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Key Points

  • Disease summary:

    • Esophageal cancers (ECs) are comprised of two main classes, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Although globally ESCC is the more common of the two, in some western countries such as the United States of America and United Kingdom, EAC has become the dominant histology. Particularly high incidence rates of ESCC are observed in Iran, East Asia, and some African regions.

    • Rarely melanoma, sarcoma, small cell carcinoma, or lymphoma may arise.

    • More than 80% of the 481,000 yearly cases occur in developing countries; the disease is two to four times more common among males.

    • EAC is associated with Barrett esophagus (BE) as a consequence of gastroesophageal reflux disease (GERD) and obesity and usually occurs in the distal esophagus. ESCC is associated with smoking and alcohol and typically occurs in the mid and proximal esophagus.

    • The clinical presentation can usually be attributed to the direct local effects of the disease: dysphagia, sometimes accompanied by pain (odynophagia) and regurgitation of saliva or food. Weight loss is an early feature due to dysphagia and tumor-related cachexia in more advanced stages.

  • Differential diagnosis:

    • It includes benign inflammatory esophageal stricture, esophagitis, gastric cancer, and achalasia or other motility disorders.

  • Monogenic forms:

    • No single hereditary gene cause of EAC or ESCC is known to exist; however, tylosis is a Mendelian genetic syndrome, inherited in an autosomal dominant manner, and is associated with a high risk of developing ESCC (95% risk of developing ESCC by age of 65 years with type A). Linkage studies have suggested an association with the 17q25 locus tylosis esophageal cancer (TOC).

  • Family history:

    • Increased risk of ESCC has been associated with a family history of upper gastrointestinal (GI) cancer probably due to inheritance of multiple low penetrance susceptibility genes. A first-degree relative is associated with one- to threefold increased risk and two or more affected first-degree relatives are associated with a 10-fold increased risk. Although several studies have shown familial aggregation of BE and EACC, linkage analysis in families has not been reported. Familial investigation of EC has primarily been performed in Asian populations; smaller Caucasian studies have shown a lack of evidence for familial susceptibility.

  • Twin studies:

    • Although there have been no twin studies on EC, a genetic component to GERD has been demonstrated.

  • Environmental factors:

    • The major risk factors for ESCC are tobacco smoking and alcohol consumption. ESCC is also associated with the consumption of burning-hot beverages and pickled foods. The main risk factor for EAC is reflux disease and obesity. There is a weaker risk association of EAC with tobacco smoking.

  • Genome-wide associations:

    • Several associations have been identified by genome-wide association studies (GWAS) for ESCC; however, it is not known whether these are functionally important. Testing for single-nucleotide polymorphisms (SNPs) is not yet clinically validated.

  • Pharmacogenomics:

    • The understanding and clinical application of genomics ...

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