Barrett’s esophagus and esophageal adenocarcinoma diagnoses have increased markedly in recent decades. Recent research with patients diagnosed with Barrett’s esophagus (the only known precursor for esophageal adenocarcinoma) and esophageal adenocarcinoma has identified several modifiable and nonmodifiable potential risk factors. Consistent risk factors for both disorders include increasing age, male sex, white non-Hispanic race/ethnicity, gastroesophageal reflux disease, lack of infection with Helicobacter pylori , smoking, abdominal obesity, and a Western diet. The authors present detailed discussions of these risk factors along with possible explanations for some apparent discrepancies and ideas for future study.
Key points
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The incidence and prevalence of esophageal adenocarcinoma and Barrett’s esophagus, respectively, have increased markedly in recent decades, without conclusive explanation.
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There are marked differences in disease incidence by region, sex, and gender.
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The main risk factors for these disorders are abdominal obesity, smoking, gastroesophageal reflux disease, a Western diet, and the absence of Helicobacter pylori colonization.
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The demographic distributions of the risk factors generally do not match the distributions of disease incidence, creating confusion regarding the underlying explanation for what is causing the incidence increases, potential interventions, and the unusual demographic patterns.
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The differences found may, in part, be related to interactions between strong risk factors.
Disease description
Esophageal adenocarcinoma is a highly fatal neoplasm of the esophagus, which has surpassed esophageal squamous cell carcinoma as the most common form of esophageal cancer in the United States. It most commonly occurs in the distal half of the esophagus and is frequently associated with Barrett’s esophagus. Its location, in the esophageal area adjacent to the stomach, by itself supports a role for gastroesophageal reflux disease (GERD) in its cause. Barrett’s esophagus is a metaplastic transformation of portions of the esophageal squamous cell lining to glandular mucosa. Barrett’s esophagus is thought to result from an aberrant healing response to esophageal mucosal injury, typically from GERD, although it has also been reported after other forms of esophageal mucosal injury, including caustic injection and therapeutic radiation exposure. Barrett’s esophagus is associated with a markedly increased risk of esophageal adenocarcinoma, and most esophageal adenocarcinomas are presumed to arise from preexisting Barrett’s esophagus. Thus, evaluating risk factors and demographic distributions for both Barrett’s esophagus and esophageal adenocarcinoma may inform modifiable risk factors along the neoplastic continuum from normal esophagus to Barrett’s esophagus to esophageal adenocarcinoma.
Disease description
Esophageal adenocarcinoma is a highly fatal neoplasm of the esophagus, which has surpassed esophageal squamous cell carcinoma as the most common form of esophageal cancer in the United States. It most commonly occurs in the distal half of the esophagus and is frequently associated with Barrett’s esophagus. Its location, in the esophageal area adjacent to the stomach, by itself supports a role for gastroesophageal reflux disease (GERD) in its cause. Barrett’s esophagus is a metaplastic transformation of portions of the esophageal squamous cell lining to glandular mucosa. Barrett’s esophagus is thought to result from an aberrant healing response to esophageal mucosal injury, typically from GERD, although it has also been reported after other forms of esophageal mucosal injury, including caustic injection and therapeutic radiation exposure. Barrett’s esophagus is associated with a markedly increased risk of esophageal adenocarcinoma, and most esophageal adenocarcinomas are presumed to arise from preexisting Barrett’s esophagus. Thus, evaluating risk factors and demographic distributions for both Barrett’s esophagus and esophageal adenocarcinoma may inform modifiable risk factors along the neoplastic continuum from normal esophagus to Barrett’s esophagus to esophageal adenocarcinoma.
National and global incidence of esophageal adenocarcinoma
The incidence rate of esophageal adenocarcinoma in the United States has increased at least 6-fold over the last 40 years and is projected to continue increasing ( Fig. 1 ). Several studies, using national cancer data from Surveillance, Epidemiology, and End Results (SEER) and international cancer registries, have demonstrated that the incidence of esophageal adenocarcinoma varies geographically, by race and by gender, as does the rate at which the incidence is increasing.
Globally, the incidence increase of esophageal adenocarcinoma during this time period has been highest among non-Hispanic white men ; within this group, in the United States, the incidence increased from 1 to ∼6/100,000 between 1977 and 2010. The regions with the highest global incidence rates of esophageal adenocarcinoma were Northern and Western Europe, Northern America, and Oceania, and the lowest rates were in Sub-Saharan Africa (range 0.4–3.5 for men) ( Fig. 2 ). The male-to-female ratio was 4.4 globally and was highest in developed countries (North America [8.5], Europe, and Oceania) and lowest in Africa (1.7). Based on data from the International Agency for Research on Cancer, the sex ratio of esophageal adenocarcinoma incidence remained relatively stable during the period of study, with a rising overall absolute incidence. However, a rising absolute incidence, with a stable ratio, led to an even greater difference between men and women in the absolute numbers of cases because a doubling of the low incidence among women leads to fewer additional cases than a doubling of the higher incidence among men. As a result, in 2012, 88% of cases of esophageal adenocarcinoma diagnoses in the United States were among men.
Less is known about changes in the prevalence of Barrett’s esophagus, the only known precursor for esophageal adenocarcinoma. The prevalence of Barrett’s esophagus is estimated to be 1.6% to 3% in the US population, although estimates vary markedly and are difficult to estimate, because the condition does not cause any symptoms. A large community-based study found a several-fold increase in the prevalence of persons diagnosed with Barrett’s esophagus between 1994 and 2006, despite adjustment for the number of endoscopic examinations. It also found demographic differences in prevalence that generally paralleled those of esophageal adenocarcinoma. These similar demographic profiles between Barrett’s esophagus and esophageal adenocarcinoma strongly suggest that risk factors acting early in the carcinogenic pathway, in the formation of Barrett’s esophagus, may partially explain the unusual demographic patterns by gender and race/ethnicity.
Risk factors overview
Extensive recent research on risk factors for Barrett’s esophagus and esophageal adenocarcinoma has shown substantial consensus on several modifiable and unmodifiable risk factors for both conditions ( Table 1 ).
| Risk Factors | Barrett’s Esophagus | Esophageal Adenocarcinoma |
|---|---|---|
| Risk factor | Direction of Association | |
| Age | + | + |
| Sex | + (male) | + (male) |
| Race | + (white) | + (white) |
| GERD | + | + |
| H pylori | − | − |
| Smoking | + | + |
| Total alcohol intake | None | None |
| BMI | None | + |
| Waist circumference | + | + |
| Dietary factors | ||
| Dietary fiber, vitamin C, diets high in fruits/vegetables/fish | − | − |
| Beta-carotene, vitamin A | ? | − |
| Omega-3 fatty acids, polyunsaturated fat, vitamin E | − | ? |
| High trans fats/red meat | + | + |
| Aspirin/Nonsteroidal anti-inflammatory drugs | ? | − |
| Hormonal status | ? | − |
The epidemiology of esophageal adenocarcinoma is troubling, in part, because although the overall incidence in esophageal adenocarcinoma has been increasing for a few decades, many of the main risk factors are fixed (eg, demographics) or have been decreasing during this same time. Risk factors for Barrett’s esophagus and esophageal adenocarcinoma include increasing age, male sex, white race, GERD, smoking, increased waist circumference, absence of prior infection with Helicobacter pylori , and Western diet. The primary risk factors, some modifiable and others not, by race and sex when available, are outlined in Table 1 .
Demographic Factors (Nonmodifiable Risk Factors: Race, Gender, and Geography)
Across racial groups, men have a consistently higher incidence of esophageal adenocarcinoma than women (see Fig. 2 ), and differences exist by race/ethnicity ( Fig. 3 ). On the basis on national SEER registry data, it was found that white men have 8 times higher incidence esophageal adenocarcinoma than white women, twice the rate of Hispanic men, and 5 times the rate of black men. Among women, although much lower absolute incidence rates are observed (0.2–0.6), white women have twice the rate of Hispanics women and 3 times the rate of black women. Geographic variation in race- and gender-specific rates has also been observed, with rates of esophageal adenocarcinoma among white men ranging from 2.4 to 5.3/100,000 person-years among 11 SEER regions and among black men ranging from 0.0 to 3.1/100,000 person-years by region. Much less variation by geography has been reported for women, likely because of lack of representative data and/or low counts. Although white men have the overall highest incidence rate in the United States, some regions have incidence rates among black men that are higher than the incidence rate for white men in other regions.
If Barrett’s esophagus is the primary precursor to esophageal adenocarcinoma, it would be expected that the 2 would have similar demographic distributions; this is generally the case. The demographic distributions of Barrett’s esophagus are generally similar to those of esophageal adenocarcinoma, although the associations are weaker, with prevalence proportions of Barrett’s esophagus being highest among whites (6.1%), and lower among blacks (1.6%) and Hispanics (1.7%), with a similar ratio of 2:1 for men:women across races (see Fig. 3 ).
Obesity and Body Composition
Both body mass index (BMI) and abdominal obesity are known risk factors for esophageal adenocarcinoma. In contrast, BMI is not independently associated with Barrett’s esophagus even among persons with GERD. However, other measures of adiposity/body composition, such as abdominal obesity or waist circumference, are associated with Barrett’s esophagus, even after adjustment for BMI. The association between abdominal obesity and Barrett’s esophagus may, in part, be through GERD, although the visceral fat area, measured in a cohort of Japanese men and women, has been associated with increased reflux esophagitis, but not Barrett’s esophagus.
According to a national survey, the prevalence of obesity among adults in the United States increased from 30% in 1999 to 2000 to more than 36% by 2011 to 2014, with even more marked increases since the 1960s ( Fig. 4 ). If obesity alone was the predominant predictor for Barrett’s esophagus or esophageal adenocarcinoma, it would be expected that the demographic groups with the highest prevalence of obesity to be at the highest risk and that the changes in risk factor prevalence over time would approximate the change in cancer incidence. However, in contrast to esophageal adenocarcinoma incidence, obesity prevalence has been generally higher among women and non-Hispanic blacks (compared with other races) ( Fig. 5 ), particularly black women, who are one of the lowest risk groups for esophageal adenocarcinoma and Barrett’s esophagus. In addition, obesity has been increasing at a similar or even greater rate among demographic groups at low risk of esophageal adenocarcinoma (eg, women and blacks) as among those at high risk (non-Hispanic white and men) ( Fig. 6 A [men] and B [women]). These discrepancies leave the biological mechanism for obesity’s carcinogenic effects poorly understood.
Related posts:
New Directions in Barrett’s Esophagus
Who Deserves Endoscopic Screening for Esophageal Neoplasia?
Alternatives to Traditional Per-Oral Endoscopy for Screening
Radiofrequency Ablation of Barrett’s Esophagus
The Role of Endoscopic Ultrasound in the Management of Patients with Barrett’s Esophagus and Superficial Neoplasia
Radiofrequency Ablation of Barrett’s Esophagus
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