Barrets esophagus

Barrett's esophagus
Classification and external resources
10 9 OMIM DiseasesDB MedlinePlus eMedicine MeSH D001471

Barrett esophagus (British English: Barrett's oesophagus), sometimes called Barrett syndrome or columnar epithelium lined lower oesophagus (CELLO), refers to an abnormal change (metaplasia) in the cells of the lower portion of the esophagus. When the normal stratified squamous epithelium lining of the esophagus is replaced by simple columnar epithelium with goblet cells (cells usually found lower in the gastrointestinal tract), Barrett's esophagus is diagnosed. The medical significance of Barrett esophagus is its strong association with esophageal adenocarcinoma, a particularly lethal cancer.

The main cause of Barrett esophagus is thought to be an adaptation to chronic acid exposure from reflux esophagitis.[1] In the last 4 years, the incidence of esophageal adenocarcinoma has been increasing in the Western world. Barrett esophagus is found in 5–15% of patients who seek medical care for heartburn (gastroesophageal reflux disease, GERD), although a large subgroup of patients with Barrett esophagus do not have symptoms.[2] It is considered to be a premalignant condition because it is associated with an increased risk of esophageal cancer (more specifically, adenocarcinoma) of about 0.5% per patient-year. If the cancer develops, it is very often deadly.[2][3] Diagnosis of Barrett esophagus requires endoscopy (more specifically, esophagogastroduodenoscopy, a procedure in which a fibre optic cable is inserted through the mouth to examine the esophagus, stomach, and duodenum) and biopsy. The cells of Barrett esophagus, after biopsy, are classified into four general categories: non-dysplastic, low-grade dysplasia, high-grade dysplasia, and frank carcinoma. High-grade dysplasia and early stages of adenocarcinoma can be treated by endoscopic resection and new endoscopic therapies such as radiofrequency ablation, whereas advanced stages (submucosal) are generally advised to undergo surgical treatment. Non-dysplastic and low-grade patients are generally advised to undergo annual observation with endoscopy, with radiofrequency ablation as a therapeutic option. In high-grade dysplasia, the risk of developing cancer might be at 10% per patient-year or greater.[2]

The condition is named after Norman Barrett (1903–1979), who described the condition in 1950.[4]

Signs and symptoms

The change from normal to premalignant cells that indicate Barrett esophagus does not cause any particular symptoms. Barrett esophagus, however, is associated with the following symptoms:

  • frequent and longstanding heartburn
  • trouble swallowing (dysphagia)
  • vomiting blood (hematemesis)
  • pain under the breastbone where the esophagus meets the stomach
  • unintentional weight loss because eating is painful

The risk of developing Barrett esophagus is increased by central obesity (vs. peripheral obesity).[5] The exact mechanism is unclear. The difference in distribution of fat among men (more central) and women (more peripheral) may explain the increased risk in males.[6]

Mechanism

Barrett esophagus occurs due to chronic inflammation. The principal cause of the chronic inflammation is gastroesophageal reflux disease, GERD (UK: GORD). In this disease, acidic stomach, bile, small intestine and pancreatic contents cause damage to the cells of the lower esophagus. Recently, it was shown that bile acids are able to induce intestinal differentiation, in gastroesophageal junction cells, through inhibition of the Epidermal growth factor receptor (EGFR) receptor and the protein kinase enzyme Akt.[7] This results in the eventual up-regulation of the p50 subunit of protein complex NF-κB (NFKB1), and ultimately activation of the homeobox gene CDX2, which is responsible for the expression of intestinal enzymes such as Guanylate cyclase 2C.[8] This mechanism also explains the selection of HER2/neu (also called ERBB2) and the overexpressing (lineage-addicted) cancer cells during the process of carcinogenesis, and the efficacy of targeted therapy against the Her-2 receptor with trastuzumab (Herceptin) in the treatment of adenocarcinomas at the gastroesophageal junction (GEJ).

Researchers are unable to predict which heartburn sufferers will develop Barrett esophagus. While there is no relationship between the severity of heartburn and the development of Barrett esophagus, there is a relationship between chronic heartburn and the development of Barrett esophagus. Sometimes people with Barrett esophagus will have no heartburn symptoms at all. In rare cases, damage to the esophagus may be caused by swallowing a corrosive substance such as lye.

Diagnosis


Both macroscopic (from endoscopy) and microscopic positive findings are required to make a diagnosis. Barrett esophagus is marked by the presence of columnar epithelia in the lower esophagus, replacing the normal squamous cell epithelium—an example of metaplasia. The secretory columnar epithelium may be more able to withstand the erosive action of the gastric secretions; however, this metaplasia confers an increased risk of adenocarcinoma.[9]

The presence of goblet cells, called intestinal metaplasia, is necessary to make a diagnosis of Barrett esophagus. This frequently occurs in the presence of other metaplastic columnar cells but only the presence of goblet cells is diagnostic.

The metaplasia of Barrett esophagus is grossly visible through a gastroscope, but biopsy specimens must be examined under a microscope to determine whether cells are gastric or colonic in nature. Colonic metaplasia is usually identified by finding goblet cells in the epithelium and is necessary for the true diagnosis of Barrett.

There are many histologic mimics of Barrett esophagus (i.e. goblet cells occurring in the transitional epithelium of normal esophageal submucosal gland ducts, "pseudogoblet cells" in which abundant foveolar (gastric) type mucin simulates the acid mucin true goblet cells). Assessment of relationship to submucosal glands and transitional-type epithelium with examination of multiple levels through the tissue may allow the pathologist to reliably distinguish between goblet cells of submucosal gland ducts and true Barrett esophagus (specialized columnar metaplasia). Use of the histochemical stain Alcian blue pH 2.5 is also frequently used to distinguish true intestinal-type mucins from their histologic mimics. Recently, immunohistochemical analysis with antibodies to CDX-2 (specific for mid and hindgut intestinal derivation) has also been utilized to identify true intestinal-type metaplastic cells. It has been shown that the protein AGR2 is elevated in Barrett esophagus,[10] and can be used as a biomarker for distinguishing Barrett epithelium from normal esophageal epithelium.[11]

After the initial diagnosis of Barrett esophagus is rendered, affected persons undergo annual surveillance to detect changes that indicate higher risk to progression to cancer: development of dysplasia. There is considerable variability in assessment for dysplasia among pathologists. Recently, gastroenterology and GI pathology societies have recommended that any diagnosis of high grade dysplasia in Barrett be confirmed by at least two fellowship trained GI pathologists prior to definitive treatment for patients.

Management

Many patients with Barrett's esophagus do not have dysplasia. Medical societies recommend that if a patient has Barrett's esophagus, and if the past two endoscopy and biopsy examinations have confirmed the absence of dysplasia, then the patient should not have another endoscopy within three years.[12][13][14]

Many professional medical societies propose endoscopic screening of patients with GERD and endoscopic surveillance of patients with Barrett esophagus, although little direct evidence supports this practice, which is common in many developed countries.[2] Treatment options for high-grade dysplasia include surgical removal of the esophagus (esophagectomy) or endoscopic treatments such as endoscopic mucosal resection or ablation (destruction).[2]

The risk of malignancy is highest in the U.S. in Caucasian men more than 50 years of age with more than 5 years of symptoms. Current recommendations include routine endoscopy and biopsy (looking for dysplastic changes). Although in the past physicians have taken a watchful waiting approach, newly published research supports consideration of intervention for Barrett's esophagus. Balloon-based radiofrequency ablation, invented by Ganz, Stern and Zelickson in 1999, is a new treatment modality for the treatment of Barrett's esophagus and dysplasia, and has been the subject of numerous published clinical trials.[15][16][17][18] The findings demonstrate radiofrequency ablation has an efficacy of 80-90% or greater with respect to complete clearance of Barrett's esophagus and dysplasia with durability up to 5 years and a favorable safety profile.[15][16][17][18]

Proton pump inhibitor drugs have not yet been proven to prevent esophageal cancer. Laser treatment is used in severe dysplasia, while overt malignancy may require surgery, radiation therapy, or systemic chemotherapy. Additionally, a recent 5-year random-controlled trial has shown that photodynamic therapy using photofrin is statistically more effective in eliminating dysplastic growth areas than sole use of a proton pump inhibitor.[19] There is presently no reliable way to determine which patients with Barrett esophagus will go on to develop esophageal cancer, although a recent study found that the detection of three different genetic abnormalities were associated with as much as a 79% chance of developing cancer in 6 years.[20]

Endoscopic mucosal resection (EMR) has also been evaluated as a management technique.[21] Additionally an operation known as a Nissen fundoplication can reduce the reflux of acid from the stomach into the esophagus.[22]

In a variety of studies, non-steroidal anti-inflammatory drugs (NSAIDS), like aspirin, have shown evidence of preventing esophageal cancer in Barrett esophagus patients.[23][24] However, none of these studies have been randomized, placebo controlled trials, which are considered the gold standard for evaluating a medical intervention. In addition, the best dose of NSAIDs for cancer prevention is not yet known.

Prognosis

Barrett esophagus is a premalignant condition. Its malignant sequela, esophageal adenocarcinoma, has a mortality rate of over 85%.[25] The risk of developing esophageal adenocarcinoma in people who have Barrett esophagus has been estimated to be 6–7 per 1000 person-years,[26][27] however a cohort study of 11,028 patients from Denmark published in 2011 showed an incidence of only 1.2 per 1000 person-years (5.1 per 1000 person-years in patients with dysplasia, 1.0 per 1000 person-years in patients without dysplasia).[28] Most patients with esophageal carcinoma survive less than 1 year.[29]

Epidemiology

The incidence in the United States among Caucasian men is 8 times the rate among Caucasian women and 5 times greater than African American men. Overall, the male to female ratio of Barrett's esophagus is 10:1.[30] Several studies have estimated the prevalence of Barrett esophagus in the general population to be 1.3% to 1.6% in two European populations (Italian[31] and Swedish[32]), and 3.6% in a Korean population.[33]

History

Barrett first described the columnar metaplasia in 1950.[4] An association with gastroesophageal reflux was made in 1953.[34] An association with adenocarcinoma was made in 1975.[35]

References

External links

  • Barrett's esophagus at National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD)
  • Barrett's Info a peer-reviewed web site of information on Barrett's esophagus and its clinical management.
  • Johns Hopkins University
  • Mayo Clinic
  • Barrett's Oesophagus Campaign Originally The Barrett's Oesophagus Foundation, the UK charity committed to research into prevention of adenocarcinoma of the esophagus
  • Information on RadioFrequency Ablation for Barrett's Oesophagus
  • Barrett's Esophagus can lead to cancer due to years of reflux Learn how to treat Barrett's esophagus with nonsurgical procedure, RFA therapy, find a physician
  • Treatment for Barrett's Esophagus
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