Esophageal cancer pathophysiology

The pathophysiology of esophageal cancer depends on the histological subtype, whether squamous cell carcinoma or adenocarcinoma.

• The esophagus is lined by nonkeratinized stratified squamous epithelium.
• This lining is maintained as long as there are no risk factors that can lead to a metaplastic change.

• The risk factors for esophageal squamous cell carcinoma include smoking and alcohol.^[1][2]
• When alcohol and tobacco are combined they have a synergistic effect and the risk for esophageal squamous cell carcinoma is higher.
• Alcohol is able to dissolve fat soluble compounds, like that of the esophageal epithelium.
• Tobacco carcinogens such as aromatic amines, nitrosamines and polycyclic hydrocarbons are, therefore, able to penetrate the esophageal epithelium deeper when in the presence of alcohol.
• Alcohol is also able to decrease the metabolic activities of epithelial cells by damaging DNA.
• When the cellular DNA is damaged, the cell cannot undergo detoxification and protect itself from oxidative damage.
• Oxidation leads to inflammation of the squamous epithelium.
• Continuous irritation of the epithelium leads to dysplasia and in situ malignant transformation.

• The risk factors for esophageal adenocarcinoma include gastroesophageal reflux disease and obesity.^{[3][4][5][6][7]}
• The chronic reflux of gastric acid and bile at the gastroesophageal junction leads to the irritation of squamous epithelium lining the esophagus.
• Chronic irritation leads to metaplasia of esophagus.
• The lining of the esophagus changes from non-keratinized stratified squamous epithelium to columnar epithelium.
• This condition is called Barrett’s esophagus .
• The progression of Barrett’s esophagus to adenocarcinoma is associated with changes in genetic and protein structure, as well as gene expression.
• These mutations include:
  • Chromosomal losses (4q, 5q, 9p, and 18q)^[8]
  • Chromosomal gains (8q, 17q, and 20q)
  • Gene amplifications (7, 8, and 17q)
  • PT53 genes and P16 genes
  • Variants in ADH and/or ALDH2 genes^[9]
  • Possibly Cyclin D1 (CCND1) G870A polymorphism
• In addition, obesity is implicated in the development of esophageal adenocarcinoma.^[10]
• Patients with central obesity tend to have hypertrophied adipocytes and inflammatory cells within their fat deposits.
• This creates a microenvironment within the adipocyte that promotes tumor development through the release of adipokines and cytokines.
• Adipocytes potentiate tumor expansion by supplying energy to support the tumor’s growth.

Squamous cell carcinoma or adenocarcinoma of the esophagus may appear as:^[11]

• Flat and irregular plaque
• Polypoid lesion
• Ulcerating, fungating mass.
  • Location:
    • Squamous cell carcinoma is usually found in the mid-third of the esophagus.
    • Adenocarcinoma is usually found in the lower third of the esophagus near the gastric opening.

• Found in both types:^[12]
  • Poikilocytosis
  • Anisocytosis
  • Staining variation
  • Mitotic activity

• Atypical squamous cells invade the basement membrane
  • Cytology of squamous cells:
    • Eccentric nucleus
    • High mitotic activity
    • Eosinophilic cytoplasm
    • Squamous whorls or keratin pearls

• Atypical adenomatous cells show:^[13]
  • Invading cell clusters or glands
  • Cribriforming
  • Desmoplasia
  • Invasion into submucosa

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