BASICSEric Ji-Yuan Mao, MD • Harlan G. Rich, MD, FACP, AGAF
BASICS
DESCRIPTION
• Metaplasia of the distal esophageal mucosa from native stratified squamous epithelium to abnormal columnar (intestinalized) epithelium, likely as a consequence of chronic GERD
• Predisposes to the development of adenocarcinoma of the esophagus
EPIDEMIOLOGY
• Predominant age: >50 years
• May occur in children (rare <5 years)
Incidence
• 10–15% of patients undergoing endoscopy for evaluation of reflux symptoms.
• Esophageal adenocarcinoma incidence is rising in the United States (1). From 1975 to 2001, there was ~6-fold increase (4 to 23 cases/million person-years.
• Attributed to changes in smoking and obesity rather than reclassification or overdiagnosis
Prevalence
• Difficult to ascertain because of different populations studied, varying definitions, and asymptomatic cases
• As many as 1.5 to 2.0 million adults in the United States (extrapolated from a 1.6% prevalence in Swedish general population)
ETIOLOGY AND PATHOPHYSIOLOGY
• Chronic gastric reflux injures the esophageal mucosa, triggering columnar metaplasia. Refluxed bile acids likely induce differentiation in gastroesophageal junction (GEJ) cells.
• Columnar cells in the esophagus have higher malignant potential than squamous cells. Activation of CDX2 gene and overexpression of HER2/neu (ERBB2) oncogene promotes carcinogenesis.
• Elevated levels of COX-2, a mediator of inflammation and regulator of epithelial cell growth, are associated with Barrett esophagus (BE) (1).
• Classic progression: normal epithelium → esophagitis → metaplasia (BE) → dysplasia (low- or high-grade) → adenocarcinoma
Genetics
• Familial predisposition to GERD and BE with multiple genetic markers have been identified.
• Acquired genetic changes lead to adenocarcinoma and are being investigated as biomarkers for risk stratification and early detection.
RISK FACTORS
• Chronic reflux (>5 years)
• Hiatal hernia
• Age >50 years
• Male gender
• White ethnicity—incidence in white males is much higher than white women and African American men.
• Smoking history
• Intra-abdominal obesity
• Family history with at least one first-degree relative with BE or esophageal adenocarcinoma
GENERAL PREVENTION
Weight loss, smoking cessation, robust dietary intake of fruits and vegetables, and moderate wine consumption may decrease risk of BE and lower progression to esophageal cancer (1)[C].
COMMONLY ASSOCIATED CONDITIONS
GERD, obesity, hiatal hernia
DIAGNOSIS
HISTORY
• Assess underlying risk factors.
• Common GERD symptoms: heartburn, regurgitation
• Less common symptoms include chest pain, odynophagia, chronic cough, water brash, globus sensation, laryngitis, or wheezing.
• Symptoms suggestive of complicated GERD or cancer include weight loss, anorexia, dysphagia, odynophagia, hematemesis, or melena.
ALERT
Up to 25% of patients with BE are asymptomatic (1).
PHYSICAL EXAM
No abnormal findings on physical exam are specific for BE. A general examination should include vital signs, oral examination, cardiopulmonary examination, abdominal examination, and lymph node examination.
DIFFERENTIAL DIAGNOSIS
• Erosive esophagitis
• GERD
DIAGNOSTIC TESTS & INTERPRETATION
Endoscopy with multiple biopsies demonstrating intestinal metaplasia extending ≥1 cm proximal to the gastroesophageal junction are required to diagnose BE.
• Gastric cardia–type epithelium on pathology does not have clear malignant significance and may reflect sampling error.
• Specialized intestinal metaplasia at the GEJ: cancer risk difficult to assess with varying definitions of GEJ landmarks
ALERT
Endoscopic screening for BE is suggested in men with chronic GERD (>5 years) and/or frequent GERD symptoms with 2 or more risk factors: age >50 years; white ethnicity; central obesity, smoking history, family history of BE or esophageal adenocarcinoma. Screening for BE in the general population with GERD or women with GERD is not recommended, though it can be considered in women with multiple risk factors (2)[C].
Initial Tests (lab, imaging)
None:
• Helicobacter pylori testing is not indicated. Meta-analyses show an inverse relationship between H. pylori infections and BE, which may be related to decreased acid production.
• No current biomarkers are effective for diagnosis; some under investigation for risk stratification (1)[B].
Diagnostic Procedures/Other
• Endoscopy: visual identification of columnar (reddish, velvety appearance) replacing squamous (pale, glossy appearance) lining of the distal esophagus
• White light endoscopy (preferably high resolution) is the standard for diagnosis. Disease extent: long-segment (≥3 cm) versus short-segment (<3 cm)
• The Prague classification is a consensus-driven grading system used to describe BE using landmarks of the squamocolumnar junction and GEJ. C is the circumferential extent of the columnar lining. M is the maximal proximal extent of columnar mucosa.
• Advanced imaging techniques, such as narrow band imaging (NBI) and confocal laser endomicroscopy, may help identify dysplasia but are preliminary.
• Systematic biopsies from endoscopy showing columnar epithelium confirm the diagnosis:
– Seattle protocol: four-quadrant biopsies at regular intervals with biopsies of visible mucosal irregularities; more time-consuming but higher diagnostic yield than random biopsies (1)[A]
– Capsule endoscopy is still developing and has lower sensitivity than conventional endoscopy.
Test Interpretation
• Specialized intestinal metaplasia (also called specialized columnar epithelium) is diagnostic: Benign BE is established by a single pathologist report (3)[C].
• Diagnosis of dysplasia (and grade) should be confirmed by two gastrointestinal pathologists before treatment (3)[C].
• Cardia-type columnar epithelium may predispose to malignancy (unclear risk); International Consensus Group currently recommends defining BE by the presence of columnar mucosa in the esophagus (noting if intestinal metaplasia is present) (3)[C].
• If screening endoscopy reveals erosive esophagitis, repeat endoscopy after 8 to 12 weeks of proton pump inhibitor (PPI) therapy to exclude underlying BE; defer biopsies until healing occurs (2)[C].
TREATMENT
ALERT
Neither suppression of gastric acid production via high-dose PPIs nor reduction in esophageal acid exposure via antireflux surgery induces regression of BE. These therapies may, however, decrease cancer risk.
MEDICATION
• The goal of medical therapy is to control GERD to reduce esophagitis.
First Line
• Unlike the stepwise management of GERD without evidence of BE, patients with BE and GERD symptoms should be treated with a once-daily PPI.
• PPIs should be dosed 30 minutes before a meal (ideally, the first meal of the day).
ALERT
Titrate PPI therapy to symptoms; pH monitoring is not recommended (1)[C].
• Chemoprevention of neoplastic progression is under active investigation.
• Case-controlled studies have shown that aspirin and NSAIDs may prevent progression to esophageal cancer due to COX-2 inhibition:
– COX-2 selective inhibitor celecoxib use not shown to affect progression of Barrett dysplasia to adenocarcinoma (1)[A].
– Use of aspirin and a PPI for chemoprevention of esophageal cancer is under investigation (1).
– Consider low-dose aspirin in patients with BE and risk factors for cardiovascular disease (1)[C].
• Statins, alone or in combination with aspirin or NSAIDs, appear to be effective in chemoprevention but are not yet routinely recommended (1)[B],(5)[A].
Second Line
If once-daily PPI does not control symptoms, move to twice-daily dosing (2)[A].
ISSUES FOR REFERRAL
• Initiate PPI therapy prior to endoscopy to reduce reactive esophagitis/atypia (2)[C].
• Refer patients considering esophagectomy to a high-volume institution.
ADDITIONAL THERAPIES
• Any combination of endoscopic mucosal resection (EMR) followed by photodynamic therapy (PDT), and radiofrequency ablation (RFA) to eliminate BE is considered “endoscopic eradication.”
• EMR: eradication rate 86–100%, excises to submucosa, allows staging, preferred for visible irregularities
• PDT: eradication rate 77–100%; strictures in 40%
• RFA: eradication rate 54–90%, comparable efficacy to PDT, fewer adverse effects
• Focal EMR combined with RFA of other areas is considered most effective eradication therapy (1)[B].
• Additional studies required before cryotherapy and other ablative procedures can be recommended.
• BE with visible lesions:
– EMR with ablation if high-grade dysplasia or intramucosal cancer detected (3)[C]
• Low-grade dysplasia: Treatment is controversial.
– Offer treatment such as RFA for low-grade dysplasia and high-risk features (multifocality, long segment length, persistence) (3)[C]. Endoscopic eradication may prevent progression to high-grade dysplasia or esophageal adenocarcinoma (1)[B],(6)[A].
• Endoscopic eradication therapy is recommended for high-grade dysplasia, without or with very limited submucosal invasion (stage T1SM1 or lower) (1,4)[B].
ALERT
Endoscopic eradication not recommended for BE without dysplasia. Continue surveillance in these patients.
SURGERY/OTHER PROCEDURES
Antireflux surgery such as fundoplication may control GERD symptoms but are not convincingly shown to reverse BE, decrease risk of cancer, or be superior to medical therapy (1)[A].
ALERT
Available data suggest that antireflux surgery does not decrease risk of esophageal cancer.
• Esophagectomy is definitive and should be offered as an alternative to endoscopic eradication therapy for high-grade dysplasia (1)[B]:
– Preferred for patients with evidence of submucosal invasion (stage T1SM2 or higher), or T1a patients with poor differentiation, lymphovascular invasion, or incomplete EMR
– Added benefit of lymph node removal
– Mortality rate: <5% in patients with high-grade dysplasia who are otherwise healthy
– Serious postoperative complications: 30–50%
– Should ideally be performed by an experienced surgeon in a high-volume center (1)[A]
COMPLEMENTARY & ALTERNATIVE MEDICINE
A prospective study of 339 men and women with BE found those taking either a multivitamin, vitamin C, or vitamin E once a day were less likely to develop esophageal adenocarcinoma.
Geriatric Considerations
Surveillance or no treatment may be preferable to endoscopic eradication therapy or esophagectomy in patients who are poor operative candidates.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• Surveillance (to detect high-grade dysplasia or early carcinoma), while controversial, is recommended in patients with histologically confirmed BE—especially for those in high-risk groups.
• Surveillance intervals depend on the grade of dysplasia (1)[C].
• Patients diagnosed with BE on initial exam do not require endoscopy in 1 year (2)[C].
• No dysplasia: Survey every 3 to 5 years.
– Discontinue surveillance if life expectancy is ≤5 years (3)[C].
• Low-grade dysplasia: Survey every 6 months.
– Routine surveillance if patients have confirmed absence of low-grade dysplasia after two consecutive endoscopies (3)[C]
• Indefinite for dysplasia: Repeat after 3 to 6 months of increased acid suppression, and if unchanged, survey every 12 months (3)[C].
• High-grade dysplasia without eradication therapy: Survey every 3 months; with eradication therapy: Survey every 3 months for 4, then every 6 months for 2, then every 12 months.
ALERT
Adherence to recommended surveillance protocols may improve rates of dysplasia and cancer detection.
• Continue surveillance even if the patient has had endoscopic ablation therapy, antireflux surgery, or esophagectomy.
DIET
Avoid foods that can trigger reflux: caffeine, alcohol, chocolate, peppermint, carbonated drinks, garlic, onions, spicy foods, fatty foods, citrus, and tomato-based products.
PATIENT EDUCATION
• Lifestyle modifications: smoking cessation, weight loss, avoid supine position after meals, avoid tight-fitting clothes, elevate head of bed.
• No evidence that treating GERD reverses BE or prevents esophageal cancer.
PROGNOSIS
Annual incidence of esophageal cancer in patients with BE is ≤0.33% per year (1)[B]:
• Low-grade dysplasia: may be transient; cancer risk 0.5–0.6% per year
• High-grade dysplasia: cancer risk 5–7% per year
• Promising areas for future research include the use of biomarkers for risk stratification, chemoprevention of neoplastic progression, capsule endoscopy for screening and the use of vitamins and antioxidants for prevention and treatment.
COMPLICATIONS
Same as GERD: stricture, bleeding, ulceration
REFERENCES
1. Spechler SJ, Sharma P, Souza RF, et al. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology. 2011;150(3):1084–1091.
2. Shaheen NJ, Falk GW, Iyer PG, et al. ACG clinical guideline: diagnosis and management of Barrett’s esophagus. Am J Gastroenterol. 2016;111(1):30–50.
3. Bennett C, Moayyedi P, Corley DA, et al. BOB CAT: a large-scale review and delphi consensus for management of Barrett’s esophagus with no dysplasia, indefinite for, or low-grade dysplasia. Am J Gastroenterol. 2015;110(5):662–682.
4. Singh S, Garg SK, Singh PP, et al. Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett’s oesophagus: a systematic review and meta-analysis. Gut. 2014;63(8):1229–1237.
5. Kastelein F, Spaander MC, Biermann K, et al. Nonsteroidal anti-inflammatory drugs and statins have chemopreventative effects in patients with Barrett’s esophagus. Gastroenterology. 2011;141(6):2000–2008.
6. Phoa KN, van Vilsteren FG, Weusten BL, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA. 2014;311(12):1209–1217.
ADDITIONAL READING
• Dunbar KB, Spechler SJ. Controversies in Barrett esophagus. Mayo Clin Proc. 2014;89(7):973–984.
• Zimmerman TG. Common questions about Barrett esophagus. Am Fam Physician. 2014;89(2):92–98.
CODES
ICD10
• K22.70 Barrett’s esophagus without dysplasia
• K22.719 Barrett’s esophagus with dysplasia, unspecified
• K22.710 Barrett’s esophagus with low grade dysplasia
CLINICAL PEARLS
• BE is a known precursor for esophageal carcinoma, the incidence of which is rising faster than any other major malignancy.
• BE has the highest incidence among white males >50 years.
• Endoscopic eradication therapy is preferred for high-grade dysplasia with or without submucosal invasion.
• Esophagectomy offers definitive therapy: Consider for all patients with high-grade dysplasia; preferred for patients with submucosal invasion.