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Barrett's esophagus: Pathogenesis and malignant transformation

Stuart J Spechler, MD
Section Editor
Nicholas J Talley, MD, PhD
Deputy Editor
Shilpa Grover, MD, MPH, AGAF


Barrett's esophagus is the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus. The condition develops as a consequence of chronic gastroesophageal reflux disease (GERD) and predisposes to the development of adenocarcinoma of the esophagus.

The pathogenesis of Barrett's esophagus and the mechanisms of transformation into adenocarcinoma will be reviewed here. The clinical manifestations, diagnosis, and management of this disorder (including surveillance for adenocarcinoma) are discussed, separately. (See "Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis" and "Barrett's esophagus: Surveillance and management".)


Barrett's esophagus develops through the process of metaplasia, in which one kind of fully differentiated (adult) tissue replaces another [1]. Metaplasia commonly is a consequence of chronic inflammation, and Barrett’s metaplasia results from chronic reflux esophagitis caused by the gastroesophageal reflux of acid, bile, and other noxious substances. In most patients, reflux-induced mucosal damage is repaired by the regeneration of more squamous cells. In some patients, for reasons that are not clear, the reflux-damaged esophagus is repaired through a columnar metaplasia in which columnar cells replace squamous cells. For more than a decade, the prevailing hypothesis has been that Barrett’s metaplasia is the result of transcommitment, in which progenitor cells in the esophagus that normally would differentiate into squamous cells instead differentiate into columnar cells. Research in animal models has challenged this transcommitment hypothesis by providing evidence that Barrett’s metaplasia might result from the proximal migration of stem cells from the gastric cardia [2], or from the expansion of a nest of residual embryonic-type cells located at the gastroesophageal junction [3]. Finally, in a rat model of reflux esophagitis, Barrett’s metaplasia appears to occur when circulating stem cells from the bone marrow are transported through the blood to the damaged esophagus, where they differentiate into columnar cells [4]. It is not clear which, if any, of these hypotheses on the pathogenesis of Barrett’s metaplasia is correct.

The metaplastic columnar cells of Barrett's esophagus are in some ways a favorable adaptation to chronic reflux since they appear to be more resistant to reflux-induced injury than the native squamous cells. Unfortunately, esophageal columnar metaplasia predisposes to the development of adenocarcinoma [5].

The pattern of acid secretion may be an important determinant in the neoplastic progression of Barrett's metaplasia. An ex vivo study demonstrated that pulsed acid exposure increased cell proliferation, but continuous acid exposure decreased cell proliferation [6]. Another report found that the length of Barrett's esophagus correlated with the percent of supine reflux and percent of total time that esophageal pH was <4 [7]. Other studies have demonstrated that patients with longstanding and severe reflux symptoms are at increased risk for adenocarcinoma of the esophagus [8].

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Literature review current through: Nov 2017. | This topic last updated: May 12, 2016.
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