Barrett's esophagus

Barrett's esophagus (British English: oesophagus) (sometimes called Barrett's syndrome, CELLO—columnar epithelium lined lower oesophagus) refers to an abnormal change (metaplasia) in the cells of the inferior portion of the esophagus. A positive diagnosis generally requires observing specific macroscopic and microscopic changes. The normal squamous epithelium lining of the esophagus is replaced by metaplastic columnar epithelium. Columnar epithelium refers to a cell type that is typically found in more distal parts of the gastrointestinal system. The medical significance of Barrett’s esophagus is its strong association with esophageal adenocarcinoma, a particularly lethal cancer.

The main cause of Barrett's esophagus is thought to be an adaptation to chronic acid exposure from reflux esophagitis. In the last 40 years, the incidence of esophageal adenocarcinoma has been increasing in the Western world. Barrett's 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's esophagus do not have symptoms. 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. Diagnosis of Barrett's esophagus requires endoscopy (more specifically, esophagogastroduodenoscopy, a procedure in which a small camera is inserted through the mouth to examine the esophagus, stomach, and duodenum) and biopsy. The cells of Barrett's esophagus, after biopsy, are classified into four general categories: non-dysplastic, low-grade dysplasia, high-grade dysplasia, and frank carcinoma. High-grade dysplasia and frank carcinoma patients are generally advised to undergo surgical treatment. Non-dysplastic and low-grade patients are generally advised to undergo annual observation with endoscopy. In high-grade dysplasia, the risk of developing cancer might be at 10% per patient-year or greater.

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

Symptoms
The change from normal to premalignant cells that indicate Barrett's esophagus does not cause any particular symptoms. Barrett's 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's esophagus is increased by central (vs. peripheral) obesity. 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.

Mechanism
Barrett's 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 which results in inhibition of Akt, upregulation of the p50 subunit of NF-kB (NFKB1) and ultimately activation of the promotor of the homeobox gene CDX2. The latter mastergene is responsible for the expression of intestinal markers such as Guanylate cyclase 2C . This mechanism explains the selecion of HER2/neu (or ERBB2) 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's esophagus. While there is no relationship between the severity of heartburn and the development of Barrett's esophagus, there is a relationship between chronic heartburn and the development of Barrett's esophagus. Sometimes people with Barrett's 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.

Recently, in a Thursday, June 23, 2011 news release from the FOCUS campus health programs newsletter, Harvard University Medical School "researchers have discovered a new mechanism for the origin of Barrett's esophagus ... Studying mice, the researchers found that Barrett's esophagus arises not from mutant cells in the esophagus but rather a small group of previously overlooked cells present in all adults that can rapidly expand to cancer precursors when the normal esophagus is damaged by acid.

This research will be published online in the June 24, issue of Cell.

Decades of cancer research tells us that most of the common cancers begin with genetic changes that occur over a period of 15 to 20 years, in some cases leading to aggressive cancers. However, for a subset of cancers that appear to be linked to chronic inflammation, this model might not hold. ...

Research from the laboratory of Frank McKeon, Harvard Medical School professor of cell biology, together with Wa Xian, a postdoctoral researcher at Brigham and Women's Hospital and the Institute of Medical Biology, Singapore, along with an international consortium including Christopher Crum, director of Women's and Perinatal Pathology at Brigham and Women's Hospital, has shown that Barrett's esophagus originates from a minor population of non-esophageal cells left over from early development.

Diagnosis
Both macroscopic (from endoscopy) and microscopic positive findings are required to make a diagnosis. Barrett's esophagus is marked by the presence of columnar epithelia in the lower esophagus, replacing the normal squamous cell epithelium&mdash;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.

The metaplastic columnar cells may be of two types: gastric (similar to those in the stomach, which is NOT technically Barrett's esophagus) or colonic (similar to cells in the intestines). A biopsy of the affected area will often contain a mixture of the two. Colonic-type metaplasia is the type of metaplasia associated with risk of malignancy in genetically susceptible people.

The metaplasia of Barrett's 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's.

There are many histologic mimics of Barrett's 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's 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's esophagus, and can be used as a biomarker for distinguishing Barrett's epithelium from normal esophageal epithelium.

After the initial diagnosis of Barrett's 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's be confirmed by at least two fellowship trained GI pathologists prior to definitive treatment for patients.

Management
Many professional medical societies propose endoscopic screening of patients with GERD and endoscopic surveillance of patients with Barrett's esophagus, although little direct evidence supports this practice, which is common in many developed countries. Treatment options for high-grade dysplasia include surgical removal of the esophagus (esophagectomy) or endoscopic treatments such as endoscopic mucosal resection or ablation (destruction). Currently, there is no intervention that has been shown to prevent the development of Barrett's esophagus or its progression to esophageal cancer.

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). If two endoscopies and biopsy sessions performed within 12 months are negative for dysplasia then surveillance can be performed every 3 years while the underlying reflux is controlled with proton pump inhibitor drugs in combination with measures to prevent reflux. For patients found to have low grade or high grade dysplasia close observation and repeat endoscopy and biopsies are indicated and the patient should be followed closely by a gastroenterologist.

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. There is presently no reliable way to determine which patients with Barrett's 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.

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

In a variety of studies, non-steroidal anti-inflammatory drugs (NSAIDS), like aspirin, have shown evidence of preventing esophageal cancer in Barrett's esophagus patients. 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's esophagus is only a premalignant condition. Its malignant sequela, esophageal adenocarcinoma, has a mortality rate of over 85%. The risk of developing esophageal adenocarcinoma in people who have Barrett's esophagus is 6–7 per 1000 person-years. Most patients with esophageal carcinoma survive less than 1 year.

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. Several studies have estimated the prevalence of Barrett's esophagus in the normal population to be 1.6%, 1.3%, and 3.6%.

History
Barrett first described the columnar metaplasia in 1950. An association with gastroesophageal reflux was made in 1953. An association with adenocarcinoma was made in 1975.