Publication:

Gastroesophageal reflux to esophageal adenocarcinoma: pathogenesis, risk stratification, and precision surveillance

Gastroesophageal reflux disease (GERD) is a global public health burden with a rising prevalence driven by urbanization, aging populations, and modifiable lifestyle factors. This narrative review delineates the progression from GERD to Barrett’s esophagus (BE) and ultimately to esophageal adenocarcinoma (EAC), emphasizing the epidemiological trends, molecular mechanisms, and clinical implications. The global prevalence of GERD has surged by over 77% since 1990, affecting an estimated 800 million individuals, with notable geographic variability and underestimation in low- and middle-income countries owing to inconsistent diagnostic criteria and reporting. BE, a metaplastic transformation of the esophageal epithelium due to chronic reflux, is recognized as the only precursor of EAC. This progression involves a complex interplay between sustained inflammation, molecular dysregulation, and genetic mutations. Key signaling pathways, including NF-κB, IL6/STAT3, NOTCH, and Hedgehog, mediate epithelial remodeling and carcinogenic transformation. Dysplasia, particularly high-grade dysplasia (HGD), remains a key histopathological predictor of malignancy, complemented by molecular biomarkers such as TP53 mutations, aneuploidy, and gene expression alterations. This review also addresses clinical risk stratification, identifying high-risk cohorts based on segment length, obesity, smoking, symptom frequency, and genetic predisposition. Despite robust knowledge, gaps in surveillance persist, with current endoscopic screening failing to capture asymptomatic or under-recognized high-risk groups of patients. Non-endoscopic tools, such as Cytosponge and liquid biopsy, are promising adjuncts for bridging these gaps. A precision prevention approach, integrating molecular diagnostics, risk-based screening, and inclusive surveillance, is essential for mitigating the rising incidence of EAC and improving outcomes in at-risk populations.