History and exam
Key diagnostic factors
common
dysphagia
The most common presenting symptom of esophageal cancer.
Dysphagia usually occurs only after there is obstruction of more than two-thirds of the lumen. Affected patients generally have progressed to locally advanced disease with at least T3 tumors and potentially nodal disease at the time of diagnosis.
odynophagia
Pain on swallowing is one of the signs of a locally advanced tumor, with possible invasion of the airway or mediastinum.
weight loss
One of the most common presenting signs. More than 50% of patients lose >5% of their body weight before admission for esophagectomy, and 40% of patients lose >10%. Weight loss (independent of body mass index) is associated with increased operative risk, reduced quality of life, and poor survival in advanced disease.[88]
When not associated with odynophagia or dysphagia, weight loss may be missed and contribute to a late presentation.
European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines can be used to aid assessment and management of nutritional status.[115]
Other diagnostic factors
uncommon
hiccups
Phrenic nerve involvement can trigger hiccups.
postprandial/paroxysmal cough
This may indicate the presence of an esophagotracheal or esophagobronchial fistula resulting from local invasion by a tumor.
Risk factors
strong
male sex
Male sex is a risk factor for both esophageal squamous cell carcinoma and esophageal adenocarcinoma.[20][21] Approximately 70% of cases occur in men.[6][7]
Between 2016 and 2020, the age-adjusted rate of new cases of esophageal cancer in the US was 7.1 per 100,000 in men, and 1.7 per 100,000 in women.[7]
The difference cannot be accounted for by other risk factors (e.g., gastroesophageal reflux disease, obesity), as these are equally divided between the sexes.[22]
older age
The risk of esophageal cancer increases with age, with peak incidence between 80 and 84 years.[19]
tobacco use
Tobacco smoking strongly increases risk of esophageal squamous cell carcinoma (ESCC) and moderately increases risk of esophageal adenocarcinoma (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]
With respect to ESCC, there appears to be a synergistic effect in the presence of alcohol consumption.[44][45]
excessive alcohol use (squamous cell carcinoma)
Relative risk (RR) for esophageal squamous cell carcinoma 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]
There is little evidence for an association between drinking alcohol and esophageal adenocarcinoma.[69][70]
Barrett esophagus (adenocarcinoma)
Barrett esophagus (metaplasia of the mucosal lining of the distal esophagus) is caused by long-standing gastroesophageal reflux. It is a premalignant condition for the development of esophageal adenocarcinoma (EAC).[28]
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 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 nonfamilial cases, suggesting a possible inherited predisposition to Barrett esophagus and/or OAC in some people.[31]
GERD (adenocarcinoma)
One population-based case-control study found that people with gastroesophageal reflux disease (GERD) had a sevenfold increase in risk of developing esophageal adenocarcinoma (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 modestly increased risk of EAC, although the association may be confounded by the presence of concomitant asthma or chronic obstructive lung disease.[33]
hiatal hernia (adenocarcinoma)
The presence of hiatal hernia increases esophageal adenocarcinoma risk twofold to sixfold, most likely by increasing gastroesophageal acid reflux.[25]
family history of esophageal or other cancer (squamous cell carcinoma)
In one population-based cohort control study, cumulative risk of esophageal cancer to age 75 was 12.2% among first-degree relatives of esophageal squamous cell carcinoma (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]
low socioeconomic status
A large number of epidemiologic studies have confirmed that the risk of esophageal cancer is higher in populations with lower socioeconomic status (SES).[25]
Various indicators of SES have been used in these studies, with most reporting an increased risk of two- to fourfold among those with lower SES compared with those who have higher SES.[25]
nonwhite race (squamous cell carcinoma)
high-temperature beverages and foods (squamous cell carcinoma)
drinking maté (squamous cell carcinoma)
Maté consumption is associated with an increased risk for esophageal squamous cell carcinoma.[56][57] Polycyclic aromatic hydrocarbons and thermal injury have been implicated.[25]
Maté is an infusion of the herb Ilex paraguayensis (yerba maté). It is commonly consumed in southern Brazil, northeastern Argentina, Uruguay, and Paraguay.[71] These areas also have the highest risks of esophageal cancer in South America (mostly squamous cell).[72][73]
low intake of fresh fruit and vegetables
hereditary cancer syndromes
Tylosis (also known as focal non-epidermolytic palmoplantar keratoderma 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 esophageal squamous cell carcinoma (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 gastroesophageal reflux disease (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]
weak
obesity (adenocarcinoma)
Elevated BMI is a risk factor for esophageal adenocarcinoma (EAC), irrespective of the presence of gastroesophageal reflux disease.[34][35][36][37]
Case-control studies demonstrate a dose-dependent relationship between BMI and EAC.[37][38]
An inverse association between BMI and risk for esophageal squamous cell carcinoma has been reported.[34][36][39][40]
human papillomavirus (squamous cell carcinoma)
achalasia
vitamin and mineral deficiencies (squamous cell carcinoma)
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