Non-Acid Fluid Exposure and Esophageal Squamous Cell Carcinoma

Dig Dis Sci. 2022 Jul;67(7):2754-2762. doi: 10.1007/s10620-021-07127-7. Epub 2021 Jul 8.


Esophageal squamous cell carcinoma (ESCC) accounts for the large majority of esophageal cancer cases worldwide. In this review, we examine the potential role of non-acidic fluid (NAF) exposure in ESCC carcinogenesis. Esophageal NAF consists of a mixture of salivary, esophageal, gastric, and duodenal fluids, containing inflammatory constituents such as digestive enzymes and bile acids that induce DNA damage, as well as known carcinogens such as acetaldehyde and N-nitrosamines. Exposure to NAF can occur in the setting of increased non-acid reflux, decreased gastric acidity, and decreased esophageal fluid clearance. Non-acid reflux has been associated with ESCC in small observational studies, and in animal models bile reflux can promote the development of ESCC. Associations have been found between increased ESCC risk and atrophic gastritis, a history of partial gastrectomy, and proton pump inhibitor use, all of which raise the pH of refluxate. Additionally, a minimally or non-acidic gastric environment contains an altered microbiome that can increase the production of acetaldehyde and N-nitrosamines. Esophageal motility disorders such as achalasia and opioid-induced esophageal dysfunction result in increased stasis and exposure to these potentially proinflammatory constituents of NAF. NAF may promote the development of ESCC via multiple mechanisms and is an understudied area of research.

Keywords: Carcinogenesis; Esophageal squamous cell carcinoma; Non-acid reflux; Risk factors.

Publication types

  • Review

MeSH terms

  • Acetaldehyde / adverse effects
  • Animals
  • Carcinoma, Squamous Cell* / chemically induced
  • Carcinoma, Squamous Cell* / genetics
  • Esophageal Neoplasms* / chemically induced
  • Esophageal Neoplasms* / genetics
  • Esophageal Squamous Cell Carcinoma*
  • Humans
  • Nitrosamines* / adverse effects


  • Nitrosamines
  • Acetaldehyde