Esophageal Cancer: Pathophysiology, Aetiology and Risk Factors

These are the risk factors for the two main types of esophageal cancer.

- Gastroesophageal reflux disease (GERD) is the most common predisposing factor for adenocarcinoma of the esophagus.

o As a consequence of the irritation caused by the reflux of acid and bile, 10-15% of patients who undergo endoscopy for evaluation of GERD symptoms are found to have Barrett epithelium.

o Chronic gastroesophageal reflux is the most important, with severe, long-standing reflux symptoms increasing the risk of cancer by a factor of 40. Chronic gastroesophageal reflux disease is associated with Barrett's metaplasia (Barrett's esophagus), a condition in which an abnormal columnar epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus.

o Adenocarcinoma may develop in these patients, representing the last event of a sequence that starts with the development of GERD and progresses to (Barrett) metaplasia, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma.

o Most esophageal ACs are believed to arise from Barrett's esophagus. Although this mucosal change appears to be a favorable adaptation to chronic reflux—columnar epithelium appears to be more resistant to reflux-induced injury than the native squamous cells—this specialized intestinal metaplasia may become dysplastic and ultimately malignant, with genetic alterations that activate proto-oncogenes, disable tumor suppressor genes, or both. Factors that increase the risk for gastroesophageal reflux, such as obesity or medications that lower the lower esophageal sphincter tone, may result in an increased risk for esophageal AC.

o The progression of Barrett metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure. The oncosuppressor gene TP53 and various oncogenes, particularly erb -b2, have been studied as potential markers. Casson and colleagues identified mutations in the TP53 gene in patients with Barrett epithelium associated with adenocarcinoma.8 In addition, alterations in p16 genes and cell cycle abnormalities or aneuploidy appear to be some of the most important and well-characterized molecular changes. However, the exact sequence of events in the progression of Barrett esophagus to adenocarcinoma is not known. Probably multiple molecular pathways interact and are involved.

o Allelic losses at chromosomes 4q, 5q, 9p, 9q, and 18q and abnormalities of p53, Rb, cyclin D1, and c-myc have been implicated.


The esophagus has no serosa, thus reducing the resistance against local spread of invasive cancer cells. Furthermore, the esophagus has an extensive network of lymphatics, allowing for early regional tumor advancement. The end result is local spread and invasion into surrounding tissue, with early metastatic disease developing in most patients.

- Plummer-Vinson syndrome—the triad of dysphagia, iron deficiency anemia, and esophageal webs

- Human papillomavirus has received the most attention. It is believed that the infection results in loss of function of the tumor suppressor genes p53 and Rb. The importance of this mechanism is not well established.

- Tylosis with esophageal cancer: A genetic disorder characterized by thickening (hyperkeratosis) of the palms and soles, white patches in the mouth (oral leukoplakia), and a very high risk of esophageal cancer. This is the only genetic syndrome known to predispose to squamous cell carcinoma of the esophagus. The risk of developing esophageal cancer is 95% by age 70. The syndrome is inherited in an autosomal dominant manner. The gene has been mapped to chromosome 17q25 but has not been identified. The syndrome is also called nonepidermolytic palmoplantar keratoderma.

- In a high-risk country such as China, deficiencies in vitamin or microelement levels may play a role in causation. Riboflavin deficiency in China may contribute to a high incidence of esophageal cancer.

- Heavy drinking: People who have more than 3 alcoholic drinks each day are more likely than people who don't drink to develop squamous cell carcinoma of the esophagus. Heavy drinkers who smoke are at a much higher risk than heavy drinkers who don't smoke. In other words, these two factors act together to increase the risk even more.