Esophageal cancer

The risk of esophageal cancer increases with age.[19]

Male sex is a risk factor for both esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC).[20][21] Approximately 70% of cases occur in men.[6][7] The difference cannot be accounted for by other risk factors (e.g., gastroesophageal reflux disease [GERD], obesity), as these are equally divided between the sexes.[22]

Achalasia is associated with an increased risk for EAC and ESCC.[23][24]

Tobacco smoking strongly increases the risk of ESCC and moderately increases the risk of EAC.[25] Current smokers have a ninefold increased risk of ESCC compared with nonsmokers.[26] Smoking increases the risk of EAC and esophagogastric junction adenocarcinoma approximately two- to threefold.[26][27]

Lower socioeconomic status is associated with a two- to fourfold increase in risk of esophageal cancer.[25]

Factors implicated in the development of EAC

Barrett esophagus

Metaplasia of the mucosal lining of the distal esophagus caused by long-standing gastroesophageal reflux. Barrett esophagus is a premalignant condition for the development of EAC.[28] People with Barrett esophagus have a 30 to 60 times greater risk of developing EAC compared with the general population.[29]
Risk of progression from Barrett esophagus to EAC is correlated with the degree of dysplasia present. The annual progression rate of low-grade dysplasia to high-grade dysplasia or EAC is 4%; the annual risk of progression from high-grade dysplasia to EAC is 25%.[30]
A familial form of Barrett esophagus has been described, with multiple reports of familial clustering of patients with the condition. In a database analysis of patients diagnosed with Barrett esophagus or EAC in the Netherlands, 7% of cases were familial. These cases have a younger average age of onset of reflux symptoms and diagnosis of EAC than nonfamilial cases, suggesting a possible inherited predisposition to Barrett esophagus and/or EAC in some people.[31]

GERD

One population-based case-control study found that people with GERD had a sevenfold increased risk of developing EAC, compared with people without GERD.[32] More frequent, more severe, and longer-lasting symptoms were associated with a higher risk of cancer.[32]
Use of theophyllines or anticholinergic medications to relax the lower esophageal sphincter has been associated with a modestly increased risk of EAC, although the association may be confounded by the presence of concomitant asthma or chronic obstructive lung disease.[33]

Hiatus hernia

The presence of a hiatus hernia increases risk of EAC twofold to sixfold, most probably by increasing gastroesophageal acid reflux.[25]

Body mass index (BMI)

Elevated BMI is a risk factor for EAC, irrespective of the presence of GERD.[34][35][36][37]
Case-control studies demonstrate a dose-dependent relationship between increasing BMI and risk of EAC.[37][38]
An inverse association between BMI and risk for ESCC has been reported.[34][36][39][40]

Dietary factors

Diets high in total fat, saturated fat, and cholesterol appear to be associated with an increased risk of EAC.[41][42]

Factors implicated in the development of ESCC

Alcohol consumption

Relative risk (RR) for ESCC is increased for heavy drinkers compared with nondrinkers and occasional drinkers (RR 4.95, 95% CI 3.86 to 6.34).[43]
There appears to be a synergistic effect in the presence of tobacco smoke.[44][45]

Human papillomavirus (HPV)

Meta-analyses report an association between HPV infection (serotypes 16 and 18) and incidence of ESCC.[46][47][48][49]
An etiologic association between HPV infection and esophageal cancer has not been demonstrated.[50][51]

Vitamin and mineral deficiencies

Vitamin and mineral deficiencies may contribute to increased risk for esophageal cancer in some regions.[52][53]

Race

Incidence of ESCC has been reported to be higher in nonwhite people.[16][17]
In the US, squamous cell carcinoma is more common than adenocarcinoma within the black population, with the incidence rate in black men being 4.5 times higher than that of white men.[10][18]

Family history of esophageal or other cancer

In one population-based cohort-control study, cumulative risk of esophageal cancer to age 75 was 12.2% among first-degree relatives of ESCC cases and 7.0% in those of controls (hazard ratio [HR] 1.91, 95% CI 1.54 to 2.37).[54]
Increased risk for ESCC has been associated with a family history of any cancer.[55]

Maté consumption

Drinking maté, a herbal infusion, is associated with an increased risk for ESCC.[56][57] Polycyclic aromatic hydrocarbons and thermal injury have been implicated.[25]

Hot beverages

Habitual consumption of very hot drinks (as occurs in some cultures in Iran, China, Kenya, and elsewhere) has been associated with increased risk for ESCC, by repeated thermal injury.[58][59][60][61]

Poor oral hygiene

Case-control studies have demonstrated an association between ESCC and poor oral hygiene, irrespective of alcohol and tobacco use.[62][63][64]

Hereditary cancer syndromes

Tylosis (also known as focal non-epidermolytic palmoplantar keratoderma [PPK] or Howel-Evans syndrome) is a rare autosomal dominant syndrome caused by germline mutations in the RHBDF2 gene. It is associated with an increased lifetime risk of developing ESCC, with an average age of diagnosis of 45 years. Routine screening by upper gastrointestinal endoscopy is recommended for patients and their family members starting from 20 years of age.[15]
Bloom syndrome is a rare autosomal recessive disorder caused by a mutation in the BLM gene, which codes for the DNA repair enzyme RecQL3 helicase.[65] It is associated with an increased risk of developing multiple cancers, especially lymphoma and acute myeloid leukemia, lower and upper gastrointestinal tract neoplasias (including ESCC), skin cancers, and cancers of the genitalia and urinary tract.[65] Screening for GERD (with or without endoscopy to detect early esophageal cancer) may be considered.[15]
Fanconi anemia (FA) is an autosomal recessive condition caused by germline mutations in any one of at least 21 genes associated with the FA pathway, which has a role in DNA repair. It presents with congenital abnormalities, progressive pancytopenia, and a predisposition to cancer (both hematologic malignancies and solid organ tumors, particularly squamous cell carcinomas, including ESCC).[66] Upper gastrointestinal endoscopy may be considered as a screening strategy.[15]

Esophageal cancer arises in the mucosa of the esophagus. It then progresses locally to invade the submucosa and the muscular layer. Metastasis typically occurs to the periesophageal lymph nodes, liver, and lungs.

Squamous cell carcinoma primarily affects the upper and middle esophagus. Cancers of the lower esophagus and esophagogastric junction are typically adenocarcinomas.[3]

The pathophysiologic mechanisms of many causes are not yet fully elucidated and are the subject of active research. However, mechanisms have been proposed for some of these etiologic factors.

Alcohol

The exact mechanism by which alcohol causes esophageal cancer is not yet known. Alcohol itself does not bind DNA, is not mutagenic, and does not cause cancer in animals. However, it may act through its conversion to acetaldehyde (a known carcinogen), acting as a solvent for other carcinogens, and causing nutritional deficiencies.
After ingestion, ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH) enzymes, and is then detoxified to acetate by acetaldehyde dehydrogenase (ALDH).
In addition to systemic absorption and metabolism, in heavy drinkers (>40 g/day), alcohol in the saliva is also oxidized to acetaldehyde by the many microbes in the mouth, and by the salivary glands and mucous membranes. This process is intensified in those with poor oral hygiene and high bacterial load. Detoxification in the mouth is limited, however, and the result is strikingly high local concentrations of carcinogenic acetaldehyde. Saliva is then swallowed, exposing the esophageal mucosa.[45]
In vitro, acetaldehyde causes point mutations in human lymphocytes, sister chromatid exchanges, and cellular proliferation, and inhibits DNA repair.

Tobacco

Smoking exposes the body to a large number of carcinogens, such as polycyclic aromatic hydrocarbons, nitrosamines, and acetaldehyde, which are present in tobacco smoke.

Gastroesophageal reflux disease (GERD) and Barrett esophagus

Chronic GERD causes metaplasia (Barrett esophagus) in which the stratified squamous epithelium that normally lines the distal esophagus is replaced by abnormal columnar epithelium. Although this might seem a favorable adaptation to chronic reflux (because columnar epithelium appears more resistant to reflux-induced injury), these metaplastic cells may become dysplastic, and ultimately malignant, through genetic alterations that activate proto-oncogenes and/or disable tumor suppressor genes.
Factors that increase gastroesophageal reflux damage, such as hiatal hernia, achalasia, obesity, or medications that lower the lower esophageal sphincter tone, may further increase the risk of esophageal carcinoma.[33][67][68] However, studies fail to consistently demonstrate increased risk associated with specific medications.[33]

Histologic classification

Diagnosis should be based on endoscopic biopsies with the histologic tumor type classified according to the World Health Organization (WHO) criteria.[1] The two main histologic types are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), which together account for >95% of cases. In the US, approximately 70% of cases are adenocarcinomas (typically arising in Barrett esophagus).[2] EAC occurs mainly in the distal esophagus and esophagogastric junction, while ESCC tends to affect the upper and middle esophagus.[3] Rarely, other histologic types, such as melanoma, sarcoma, small cell carcinoma, or lymphoma, can occur in the esophagus.

Siewert classification

Siewert tumor type should be assessed in all patients with EAC involving the esophagogastric junction.[4][5] The classification can be performed based on careful endoscopy with appropriate description of tumor length in relation to anatomic landmarks. Siewert classification allows comparison of data between various centers and facilitates the choice of surgical therapy. Tumors are classified into three types:

Siewert Type 1: tumor of the lower esophagus with the epicenter located within 1-5 cm above the anatomic esophagogastric junction
Siewert Type 2: true carcinoma of the cardia with the tumor epicenter within 1 cm above and 2 cm below the esophagogastric junction
Siewert Type 3: subcardial carcinoma with the tumor epicenter between 2 cm and 5 cm below the esophagogastric junction, which infiltrates the esophagogastric junction and lower esophagus from below.

Siewert Type 1 and 2 tumors are treated as esophageal cancer whereas Siewert Type 3 tumors are treated according to gastric cancer guidelines.

Pathophysiology

Classification

Histologic classification

Siewert classification