
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When GERD is controlled by either medical or surgical therapy, ablation of metaplastic epithelium usually leads to replacement by normal squamous epithelium. Because only a minority of patients with Barrett esophagus progress to high-grade dysplasia or carcinoma, endoscopic eradication therapy is not recommended for the general population of patients with nondysplastic Barrett esophagus.

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Endoscopic eradication therapy is becoming the treatment of choice for low-grade dysplasia and is the treatment of choice for high-grade dysplasia. Radiofrequency ablation or photodynamic therapy, combined with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of visible mucosal irregularities, should be performed in conjunction with aggressive surveillance and eradication of all remaining Barrett epithelium. Endoscopic therapy is preferred over surgical treatment in properly staged individuals. These therapies may even be considered for patients with focal intramucosal carcinoma, if properly staged (T1SM1 or lower). Cryotherapy is being evaluated for the complete eradication of both dysplasia and intestinal metaplasia and reduced risk for disease progression. All these options run the risk for residual or buried metaplasia. Modalities for endoscopic treatment of Barrett esophagus are summarized in Table 2.

TABLE2 Modalities for Endoscopic Treatment of Barrett EsophagusFrom Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

Modality	HGD Resolved	BE Resolved	Recurrence Rate	Subsquamous BE Rate	Stricture Rate	Complication Rate	Advantages	Disadvantages
APC	67%-98.6%	38%-98%	33%-68% low power	25%-45% low power 0-30% high power	4%-10%	24% low power 40%-60% high power	Noncontact, technically simple	Requires several treatment sessions
MPEC	–	25%-88%	7%	7%	2%	41%-43%	Noncontact, technically simple, relatively inexpensive, readily available	Requires several treatment sessions
PDT	77%-88%	13%	5%-11%	2%-24%	4.8%-53%	4.8%-53%	Easy to perform; only FDA-approved ablation method for treatment of precancerous lesions in BE	Photosensitivity, relatively high stricture rate
EMR	59%-97%	53%	4%-30%	–	3%-30%	12%-60%	Histologic assessment; Complete removal of circumferential short-segment BE; 1-2 sessions	Difficulty treating long-segment BE
APC, Argon plasma coagulation; BE, Barrett esophagus; EMR, endoscopic mucosal resection; FDA, U.S. Food and Drug Administration; HGD, high-grade dysplasia; MPEC, multipolar electrocoagulation; PDT, photodynamic therapy.

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Surgical resection is definitive therapy and may be offered for multifocal high-grade dysplasia, carcinoma that has extended into the submucosa (T1 SM2 or 3), or patients with poorly differentiated carcinomas or with evidence of lymphovascular invasion. Mortality appears to be lower with experienced surgeons operating in high-volume centers.
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Patients with cardiovascular risk factors may be considered for low-dose aspirin therapy for chemoprevention of esophageal adenocarcinoma. NSAIDs or NSAIDs combined with statins are potentially effective at reducing the risk of esophageal adenocarcinoma but are not currently recommended for use because of the risk of adverse effects.

Disposition

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The relative risk of developing esophageal adenocarcinoma for a patient with Barrett esophagus, as compared with the general population, is 11.3, a substantial drop from the relative risk of 30 or 40 estimated in earlier reports. The risk is greater in men and in patients with longer (≥8 cm) columnar-lined segments.
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The risk of progression to esophageal adenocarcinoma from untreated Barrett with low-grade dysplasia is 0.5% per year and with high-grade dysplasia ranges from 6% to 19% per year.
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Frequency of monitoring is controversial. No prospective studies have proven that endoscopic surveillance is cost effective or increases life expectancy. Although some studies have suggested that close adherence to surveillance protocols is associated with higher rates of detection of dysplasia and cancer, a recent case-control study showed no reduction in mortality.
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Patients with Barrett esophagus currently undergo surveillance EGD and systematic four-quadrant biopsy at intervals determined by the presence and grade of dysplasia. All mucosal abnormalities should undergo biopsy. Patients without dysplasia should have follow-up every 3 to 5 yr. Patients with low-grade dysplasia should have aggressive antisecretory (proton pump inhibitor) therapy, repeat endoscopy within 2 to 6 months, and endoscopic ablation therapy or extensive mucosal sampling every 12 months or until dysplasia is no longer present. They then revert to a 3- to 5-yr interval. Patients with high-grade dysplasia should have expert confirmation and extensive mucosal sampling. High-grade dysplasia with visible mucosal irregularities should be removed by EMR or ESD, followed by mucosal ablation. Consider intensive surveillance every 3 months for at least a year; the optimal timing and duration of surveillance over the long term is unknown. Indefinite dysplasia requires aggressive medical therapy and close follow-up and resampling. Endoscopic treatment is preferred over intensive surveillance in patients with high-grade dysplasia.
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Patients should be treated aggressively for GERD before surveillance.

Referral

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Consider EGD with biopsy in male or selected female patients with multiple risk factors who have not had previous EGD.
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Refer patients with GERD for evaluation if “red flag” symptoms are present (dysphagia, odynophagia, weight loss, vomiting, early satiety, GI bleeding, iron deficiency).
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Refer patients with biopsy-proved Barrett esophagus for surveillance.
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For those with low-grade or high-grade dysplasia, refer for ablative therapy with EMR or ESD if appropriate, followed by intensive surveillance. Esophageal resection may be considered.

Ferri – Barrett Esophagus