Risk and Protective Factors
Epidemiologic and clinical research has revealed many risk factors which, taken together, can help estimate a person’s probability of developing esophageal adenocarcinoma (EAC). These include:
- demographic factors,
- host and lifestyle factors,
- family history, and
- genetic markers.
In the general population, symptomatic gastroesophageal reflux (sGERD), obesity, cigarette smoking, and family history of BE or EAC are the major factors associated with increased risk.(1–6) Conversely, physical activity, use of non-steroidal anti-inflammatory drugs (NSAIDs) and statin drugs have been associated with decreased risk in observational studies and randomized clinical trials.(7–11) Many of these factors are thought to affect EAC risk through the exacerbation (or reduction) in inflammation (figure 1.)
It is important to note that while the observational studies are generally very consistent in finding the above associations, they are not necessarily causal, and no randomized clinical trials have examined the extent to which behavioral change (e.g., losing weight, quitting smoking) actually affects risk of esophageal adenocarcinoma. In contrast, a number of clinical trials have reported on reduced risk associated with statin use, although esophageal cancer was not the primary endpoint. A recent trial(11) of use of aspirin and/or a proton pump inhibitor did find a suggestion (not quite statistically significant) that aspirin might be effective, especially along with proton pump inhibitors; this finding is supported by a number of observational studies.
Regarding other potential risk factors, a strong body of epidemiologic evidence suggests that infection with the Helicobacter pylori bacterium is associated with an approximately 50% decreased risk of EAC although the mechanism(s) remain unclear.(12, 13) Similarly, there is some evidence from observational studies that diet, in particular higher intake of fat and lower intake of fruits and vegetables, is associated with increased EAC risk.(14, 15) Finally, while almost two dozen genetic loci have been identified as associated with EAC risk(16), as a whole, their added discriminatory ability is still rather modest, especially compared to family history.(17,18)
Esophageal Squamous Cell Carcinoma
In the U.S., tobacco smoking and alcohol use, with a lesser contribution from a poor diet (e.g., low intake of fruit and vegetables), account for almost 90% of ESCC cases.(19) In other regions of the world, the situation is more complicated with numerous risk factors that are population-specific.(20-22)
The highest ESCC incidence rates in the world occur in Central and Eastern Asia, Eastern Africa, and Uruguay and neighboring parts of Brazil; within these broad regions, a number of well demarcated hotspots have been observed. In many, observational studies and cancer prevention trials have investigated potential underlying causes and prevention methods. One area of particular interest has been Linxian, China, where research has identified a number of factors that influence EC risk, including diet (e.g., eating pickled vegetables and low intake of fruits and vegetables), nutritional and micronutrient deficiencies, intake of hot beverages, exposure to indoor air pollutants, and poverty, along with smoking and genetics.(23) Public health efforts to reduce risk factor prevalence and increase screening and early detection have begun to lead to lower incidence and mortality rates.
Similarly, in Golestan Province in NE Iran, another high-risk area, no single risk factor has been identified, but rather a number of factors seem to be at work, including drinking hot tea and un-piped water, smoking opium, poor diet, poor oral health and exposure to indoor air pollution.(24) In other populations, betel quid chewing in the Asia-Pacific region, drinking (Yerba) mate tea in Uruguay and drinking Calvados in Northern France. High risk areas of Africa have been the focus of fewer studies, although smoking and alcohol appear to be important.(25) Recently indoor air pollution, specifically PAHs from burning wood, has been linked with precancerous esophageal lesions.(26)
EAC and ESCC are two distinct cancers with vastly different incidence and risk factor profiles. Figure 2 summarizes and contrasts many of the known and suspected risk factors for EAC and ESCC.(22)
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