We found a strong monotonically increasing association between BMI and the risk of esophageal adenocarcinoma; compared to subjects with a normal BMI of 18.5-25, we saw significantly and progressively increased risk for subjects in BMI categories of 25-<30, 30-<35, and ≥ 35. For gastric cardia adenocarcinoma, compared to our referent group, there was no increased risk for subjects with a BMI of 25-<30, but risk was significantly increased in subjects with BMIs of 30-<35 and for those with a BMI ≥ 35. We found no clear pattern of association between increasing BMI and risk of gastric noncardia adenocarcinoma using either categorical or nonlinear continuous models.
Case-control studies have consistently shown an association between higher BMI and increased risk of EADC (12
). This association has also been reported in three prospective studies (14
), which lacked or had limited information on potentially important confounders. The consistency between the results of the current study and previous reports suggest that the theoretical limitations of those studies did not preclude them from obtaining the same general results as this prospective study. When reported, the association between BMI and gastric cardia adenocarcinoma has been weaker than that for EADC (8
The association between BMI and gastric noncardia adenocarcinoma has not been consistently seen in previous studies, with several studies showing no association (10
) and one showing significantly increased risk with increasing BMI among women (22
). Reduced risk of gastric noncardia adenocarcinoma with increasing BMI has been seen in at least one prospective study of a lean population in China (23
). In the Nutrition Intervention Trial cohort from Linxian, China the 25th
percentiles of BMI were 20 and 23 kg/m2
. A BMI greater then 23 was associated with a 32% decreased risk of gastric noncardia adenocarcinoma compared to subjects with a BMI <20 (23
). Another study showed significantly decreasing risk of gastric noncardia adenocarcinoma with increasing BMI among lean subjects at the time of diagnosis, but the risk increased among subjects with a BMI >26 (24
EADC and gastric cardia adenocarcinoma are adjacent tumors that are difficult to separate clinically and are thought to have similar risk factors. Misclassification of the site of the tumor origin is almost certain to occur (6
). Several groups have proposed novel classification systems that seek to more consistently group tumors at or near the gastro-esophageal junction (7
). The SEER classification system based on current ICD-O codes for upper gastrointestinal adenocarcinomas has been used to demonstrate the changing incidence trends (1
) and we used the same classification system in our study. We found similar associations between BMI and risk of EADC compared to gastric cardia adenocarcinoma in the highest BMI category, but our nonlinear models produced different curves at the low end of the BMI range. Our results coupled with the differences in the time trends for cancer incidence for EADC and gastric cardia adenocarcinoma suggest that is useful to maintain the current distinction between the tumor sites for etiologic studies, especially given that the necessary clinical information is not routinely available from cancer registries (25
The use of nonlinear models revealed an important aspect of the association between higher BMI and esophageal adenocarcinoma. Most previous studies have relied solely on categorical analyses using either the WHO classifications of BMI or population quantiles. In these studies, and in our categorical analysis, the entire range of normal BMI is used as the reference group. This method of modeling eliminates the possibility of understanding the association between BMI and EADC within the normal range. A recent study of BMI and gastro-esophageal reflux disease demonstrated an essentially linear association between increasing BMI and gastro-esophageal reflux disease, even across the normal BMI range (26
). Likewise, our nonlinear models suggest that higher BMI is associated with increased risk of EADC even in subjects that are not classified as overweight or obese.
To our knowledge, our study is the largest prospective study of the association between BMI and EADC to date with complete information on important confounders such as smoking and had nearly complete follow-up. On the other hand, we relied on self-reported rather than measured weight and height.
In summary, in this prospective cohort study, we found a clear, monotonic association showing an increased risk of EADC with increasing BMI, which conforms well to previous case-control study results. The associations between increasing BMI and risk of EADC and gastric cardia adenocarcinoma were distinct from each other.