Causes of Esophageal Cancer
Histologic Type Determines Etiology
The causes of esophageal cancer differ fundamentally by histologic subtype: squamous cell carcinoma (SCC) is primarily driven by tobacco and alcohol exposure, while adenocarcinoma (ACA) is predominantly caused by gastroesophageal reflux disease (GERD), Barrett's esophagus, and obesity. 1
Squamous Cell Carcinoma Risk Factors
Primary Causative Factors
- Tobacco smoking is the strongest modifiable risk factor for SCC, with pipe smokers, hand-rolled cigarette users, and high-tar cigarette smokers having the highest risk 1
- Alcohol consumption shows a synergistic, dose-dependent effect with smoking, substantially increasing risk in those who both smoke and drink (odds ratio 16.9 for combined exposure) 1
- The risk of SCC decreases substantially after smoking cessation, unlike adenocarcinoma where risk remains elevated 1
Dietary and Nutritional Factors
- Diets lacking in fresh fruits and vegetables with low intakes of vitamins A, C, and riboflavin predispose to SCC 1, 2, 3
- Consumption of pickled vegetables increases risk 1, 4
- Hot beverage consumption (particularly hot tea) causes thermal injury and increases SCC risk in certain populations 5, 4
- Iron deficiency anemia through Paterson-Brown-Kelly syndrome is associated with SCC 1
Other Established Risk Factors
- Low socioeconomic status is consistently associated with higher SCC risk 2, 3, 4
- Achalasia confers a 16-fold increased risk of developing SCC after the first year following diagnosis 1
- Poor oral health has been linked to increased SCC risk 2, 4
Adenocarcinoma Risk Factors
Primary Causative Factors
- Gastroesophageal reflux disease (GERD) is the most important risk factor for adenocarcinoma (odds ratio 4.64), with longstanding severe symptoms conferring an odds ratio of 44 1, 6
- Barrett's esophagus is the only known precursor to esophageal adenocarcinoma, conferring a 30-60 times greater risk than the general population, with an absolute progression rate of approximately 0.5% per patient-year 1, 7, 6
- Obesity and high body mass index (BMI) are the second strongest risk factors, with individuals in the highest BMI quartile having a 7.6-fold increased risk compared to the lowest quartile 1, 6
Secondary Risk Factors
- Tobacco use is a moderate established risk factor for adenocarcinoma, though the association is weaker than for SCC 1, 6
- Male gender carries substantially higher risk, with a male-to-female incidence ratio of 7:1 6
- Age, long-standing GERD, hiatal hernia size, and length of Barrett's esophagus are associated with higher grades of dysplasia and progression to adenocarcinoma 1, 7
Important Distinction
- Unlike SCC, adenocarcinoma risk does not decrease after smoking cessation, remaining elevated for years 1
- Central (visceral) obesity appears more important than overall obesity for adenocarcinoma risk 6
Genetic and Hereditary Factors
Limited Hereditary Component
- The vast majority of esophageal cancers are sporadic, caused by environmental and lifestyle factors rather than inherited genetic mutations 6
- Host genetics contribute up to one-third of the risk for Barrett's esophagus and adenocarcinoma development, with approximately 7% of cases being familial 6
- Tylosis, an autosomal dominant disorder caused by germline mutation in RHBDF2, is associated with a 90% cumulative risk of SCC by age 70, though this is rare 6
Clinical Implication
- Routine genetic testing is not recommended for esophageal cancer except in cases with strong family history or known hereditary cancer syndromes like Lynch syndrome 6
Geographic and Population Variations
Regional Differences
- In Western countries, SCC is strongly related to smoking and alcohol, whereas in China and other Asian regions, the etiology is more complex and multifactorial 1
- Adenocarcinoma is gradually increasing in men of all ethnic backgrounds and also in women, particularly in developed countries 1, 3
- Esophageal cancer is essentially a disease of older age, with two-thirds of cases diagnosed over 65 years 1
Common Pitfalls and Clinical Considerations
Screening Implications
- Most patients who develop adenocarcinoma in the setting of Barrett's esophagus were unaware of having the condition before their cancer diagnosis 7
- Screening for Barrett's esophagus is recommended in patients with chronic GERD symptoms, particularly those aged 50 years or older 7
- For achalasia patients, the increased cancer risk is highest in the first year (likely due to prevalent cancers causing dysphagia), followed by a persistent 16-fold increased risk 1
Prevention Strategies
- Public health education should focus on smoking cessation, avoidance of excess alcohol intake, and encouraging diets rich in fruits and vegetables (up to five servings per day) 1
- Weight management and GERD control are critical for adenocarcinoma prevention 1, 6
- HPV testing or HPV-targeted prevention strategies are not supported for esophageal cancer, as comprehensive genomic analysis does not support a significant causative role 5
Second Primary Cancers
- Patients with esophageal cancer (both SCC and adenocarcinoma) are at increased risk of developing second primary cancers, particularly head and neck and lung cancers 1