One of the most striking phenomena in cancer in the past 3 decades has been the rapid rise in the incidence of esophageal adenocarcinomas at a time when the incidence of many other common cancers has plateaued and started to decrease.
Similar increases have been noted in Europe as shown here in a study from a Danish registry, and also in Australia
As endoscopist we recognize the normal state of the esophagus is a smooth Z-line and the absence of a hiatal hernia.
We believe refllux and injury often in the presence of a hiatal hernia leads to columnar metaplasia recognizable at endoscopy
Histologically, squamous epithelium is replaced by metaplastic intestinal columnar epithelium. We also know that there is a somewhat stepwise progression from Barrett’s esophagus to cancer. Barrett’s may or may not progress to low grade dysplasia. low grade may or may not progress to high grade; high grade may or may not progress to cancer;
The incidence of Barrett’s remains undefined because the development of Barrett’s is asymptomatic and cannot be monitored. The prevalence of Barrett’s also is poorly defined ranging from as little as 1% to 25%. The reasons for this variability is a lack of true population based endoscopy studies and disagreements even about the very definition of Barrett’s esophagus. In the UK the definition of Barrett’s requires only the presence of columnar metaplasia whereas in the US we require the presence of intestinal metaplasia. Some studies likely include intestinal metaplasia of the cardia in their definition whereas others are more rigorous.
A number of risk factors for both Barrett’s esophagus and esophageal adenocarcinoma have been identified. These include age, gender, race, and family history, factors which cannot be altered. And envrionmental factors such as gastroesophageal reflux, obesity and diet, smoking and alcohol, Helicobacter pylori, and medication use. factors that can be altered.
Esophageal adenocarcinoma is a disease of aging. The mean age of diagnosis in most studies in Europe and the United States is 62 to 64. This is a histogram from our study.
For Barrett’s esophagus we don’t know the age of onset. But from prevalence studies such as this one by Cameron et al. from Olmsted county Mayo Clinic we can guess that Barrett’s likely develops by age 50 at least ten years before the development of cancer.
Both Barrett’s esophagus and esophageal adenocarcinoma `have a strong male dominance. In these 3 studies from the US, Denmark, and Sweden of esophageal adenocarcinoma the ratio of men to women varied from 4 is to 1 to nearly 7 is to 1. These studies from the UK, Italy, and the US that looked at Barrett’s reported lower ratios with a men to women ratio of 1.7, 2.6 or 3 is to 1.
Barrett’s esophagus and esophageal adenocarcinoma are primarily a disease of Caucasians. There is one study by Younes et al. that reported an increase of Barrett’s in Hispanics in the US but this is minor. And there have been reports of a slight rise in Barrett’s in Japan and Asia but the rates are minuscule compared to the rates seen in the US, Europe, and Australia. It remains unclear whether these differences represent underlying genetic differences or environmental differences.
In the best population based case control study to date from Sweden, Lagregren et al. found a striking Adjusted Odds Ration of nearly 8 for the association of Chronic GERD, at least 5 years of symptoms of heartburn or regurgitation and subsequent development of Cancer. Note the other striking finding in this study was that 40% of patients with cancer reported no prior symptoms of reflux.
In this study, the Frequency, Severity, and Duration of GERD symptoms were all associated with an increasing risk of cancer. The adjusted Odds ratios in each category increased gradually with increasing grade.
Many studies have reported on the association of GERD with BE. One study performed by Massimo here in Italy prospectively collecting data from 8 centers. Comparing BE patients with negative controls this study found an odds of 5.8 for Barrets in the presence of weekly GERD symptoms. There was also an increased odds of 3.9 with the presence of a hiatail hernia,
Eisen performed a single center study at Duke on patients undergoing endoscopy. Using two control groups, one with GERD symptoms and no Barrett’s and another with no Barrett’s who had endosocpy for other indications. Controls were matched for age, gender, and race. They found no differences in the presence of heartburn or regurgitation but did find that BE patients had more severe GERD symptoms.
In this Eisen study, the duration of GERD symptoms was the most significant risk for BE. BE patients developed GERD symptoms at an earlier age and had a longer duration of GERD.
Lieberman’s study of a large community based endoscopy database also found that the duration of GERD was the important predictor of BE. The Odds Ration increased from 3 to 5 to 6 as the duration of GERD symptoms increased from less than 1, 1 to 5, 5 to 10, to greater than 10 years.
Obesity is also a risk factor for esophageal adenocarcinoma and Barrett’s esophagus. The challenge with studying obesity and its effect on Barrett’s esophagus or esophageal adenocarcinoma is that as shown by a number of investigators increasing obesity also increases the risk of gastroesophageal reflux symptoms linearly.
In the Swedish population studiy of the association of esophageal cancer with obesity Lagregren et al. found that the association was similar in those with reflux symptoms and those without reflux symptoms. The risk of cancer increased in each quartile of BMI. Thus, it appears that obesity leads to esophageal cancer by predisposing to gastroesophageal reflux and also by mechanisms that are independent of relfux.
There have been a number of studies since then. In this meta-analysis, Corley et al. found that most studies showed a positive association between obesity and esophageal adenocarcinoma. The aggregated Odds of esophageal adenocarcinoma in the presence of obesity in this meta analysis was more like a 2 fold increased risk.
In our own study determining factors that lead to early onset of disease, we found that esophageal adenocarcinomas were diagnosed at an earlier age in cancer patients with a history of obesity compared to those with no history of obesity.
The association of Barrett’s esophagus and obesity is more complex. In a case control study in the California Kaiser population of Barretts patients Doug Corley and his group found that central adiposity defined by waist circumference > 80 cm had a 2,24 fold greater odds of Barrett’s esophagus than population controls. In this study Body Mass Index was not a predictor of Barrett’s esophagus.
Vaughan et al. published another case control study comparing BE cases with population controls. Increased BME was not associated with BE but central adiposity measured by waist hip ratio was associated with an increased odds of 4.1 for BE,
Again, the association of central adiposity with BE was independent of reflux symptoms.
Neither smoking nor alcohol appear to be strong risk factors for Barrett’s or esophageal adenocarcinoma. In a Case Control study from Southern US surveying white men with esophageal and junctional adenocarcinoma versus matched controls, Brown found a mild to moderate odds of 2.1 for smoking cigarettes but no increase in the odds for alcohol. Note the fairly wide confidence interval ranging from 1.2 to 3.8
Gammon did a multicenter pupulation based case control study from the US with far larger numbers. Similar results. Increased odds for esophageal adenocarcinoma with smoking about 2 and no association with alcohol
Massimo’s study from Italy looking at Barretts found, no association between alcohol or smoking.
A number of cohort and case control studies have noted a protective effect of aspirin and non-steroidals on the development of esophageal adenocarcinoma. Prostaglandin E2 associated with inflammation leads to increased proliferation and decreased apoptosis. Inhibition of prostglandins with asprini or non-steroidals in the laboratory decreases proliferation of cell lines. In this meta-analysis published by Doug Corley, aspirin or NSAIDs had a protective effect in these six studies with a combined effect ratio of 0.6.
Lagrgren et al. also performed a case control population based Swedish study evaluating medications that lower LE sphincter pressure such as nitrates and calcium channel blockers. Increased use of these medications was indeed associated with an increased Odds of esophageal adenocarcinoma, an Odds Ratio of 1.8 for any use of such medication and an Odds of 2.4 if the medications had been used for more than 5 years. But when they adjusted the analysis for presence of GERD symptoms they did not see an effect. So the association of medications that lower esophageal sphincter pressure with esophageal adenocarcinoma is indeed mediated by the fact that these medications lead to increased reflux.
Finally, the association of H. pylori with Barretts and esophageal adenocarcinoma is intriguing and remains unresolved. Chronic fundic gastritis from H. pylori is theorized to lead to reduced reflux and is proposed to be protective against Barrett’s and esophageal adenocarcinoma. In this case control study from the Kansas VA, Weston et al. found a higher prevalence of H. pylori gastritis in a GERD control group than Barrett’s patients with high grade dysplasia or cancer.
The Cleveland Clinic group moved this field further by looking at the specific strain of H. pylori. They found that the Cag A positive H. pylori strains were protective against the development of Barrett’s esophagus. Patients with long segment Barrett’s were very unlikely to have Cag A poistive H. pylori. Other studies however have not found a protective association between H. pylori and Barretts esophagus so the jury is still out.
So what lessons can we learn from this mountain of data on the epidemiology and risk factors for Barrett’s esophagus and esophageal adenocarcinoma. First, if we are going to develop screening programs it would be reasonable to target white men over the age of 50. Perhaps those who have chronic reflux symptoms greater than 5 years. The advantage to examining those with reflux is they are a higher risk group and more likely to have endoscopy because they have symptoms. The disadvantage is that we will miss nearly 40% of those who will go on to cancer. The other question that arises is do these factors explain the rise in incidence of adenocarcinoma and give us targets for intervention. Factors that have changed in the last 3 decades are obesity had gone up, calcium channel blocker use has gone up, and H. pylori has been increasingly eradicated. But we have no causal proof that any of these factors are responsiblel and thus it is hard to recommend an intervention. Finally, what interventions are reasonable to recommend for our patients with Barrett’s. More and more I try to stress weight loss as an intervention over GERD therapy. In those who smoke it also gives me an opportunity to discuss smoking cessation. These are interventions that can help overall health.
A. Chak - Slide 1
Epidemiology and Risk Factors for Barrett’s Esophagus and Esophageal Adenocarcinoma Amitabh Chak, MD University Hospitals Case Medical Center Cleveland, OH
Pohl, H. et al. J Natl Cancer Inst 2005;97:142-146 EAC melanoma prostate breast/lung colon
Men:Women Ratio in EAC and BE Country (N) Disease M:W Gammon et al., JNCI, 1992 USA 293 EAC 5:1 Byzer et al., AJG 1999 Denmark 524 EAC 4:1 Lagergren, et al. NEJM 1999 Sweden 189 EAC 6.7:1 Caygill et al., AJG 2002 UK 507 BE 1.7:1 Conio et al., IJC, 2002 Italy 149 BE 3:1 Rex, et al., Gastro 2003 USA 65 BE 2.6:1
Race Predominance <ul><li>Primarily Caucasian diseases - Majority of studies report > 90% of BE and EAC patients are Caucasians </li></ul><ul><li>Younes et al. reported an increase of BE in Hispanics in US </li></ul><ul><li>Although there are reports of increasing BE and EAC in Japan it is very small compared to US/Europe/Australia </li></ul><ul><li>Unclear whether race predominance represents a genetic or environmental factor </li></ul>
Chronic GERD and EAC (Lagergren, et al. NEJM 1999) Multivariate adjustment for age. Sex, BMI, smoking, etc.
ASA/NSAIDs and EAC (Corley et al., Gastro 2003)
LES Lowering Meds and EAC (Lagergren, et al. AIM 2000)
H. Pylori and BE/EAC (Weston et al., AJG 2000)
Strain Specific H. pylori (Vaezi et al., AJG 2000)
Implications of Epidemiological Associations <ul><li>Selection of screening population </li></ul><ul><ul><li>Consider screening of white men > 50 with GERD symptoms of greater than 5 years </li></ul></ul><ul><li>Possible explanations for rising incidence of EAC </li></ul><ul><ul><li>obesity, meds that lower LES, eradication of H. pylori </li></ul></ul><ul><li>Interventions for patients with BE </li></ul><ul><ul><li>Weight loss, smoking cessation, GERD therapy </li></ul></ul>