Risk Factors of Esophageal Squamous Cell Carcinoma beyond Alcohol and Smoking

Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of death worldwide. Incidence rates vary internationally, with the highest rates found in Southern and Eastern Africa, and central Asia. Initial observational studies identified multiple factors associated with an increased risk of ESCC, with subsequent work then focused on developing plausible biological mechanistic associations. The aim of this review is to summarize the role of risk factors in the development of ESCC and propose future directions for further research. A systematic search of the literature was conducted by screening EMBASE, MEDLINE/PubMed, and CENTRAL for relevant publications. In total, 73 studies were included that sought to identify risk factors associated with the development of esophageal squamous cell carcinoma. Risk factors were divided into seven subcategories: genetic, dietary and nutrition, gastric atrophy, infection and microbiome, metabolic, epidemiological and environmental and other risk factors. Risk factors from each subcategory were summarized and explored with mechanistic explanations for these associations. This review highlights several current risk factors of ESCC. These risk factors were explored, and explanations dissected. Most studies focused on investigating genetic and dietary and nutritional factors, whereas this review identified other potential risk factors that have yet to be fully explored. Furthermore, there is a lack of literature on the association of these risk factors with tumor factors and disease prognosis. Further research to validate these results and their effects on tumor biology is absolutely necessary.