Risk Factors in the Development of Esophageal Adenocarcinoma

Heiko Pohl MD; Katharina Wrobel MD; Christian Bojarski MD; Winfried Voderholzer MD; Amnon Sonnenberg MD; Thomas Rösch MD; Daniel C Baumgart MD


Am J Gastroenterol. 2013;108(2):200-207. 

In This Article

Abstract and Introduction


Objectives It is assumed that esophageal adenocarcinoma is the end result of a stepwise disease process that transitions through gastroesophageal reflux disease (GERD) and Barrett's esophagus. The aim of this study was to examine at what stage known risk factors exert their influence toward the progression to cancer.

Methods We enrolled 113 consecutive outpatients without GERD, 188 with GERD, 162 with Barrett's esophagus, and 100 with esophageal adenocarcinoma or high-grade dysplasia (HGD). All patients underwent a standard upper endoscopy and completed a standardized questionnaire about their social history, symptoms, dietary habits, and prescribed medications. We used adjusted logistic regression analysis to assess risk factors between each two consecutive disease stages from the absence of reflux disease to esophageal adenocarcinoma.

Results Overall, male gender, smoking, increased body mass index (BMI), low fruit and vegetable intake, duration of reflux symptoms, and presence of a hiatal hernia were risk factors for cancer/HGD. However, different combinations of risk factors were associated with different disease stages. Hiatal hernia was the only risk factor to be strongly associated with the development of GERD. For GERD patients, male gender, age, an increased BMI, duration of reflux symptoms, and presence of a hiatal hernia were all associated with the development of Barrett's esophagus. Finally, the development of cancer/HGD among patients with Barrett's esophagus was associated with male gender, smoking, decreased fruit and vegetable intake, and a long segment of Barrett's esophagus, but not with age, BMI, or a hiatal hernia.

Conclusions While some risk factors act predominantly on the initial development of reflux disease, others appear to be primarily responsible for the development of more advanced disease stages.


Esophageal adenocarcinoma has been increasing in the United States more than six-fold over the past three decades.[1] The reasons for this steep increase are unknown. Several risk factors have been identified, including age, male gender, white ethnicity, history of reflux disease, a high body mass index (BMI), a low fruit and vegetable intake, the presence of a hiatal hernia, and the absence of H. pylori infection.[2,3,4,5,6,7] Because each individual risk factor is common it has been difficult to identify a population at high risk for progression to cancer.

It is assumed that the development of esophageal adenocarcinoma follows a stepwise progression from no reflux disease to reflux disease, from reflux disease to Barrett's esophagus, and from Barrett's esophagus to cancer. This assumption is based on animal studies, in which pathological acid reflux was a prerequisite for the development of cancer.[8] The assumption is further supported by population-based studies that found an association between reflux disease and esophageal adenocarcinoma.[9,10,11] Barrett's esophagus is considered as a premalignant condition for the development of esophageal adenocarcinoma with an estimated annual transition rate to cancer between 0.12 and 0.5%.[2,12,13,14] Although it is likely that reflux disease precedes Barrett's esophagus, and that Barrett's esophagus precedes cancer, only very few patients with reflux disease will progress to Barrett's esophagus and only few patients with Barrett's esophagus will ever progress to cancer.

Risk factors that have been identified for the overall progression to cancer, where the general population was used as the reference group, may pose a risk for an intermediary stage, but possibly less so for the final transition stage from Barrett's esophagus to cancer. It is not well known to what extent known risk factors are responsible for the development of different disease stages from the absence of reflux disease to cancer. In this study, we recruited a large group of patients with and without reflux disease, with Barrett's esophagus, and with esophageal adenocarcinoma who were referred for an endoscopy. We assessed the risk factors for different disease stages on the path to esophageal adenocarcinoma. The aim of this study was to examine which risk factors to what extent influence different disease stages, ranging from the absence of reflux disease to gastroesophageal reflux disease (GERD), Barrett's esophagus, and esophageal adenocarcinoma.