Oesophageal cancer

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

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

Achalasia is associated with an increased risk for OAC and OSCC.[23][24]

Tobacco smoking strongly increases the risk of OSCC and moderately increases the risk of OAC.[25] Current smokers have a ninefold increased risk of OSCC compared with non-smokers.[26] Smoking increases the risk of OAC and oesophago-gastric junction adenocarcinoma approximately two- to threefold.[26][27]

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

Factors implicated in the development of OAC

Barrett's oesophagus

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

GORD

One population-based case-control study found that people with GORD had a sevenfold increased risk of developing OAC, compared with people without GORD.[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 oesophageal sphincter has been associated with a modestly increased risk of OAC, 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 OAC twofold to sixfold, most probably by increasing gastro-oesophageal acid reflux.[25]

Body mass index (BMI)

Elevated BMI is a risk factor for OAC, irrespective of the presence of GORD.[34][35][36][37]
Case-control studies demonstrate a dose-dependent relationship between increasing BMI and risk of OAC.[37][38]
An inverse association between BMI and risk for OSCC 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 OAC.[41][42]

Factors implicated in the development of OSCC

Alcohol consumption

Relative risk (RR) for OSCC is increased for heavy drinkers compared with non-drinkers 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 OSCC.[46][47][48][49]
An aetiological association between HPV infection and oesophageal cancer has not been demonstrated.[50][51]

Vitamin and mineral deficiencies

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

Race

Incidence of OSCC has been reported to be higher in non-white 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 oesophageal or other cancer

In one population-based cohort-control study, cumulative risk of oesophageal cancer to age 75 was 12.2% among first-degree relatives of OSCC cases and 7.0% in those of controls (hazard ratio [HR] 1.91, 95% CI 1.54 to 2.37).[54]
Increased risk for OSCC 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 OSCC.[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 OSCC, by repeated thermal injury.[58][59][60][61]

Poor oral hygiene

Case-control studies have demonstrated an association between OSCC 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 OSCC, 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 leukaemia, lower and upper gastrointestinal tract neoplasias (including OSCC), skin cancers, and cancers of the genitalia and urinary tract.[65] Screening for GORD (with or without endoscopy to detect early oesophageal cancer) may be considered.[15]
Fanconi anaemia (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 haematological malignancies and solid organ tumours, particularly squamous cell carcinomas, including OSCC).[66] Upper gastrointestinal endoscopy may be considered as a screening strategy.[15]

Oesophageal cancer arises in the mucosa of the oesophagus. It then progresses locally to invade the submucosa and the muscular layer. Metastasis typically occurs to the peri-oesophageal lymph nodes, liver, and lungs.

Squamous cell carcinoma primarily affects the upper and middle oesophagus. Cancers of the lower oesophagus and oesophago-gastric junction are typically adenocarcinomas.[3]

The pathophysiological 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 aetiological factors.

Alcohol

The exact mechanism by which alcohol causes oesophageal 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 oxidised 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 oesophageal 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.

Gastro-oesophageal reflux disease (GORD) and Barrett's oesophagus

Chronic GORD causes metaplasia (Barrett's oesophagus) in which the stratified squamous epithelium that normally lines the distal oesophagus is replaced by abnormal columnar epithelium. Although this might seem a favourable 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 tumour suppressor genes.
Factors that increase gastro-oesophageal reflux damage, such as hiatus hernia, achalasia, obesity, or medications that lower the lower oesophageal sphincter tone, may further increase the risk of oesophageal carcinoma.[33][67][68] However, studies fail to consistently demonstrate increased risk associated with specific medications.[33]

Histological classification

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

Siewert classification

Siewert tumour type should be assessed in all patients with OAC involving the oesophago-gastric junction.[4][5] The classification can be performed based on careful endoscopy with appropriate description of tumour length in relation to anatomical landmarks. Siewert classification allows comparison of data between various centres and facilitates the choice of surgical therapy. Tumours are classified into three types:

Siewert Type 1: tumour of the lower oesophagus with the epicentre located within 1-5 cm above the anatomical oesophago-gastric junction
Siewert Type 2: true carcinoma of the cardia with the tumour epicentre within 1 cm above and 2 cm below the oesophago-gastric junction
Siewert Type 3: subcardial carcinoma with the tumour epicentre between 2 cm and 5 cm below the oesophago-gastric junction, which infiltrates the oesophago-gastric junction and lower oesophagus from below.

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

Pathophysiology

Classification

Histological classification

Siewert classification