- The values of endoscopic surveillance for Barrett’s esophagus is currently not fully elucidated and is being tested in the Barrett’s Oesophagus Surveillance Study (BOSS) trial, although it can lead to detection in some patients of lower stage cancers.
- The presence of a hiatal hernia should be determined and distinguished from Barrett’s esophagus during endoscopy to avoid any misdiagnosis.
Epidemiology
Esophageal adenocarcinoma is one of the most important gastrointestinal cancers because its incidence has risen substantially in the United States, Western Europe (especially the United Kingdom), Australia, and other developed countries over the past four decades, and continues to rise.1,2 Some Asian countries have also begun to report an increase in the incidence of esophageal adenocarcinoma.3,4 In the United States, the highest incidence is seen in non-Hispanic white men, in whom the incidence is eight times higher than in non-Hispanic white women and approximately five times higher than in African American men.5 The peak age of incidence of esophageal adenocarcinoma is in the seventh decade and beyond. In a Dutch study of 42,207 patients with Barrett’s esophagus, age was a significant predictor of the development of esophageal adenocarcinoma (hazard ratio 12; 95% CI, 8.0-18).6 In a study from the Cleveland Clinic, the odds of those 50 years or older having a prevalent case of high-grade dysplasia or cancer was five times the odds of those younger than 50 years.7
Several case control studies have suggested that obesity is a risk factor for esophageal adenocarcinoma. The strongest data come from a prospective study that evaluated cancer risk in a large cohort of European subjects. 346,554 men and women participating in the European Prospective Investigation into Cancer and Nutrition were evaluated.8 BMI, waist circumference, and waist-to-hip ratio were positively associated with the risk of esophageal adenocarcinoma: relative risk (RR), 2.60 (95% CI, 1.23-5.51); RR, 3.07 (95% CI, 1.35-6.98), and RR, 2.12 (95% CI, 0.98-4.57).
Symptomatic reflux disease is one of the best-recognized risk factors for esophageal cancer.9 The longer the duration of reflux disease, the worse the symptoms and the more frequently they occur, the higher the risk. In one study, the odds ratios for esophageal adenocarcinoma was 43.5 (95% CI, 18.3-103.5) for patients with frequent heartburn for decades compared with patients without heartburn. Other risk factors for esophageal adenocarcinoma include cigarette smoking, which doubles the risk of esophageal adenocarcinoma.10 A diet low in fruit and vegetables, folate deficiency, and especially low selenium have been associated with increased risk.11,12 Alcohol intake has been associated with increased risk in some countries, but not in others. Chronic Helicobacter pylori infection may have a protective effect although the mechanism remains unclear.13 One suggested mechanism is that the development of atrophy results in hypochlorhydria, reducing acid secretion and decreasing distal acid exposure.
Medications have been associated with both an increased and a decreased risk of esophageal cancer. Drugs that inhibit the lower esophageal sphincter are associated with a higher risk of esophageal cancer.14 In contrast, proton pump inhibitors and aspirin have been associated with a decreased risk of Barrett’s esophagus and cancer although these studies have several limitations.15,16
Family Screening and Studies
Screening for Barrett’s esophagus and esophagus cancer
Your patient was just diagnosed with Barrett’s esophagus or esophageal adenocarcinoma. Should you recommend that their family members be screened for Barrett’s esophagus or early cancer? Will your recommendation be based on whether the family member reports heartburn or acid regurgitation? Before attempting to provide data to inform your clinical recommendations, it is necessary to understand some basic genetic concepts, and the limitations of family studies performed to date, especially as differences in study design may have contributed to mixed results. Understanding these concepts will help you explain the rationale behind your recommendations for each unique patient and their family.
Many of the known risk factors for Barrett’s esophagus and the adenocarcinoma cell type of esophagus cancer have a heritable (also known as germline) genetic component including male sex and white ethnicity. In this regard the world’s first genome wide paper has shown that several SNPs lead to Barrett’s esophagus.17 Obesity, which is a strong risk factor for esophageal adenocarcinoma, is thought to be 33% attributable to germline genetics, with environment (e.g., the foods available) and behavior (e.g.,the portion size the person chooses to eat) playing major roles in the development of obesity. Central obesity, in which the person demonstrates an elevated waist-to-hip circumference ratio, is mildly associated with Barrett’s esophagus. On the basis of twin studies, it has been estimated that 31% of gastroesophageal reflux disease (GERD) symptoms, namely, heartburn and acid regurgitation, also have a heritable component.18
Conversely, somatic genomic changes are due to the accumulation of genetic mutations over time. Somatic mutations are not inherited. A major risk factor for esophageal adenocarcinoma is advancing age. The average age at which esophageal adenocarcinoma is diagnosed in the United States is 68 years.19 When a person’s risk of a specific cancer increases as they age, this implies that a time-related accumulation of somatic mutations is playing a role. Usually, cancers that are inherited due to germline genetic factors are diagnosed at a younger age when compared with people who develop sporadic, nonfamilial cancer.
Most people with Barrett’s esophagus are unaware that they have an abnormal lining of their swallowing tube that increases their risk for the adenocarcinoma type of esophagus cancer. Although heartburn and acid regurgitation are the hallmark symptoms of GERD, not all people with Barrett’s esophagus or esophageal adenocarcinoma (diseases thought to be due to reflux) perceive GERD symptoms. GERD symptoms cannot be used in the general population to direct screening as 20% of US adults report weekly symptoms, and esophageal adenocarcinoma is rare (fewer than 10,000 cases per year among 300 million people in the United States). As a result, millions of patients with reflux would need to be screened to find a relatively small number of patients with Barrett’s. Conversely, 40% of people with esophageal adenocarcinoma in a background of Barrett’s esophagus deny ever experiencing GERD symptoms and are astounded to learn they have been diagnosed with a reflux-induced malignancy.20 As a result, patients would not be detected by screening programs based on symptoms.
Aging clearly increases the risk of esophageal adenocarcinoma, suggesting that nonheritable (somatic) factors are important in the development of this highly lethal malignancy. However, the precise relationship between age and Barrett’s esophagus is not clear, hampered largely by the need for endoscopy to diagnose Barrett’s esophagus. Thus, how much of Barrett’s esophagus is heritable (germline) versus sporadic (somatic) is not known. Barrett’s esophagus is rarely diagnosed in infants and children.21 Although Barrett’s esophagus is commonly diagnosed in the sixth and seventh decades of life, it is possible that the person had Barrett’s esophagus for decades prior to its diagnosis as endoscopy is infrequently recommended for young adults and children, especially those who lack GERD symptoms.
The attributable risk of family history of Barrett’s esophagus and/or esophageal adenocarcinoma on the predisposition to the development of Barrett’s esophagus and esophageal adenocarcinoma is an area of active investigation. As people in a family tend to eat similar foods and share similar behaviors, family studies have to be interpreted with caution, keeping environmental and behavioral factors in mind.
GERD symptoms
Three independent studies have shown that GERD symptoms tend to aggregate in families.22-24 One study compared how frequently people with a first-degree relative with esophageal adenocarcinoma or long-segment (greater than 3 cm in length) biopsy-proven Barrett’s esophagus (having intestinal metaplasia with goblet cells on their biopsies from the tubular esophagus) reported GERD symptoms compared with people who did not have a first-degree relative with esophageal adenocarcinoma or Barrett’s esophagus. The key strength of the study design was that they compared the first-degree relatives of patients with esophagus cancer or Barrett’s esophagus with the first-degree relatives of the SPOUSE of the person with the positive family history. By doing so, the researchers were attempting to adjust for environmental factors as it is quite likely that members of the entire extended family eat similar types of foods. Thus, there is very good evidence that GERD symptoms aggregate in families, but how much is due to shared environment and behavior versus germline genetics is not yetclear.
Hiatal hernia, reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma
Case reports have described families in which multiple members have been diagnosed with GERD symptoms, hiatal hernia, reflux esophagitis, Barrett’s esophagus, or esophageal adenocarcinoma.25,26 Whether this is due to shared inherited germline mutations, or shared environmental and behavioral factors (contributing to somatic mutations) is under investigation. It also remains possible that the appearance of familial clustering of disease is merely due to chance. Reflux esophagitis is a chemical burn of the inner lining of the esophagus caused by the backward motion of stomach contents (e.g., acid, bile, and food) into the esophagus. It has been postulated that years of inflammation from reflux esophagitis may contribute to the formation of Barrett’s esophagus, especially in genetically predisposed individuals. The presence of a hiatal hernia, where the stomach has migrated from the abdomen into the chest, increases a person’s propensity to reflux. Studies investigating the prevalence of GERD and its complications in families in which at least one person has Barrett’s esophagus and/or esophageal adenocarcinoma have generated mixed results.
One investigative group conducted a study in which they offered a research upper endoscopy to first-degree relatives of patients with long-segment biopsy-proven Barrett’s esophagus and/or adenocarcinoma of the tubular esophagus (not the gastroesophageal junction or proximal stomach), who had never before been endoscoped.27 People with and without GERD symptoms were invited to undergo endoscopy. For comparison, the research group also asked patients scheduled for a clinically indicated endoscopy to complete a questionnaire about their family history and their personal GERD symptoms. The original manuscript describing the details of this study was under review at the time of this publication. The unpublished results of this prospective study of 315 first-degree relatives and 360 controls found that advancing age (p = 0.001), male sex (p = 0.005), and GERD symptoms of prolonged duration (p = 0.001) are independent predictors of Barrett’s esophagus. Strikingly, even after adjusting for age, sex, and GERD symptoms, first-degree relatives were over twice as likely to have Barrett’s esophagus compared with controls without such a family history. Reflux esophagitis was frequently found in both relatives and controls who reported weekly GERD symptoms of prolonged duration, who were not using proton pump inhibitors or histamine receptor antagonist medications. Somewhat surprisingly, among people who denied experiencing GERD symptoms, first-degree relatives were three times more likely to have reflux esophagitis compared with controls. This study suggests that a person who has a first-degree relative with long-segment Barrett’s esophagus has an increased chance of having Barrett’s esophagus and reflux esophagitis themselves compared with people who do not have this family history. People with a family history who reported GERD symptoms had the highest chance of having Barrett’s esophagus and reflux esophagitis. Importantly, lack of GERD symptoms did not confer absence of reflux esophagitis or Barrett’s esophagus. People with a family history who denied GERD symptoms still had a moderately high chance of having reflux esophagitis, with a few also having Barrett’s esophagus.
The group of first-degree relatives who participated in this research study have been prospectively followed. Three of these people with a family history of long-segment biopsy-proven Barrett’s esophagus, with or without esophageal adenocarcinoma, who have Barrett’s esophagus themselves, have progressed to esophageal adenocarcinoma in their 50s. This is nearly two decades younger than the average age of diagnosis of sporadic esophageal adenocarcinoma, raising the possibility of germline genetic factors.
In contrast, a separate family study found that the age of diagnosis of esophageal adenocarcinoma was not different in people with a family history of Barrett’s esophagus or cancer compared with people without a known family history.28 These two major studies differed in their criteria for family history. The first study required a family history of long-segment biopsy-proven Barrett’s esophagus, while the second study was more liberal and included people with shorter segment disease. The second study included people with gastroesophageal and tubular esophageal adenocarcinoma, while the first study excluded families with gastroesophageal junction tumors for the theoretical possibility that tumors found at that location might behave more like stomach cancers than reflux-induced esophagus cancer. Importantly, both studies confirmed the importance of obesity as a risk factor for esophageal adenocarcinoma. Currently, at least two large genome-wide collaboratives are in the final stages of reporting their findings in ~5000 cases each (EAGLE using a UK and North European cohort and BEACON using a more dispersed worldwide cohort).
From a collaboration of EAGLE and BEACON – 8,000 patients with Barrett’s and 18,000 controls, we have identified 2 genetic regions predisposing to hereditary predisposition. These genetic regions termed single nucleotide polymorphisms (SNPs) are located on 6p and 16q. This important discovery will lay the foundation for genetic stratification of risk.17
When counseling your patient and their family, it is best to keep the following in mind: The results of the first study have not yet undergone peer review, and their results have not been confirmed by a separate independent group. With these caveats in mind, applying the results of both studies, if three or more members in a family have objective evidence of long-segment Barrett’s esophagus and/or adenocarcinoma of the esophagus, one may consider offering screening endoscopy to other first-degree relatives, especially if the relative reports heartburn or acid regurgitation, and the affected family member with Barrett’s esophagus or cancer was diagnosed before age 50 (young onset disease). Until the results of these studies are confirmed, there is not enough data to support recommending screening endoscopy to relatives who deny GERD symptoms. It is important to remember that the report of difficulty in swallowing (dysphagia) is considered an alarm symptom. People reporting new onset dysphagia, especially if accompanied by a second alarm symptom, unintentional weight loss, should undergo diagnostic endoscopy. Endoscopy prompted to investigate an alarm symptom is not a screening procedure.
Esophageal squamous cell carcinoma
Although extremely rare, there are families in whom multiple members have the squamous cell type of esophagus cancer (as opposed to the adenocarcinoma type of cancer discussed in the Barrett’s esophagus section).29
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