(A) Specialized intestinal metaplasia is a well differentiated epithelium with crypt architecture in which putative stem cells residing at the base give rise to proliferating transient amplifying cells and differentiated cells that are sloughed into the lumen. This architecture has been proposed to be tumor suppressive because mutations occurring in transient amplifying or differentiated non-stem cells would be shed from the body before they could accumulate the serial mutations leading to cancer10. (B) The intestinal metaplasia also secretes anions, including bicarbonate, at levels more than fivefold greater than oesophageal squamous epithelium11. (C) Specialized intestinal metaplasia also secretes thick adherent mucus not present in normal squamous oesophageal cells12. Ultrastructural studies have shown that mucus secretion can be disrupted in Barrett’s oesophagus at increased risk of progression to oesophageal adenocarcinoma, including those with evidence of chromosomal instability and aneuploidy16. (D) Barrett’s oesophagus has claudin-18 tight junctions that provide greater protection against acid permeation than the claudin-18 deficient tight junctions of the oesophageal squamous epithelium13. (E) Barrett’s oesophagus also overexpresses genes involved in mucosal defence and repair14, and (F) Barrett’s oesophageal cells maintain physiologic intracellular pH following prolonged and repeated reflux exposure15. Abbreviation: Barrett’s oesophagus (BE).

Recent research has identified multiple factors that contribute to underdiagnosis of life threatening early oesophageal adenocarcinoma (A-E) and overdiagnosis of benign Barrett’s oesophagus that will follow an indolent course for the lifetime of the individual (F). Abbreviations: Gastroesophageal reflux disease (GERD), Barrett’s oesophagus (BE), oesophageal adenocarcinoma (EA).

A new strategy is proposed to build on research advances and overcome the limitations inherent in current approaches to controlling EA incidence and mortality (see Figure 2 and Box 2). A key goal is to cost-effectively classify persons into increasingly high-risk target populations (left side of figure), based on comprehensive risk models using the increasing amount and sophistication of information available in each setting. Each stratum then can be offered programs of prevention and early detection appropriate for their absolute risk of developing EA. A key to success of such an approach is substantial improvement of specificity at each stratum, most likely aided by blood and tissue-based biomarkers of risk, which will allow identification of the large fraction of persons who are unlikely to develop EA, allowing them to avoid or minimize worrisome, costly and risky endoscopic surveillance and interventions. At each level of risk, research needed to create effective prevention programs is listed on the right side of the figure. As suggested by Khoury, et al.199, such translational research typically involves developing and validating tests, risk models and prediction tools, and implementing corresponding preventive interventions in the target population/setting, followed by an evaluation component (not shown) to identify tools and interventions in need of improvement. Abbreviations: EA, oesophageal adenocarcinoma; BE, Barrett’s oesophagus.