Aspects on the etiology of esophageal and gastric cancer

In a global perspective esophageal and gastric cancer present major health concerns, whereas these tumors are comparatively uncommon in most western countries. Striking and hitherto unexplained rising incidence trends of esophageal adenocarcinoma, and moderately increasing rates of gastric cardia adenocarcinoma have recently been reported from several western countries, however. Given the poor prognosis of these tumors, persisting regardless of decades of attempts to improve the treatment and diagnostic procedures, identification of key etiological factors that can reveal possible preventive actions could be of utmost importance to decrease the mortality in these diseases.

However, the rising trends of esophageal and gastric cardia adenocarcinoma reported are based on information recorded in cancer registers only and could, at least in part, be due to tumor misclassification in these registers. Therefore, the first paper evaluated the diagnostic accuracy of these tumors in the Swedish Cancer Register, by comparing the thorough, uniform and prospective tumor classification in a nationwide case-control study with the classification in the Cancer Register, which is based on routine clinical practice. Among 757 cases included, we found an excellent overall completeness of the Cancer Register of 98.3%, while the site-specific accuracy was only 63% for esophageal adenocarcinoma, 74% for gastric cardia adenocarcinoma, and 91% for esophageal squamous-cell carcinoma. The increasing incidence rate of esophageal adenocarcinoma in Sweden did not seem to be explained by sub-site inaccuracies of the tumors in the Swedish Cancer Register, however.

The unique global pattern of a male predominance in gastric cancer remains unexplained. The second paper tested the hypothesis that the female sex hormone estrogen prevents gastric cancer in a nationwide historical cohort study of men heavily exposed to estrogen, i.e. men with prostate cancer diagnosed before the 1980s. In 515,961 person-years of follow-up, we found a significant 13% decreased risk among cohort members exposed to estrogen in a seemingly dose-dependent manner. Hence, estrogen might play a role in the etiology of gastric cancer.

Risk factors for esophageal and gastric cancer were investigated in paper three and four. We conducted a prospective nested case-control study to in a large database in the United Kingdom. Among 4,340,207 person-years of follow-up, we identified 909 esophageal cancer cases, 1023 gastric cancer cases, and 10,000 control subjects. We found an inverse association between use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) and gastric cancer, but not with esophageal cancer. A predetermined set of upper gastrointestinal disorders seemed to distort the association between NSAIDs and esophageal and gastric cancer. If this is true, previous findings that NSAIDs reduce the risk of these tumors might, at least partly, be explained by lack of appropriate adjustments for such disorders. Moreover, we revealed that overweight increases the risk of both esophageal and gastric cardia adenocarcinoma in a dose-dependent manner, whereas no such association was found with esophageal squamous-cell carcinoma or non-cardia gastric adenocarcinoma. Tobacco smoking increases risk of esophageal cancer of both main histological subtypes and gastric cancer independent of subsite. Alcohol consumption was associated with an increased risk of esophageal squamous-cell carcinoma, but not with the other tumors studied.

List of scientific papers

I. Lindblad M, Ye W, Lindgren A, Lagergren J (2004). The misclassification of esophageal and cardia cancer and its influense on incidence rates. [Submitted]

II. Lindblad M, Ye W, Rubio C, Lagergren J (2004). Estrogen and risk of gastric cancer: A protective effect in a nationwide cohort study of prostate cancer patients in Sweden. Cancer Epidemiol Biomark. [Accepted]

III. Lindblad M, Lagergren J, García Rodríguez LA (2004). Nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiol Biomark. [Accepted]

IV. Lindblad M, García Rodríguez LA, Lagergren J, (2004). Body mass, tobacco and alcohol and risk of esophageal, gastric cardia, and non-cardia gastric adenocarcinoma among men and women in a nested case-control study. Cancer Causes Control. [Accepted]