Barrett's esophagus: recent insights into pathogenesis and cellular ontogeny

Esophageal adenocarcinoma (EAC) has increased 6-fold in its incidence in the last 2 decades. Evidence supports the hypothesis of stepwise progression from normal squamous epithelium → reflux esophagitis → metaplasia (Barrett's esophagus, BE) → dysplasia → adenocarcinoma. The precursor, BE, stands as the bridge connecting the widespread but naive reflux disease and the rare but fatal EAC. The step of metaplasia from squamous to intestine-like columnar phenotype is perhaps pivotal in promoting dysplastic vulnerability. It is widely accepted that chronic inflammation because of gastroesophageal reflux disease leads to the development of metaplasia, however the precise molecular mechanism is yet to be discovered. Additionally, how this seemingly adaptive change in the cellular phenotype promotes dysplasia remains a mystery. This conceptual void is deterring further translational research and clouding clinical decision making. This article critically reviews theories on the pathogenesis of Barrett's esophagus and the various controversies surrounding its diagnosis. We further discuss unanswered questions and future directions, which are vital in formulating effective preventive and therapeutic guidelines for Barrett's esophagus.