What are the risk factors for esophageal cancer?

Esophageal Cancer Risk Factors

Esophageal cancer risk factors differ fundamentally by histologic subtype: squamous cell carcinoma (OSCC) is driven primarily by tobacco and alcohol use, while adenocarcinoma (OAC) is most strongly associated with gastroesophageal reflux disease and obesity. 1

Risk Factors by Histologic Type

Esophageal Squamous Cell Carcinoma (OSCC)

Tobacco and Alcohol

• Active smoking increases OSCC risk 5 to 9-fold overall, though this effect is lower in endemic high-risk geographic areas (relative risk 1.3 in Linxian, China) 1
• Tobacco smoke contains carcinogens including polycyclic hydrocarbons, nitrosamines, and acetaldehyde 1
• Alcohol's deleterious effects are mediated by acetaldehyde from oral microbiota and salivary oxidation 1
• Smoking and alcohol synergize to increase OSCC risk threefold 1
• Smokers of pipes, hand-rolled, and high tar cigarettes have the highest risk among smokers 1
• Continued smoking after esophageal cancer diagnosis increases recurrence risk (HR 1.42), with risks even higher when combined with ≥7 alcoholic beverages weekly (HR 3.84) 1

Dietary and Nutritional Factors

• Low intake of fresh fruits and vegetables increases OSCC risk 1
• Specific regional micronutrient deficiencies (vitamins A, C, riboflavin) predispose to OSCC, particularly in endemic areas 1
• Consumption of pickled vegetables increases risk 1
• Iron deficiency anemia through Paterson-Brown-Kelly syndrome is associated with OSCC 1

Thermal and Chemical Injury

• Recurrent thermal injury from high-temperature beverages (such as tea) contributes to regional OSCC variation, particularly in Northern Iran 1
• Recurrent chemical or physical insult to esophageal mucosa increases OSCC risk 1

Socioeconomic and Medical Conditions

• OSCC is more common in economically deprived groups and regions, as many risk factors associate with lower socioeconomic status 1
• Achalasia increases OSCC risk 16-fold after the first year following diagnosis 1

Genetic Factors

• The role of inherited genetic variants is modest except in rare familial cases 1, 2
• Tylosis (autosomal dominant disorder from RHBDF2 germline mutation) carries a 90% cumulative OSCC risk by age 70 1, 2
• GWAS studies identified susceptibility loci at 10q23 (PLCE1), 5q31.2 (TMEM173), 17p13.1 (ATP1B2), and HLA class II region (6p21.32) with odds ratios of 1.3-1.4 1

Esophageal Adenocarcinoma (OAC)

Gastroesophageal Reflux Disease

• Gastroesophageal reflux is the most important risk factor for OAC, with an odds ratio of 4.64 (95% CI 3.28-6.57) 1, 2
• Reflux (acid and bile) is associated with Barrett's esophagus development (OR 12.0,95% CI 7.64-18.7) 1
• Longstanding severe reflux symptoms carry an odds ratio of 44 for OAC 1
• Barrett's esophagus progresses to invasive OAC at a rate of 0.12-0.6% annually 1

Obesity

• Central (visceral) obesity is the second strongest risk factor for OAC after reflux, and these two factors display synergy 1, 2
• Obesity increases reflux through elevated intra-abdominal pressure 1
• Obesity-related metabolic syndrome is a risk factor for Barrett's esophagus independent of reflux symptoms 1
• Patients with raised body mass index have an odds ratio of 7.6 for OAC 1

Tobacco and Alcohol

• Smoking is a moderately strong risk factor for OAC, though its association with Barrett's esophagus is less clear 1
• Alcohol does not appear to substantially increase OAC risk, contrasting sharply with OSCC 1

Dietary Factors

• High red meat intake increases risk (OR 1.91,95% CI 1.07-3.38 for highest vs. lowest tertile) 1
• Lower fruit/vegetable intake increases risk (OR 0.86,95% CI 0.80-0.93 per portion/day) 1

Protective Factor

• Helicobacter pylori infection demonstrates an inverse association with OAC risk, and decreasing population seropositivity may contribute to rising OAC rates 1

Demographic and Genetic Factors

• Male gender carries substantially higher risk (male:female incidence ratio 7:1) 1, 2
• Host genetics contribute up to one-third of sporadic OAC risk, with approximately 7% of cases being familial 1, 2
• GWAS identified risk loci linked to esophageal embryonic development (FOXF1, BARX1, ABCC5), host immune response (MHC locus), and cellular proliferation (CRTC1) 1

Common Pitfalls and Clinical Considerations

Critical Distinction Between Subtypes

• Do not apply OSCC risk factor profiles to OAC patients and vice versa—the etiologies are fundamentally different 1
• Alcohol is a major OSCC risk factor but not for OAC; conversely, reflux and obesity are critical for OAC but less relevant for OSCC 1

HPV Controversy

• Despite earlier suggestions, TCGA data demonstrates OSCC has a molecular profile consistent with HPV-negative squamous cell carcinoma, suggesting HPV association may reflect geographic heterogeneity rather than causation 1

Screening Implications

• Patients with achalasia require awareness of OSCC risk, though endoscopic surveillance cost-effectiveness is uncertain (406 endoscopies in males, 2220 in females needed to detect one case) 1
• Barrett's esophagus patients warrant surveillance given the established progression pathway to OAC 1

Prevention Strategies

• Public health programs should emphasize smoking cessation and limiting alcohol to ≤1 drink/day for women, ≤2 drinks/day for men 1
• Encourage diets with at least five servings of fruits and vegetables daily, limited processed foods and red meat 1
• Weight management is critical for OAC prevention given the strong obesity association 1