Two distinct aetiologies of cardia cancer, evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status

Background: Non-cardia gastric adenocarcinoma is positively associated with Helicobacter pylori infection\ud and atrophic gastritis. The role of H pylori infection and atrophic gastritis in cardia cancer is unclear.\ud Aim: To compare cardia versus non-cardia cancer with respect to the premorbid state of the stomach.\ud Methods: Nested case–control study. To each of 129 non-cardia and 44 cardia cancers, three controls were\ud matched. Serum collected a median of 11.9 years before the diagnosis of cancer was tested for anti-H pylori\ud antibodies, pepsinogen I:II and gastrin.\ud Results: Non-cardia cancer was positively associated with H pylori (OR 4.75, 95% CI 2.56 to 8.81) and\ud gastric atrophy (pepsinogen I:II ,2.5; OR 4.47, 95% CI 2.71 to 7.37). The diffuse and intestinal histological\ud subtypes of non-cardia cancer were of similar proportions and both showed a positive association with\ud H pylori and atrophy. Cardia cancer was negatively associated with H pylori (OR 0.27, 95% CI 0.12 to\ud 0.59), but H pylori-positive cardia cancer showed an association with gastric atrophy (OR 3.33, 95% CI 1.06\ud to 10.5). The predominant histological subtype of cardia cancer was intestinal and was not associated with\ud gastric atrophy compared with the diffuse subtype ((OR 0.72, 95% CI 0.19 to 2.79) vs (OR 3.46, 95% CI 0.32\ud to 37.5)). Cardia cancer in patients with atrophy had an intestinal: diffuse ratio (1:1) similar to non-cardia\ud cancer (1.9:1), whereas cardia cancers in patients without atrophy were predominantly intestinal (7:1).\ud Conclusion: These findings indicate two aetiologies of cardia cancer, one associated with H pylori atrophic\ud gastritis, resembling non-cardia cancer, and the other associated with non-atrophic gastric mucosa,\ud resembling oesophageal adenocarcinoma. Serological markers of gastric atrophy may provide the key to\ud determining gastric versus oesophageal origin of cardia cancer.