Upper gastrointestinal adenocarcinoma : associations with gastric secretory function and gender

Gastric and oesophageal cancers were responsible for more than one million deaths in 2002. Although global incidence of gastric cancer is decreasing, this malignancy is still the fourth most common cause of cancer worldwide. The incidence of oesophageal adenocarcinoma is rising rapidly, three-fold in the last two decades. The incidence of adenocarcinoma of gastric cardia is stable. In the pathogenesis of both gastric and oesophageal adenocarcinomas, the state of the gastric mucosa and its secretory function plays a central role. Non-cardia adenocarcinoma develops in subjects with H.pylori associated atrophic gastritis and hypochlorhydria. Little is known about the gastric phenotype in patients with adenocarcinoma of the cardia and gastroesophageal junction. Another important but poorly understood risk factor for upper GI adenocarcinoma is male gender. In the first study we aimed to investigate the association between the pattern of H.pylori gastritis and gastric secretory function in 255 H.pylori-infected patients with dyspepsia showing normal endoscopy. Our findings showed that maximal acid output correlates inversely with severity of corpus gastritis, corpus atrophy, and positively related to male gender and serum pepsinogen I. In the second study we compared cancers at the cardia and non-cardia subsites with respect to pre-morbid gastric mucosal atrophy and acid secretion. In a nested case-control study comprising 101,601 men and women enrolled in the Norwegian JANUS cohort, 230 cases of gastric cancer were identified. 173 cases including 144 non-cardia and 44 cardia cancer were enrolled to study. Three controls were matched to each case. Serum pepsinogen I, pepsinogen II, anti-H.pylori IgG antibody and gastrin were measured using serums which had been collected a median of 11.9 years before cancer diagnosis radioimmunoassay method. Non-cardia cancer was positively associated with H.pylori and gastric atrophy. The diffuse and intestinal histological subtypes of non-cardia cancer were of similar proportions and both showed a positive association with H.pylori and atrophy. Cardia cancer was negatively associated with H.pylori, but H.pylori positive cardia cancer showed a positive association with gastric atrophy. The predominant histological subtype of cardia cancer was intestinal and it was not associated with gastric atrophy compared to the diffuse subtype. Cardia cancer in atrophic patients had an intestinal: diffuse ratio similar to non-cardia cancer, whereas cardia cancers in persons without atrophy were predominantly intestinal. These findings indicate two aetiologies of cardia cancer, one associated with H.pylori atrophic gastritis, resembling non-cardia cancer, and the other associated with non-atrophic gastric mucosa, resembling oesophageal adenocarcinoma. Serological markers of gastric atrophy may provide the key to determining gastric versus oesophageal origin of cardia cancer. In the third study we extended our investigation of the aetiology of cardia cancer by examining the association of both serological evidences of gastric atrophy and gastroesophageal reflux disease (GORD) symptoms with adenocarcinoma of the oesophagus, cardia and non-cardia regions of the stomach. This has been performed for the different histological subtypes of the cancer. We have also included H.pylori status and smoking history which are other well established risk factors for upper GI cancer. This has been undertaken in a population in Northwest Iran with a high incidence of upper gastrointestinal cancer. Serum pepsinogen I/II was used as a marker of atrophic gastritis and categorised to five quintiles. History of GORD symptoms, smoking and H.pylori infection was incorporated in logistic regression analysis. Lauren classification was used to subtype gastric and oesophageal adenocarcinoma. Non-cardia cancer was associated with atrophic gastritis but not with GORD symptoms; 55% of these cancers were intestinal subtype. Oesophageal adenocarcinoma was associated with GORD symptoms, but not with atrophic gastritis; 84% were intestinal subtype. Cardia cancer was positively associated with both severe gastric atrophy and with frequent GORD symptoms though the latter was only apparent in the non-atrophic subgroup and in the intestinal subtype. The association of cardia cancer with atrophy was stronger for the diffuse versus intestinal subtype and this was the converse of the association observed with non-cardia cancer. These findings indicate two distinct aetiologies of cardia cancer, one arising from severe atrophic gastritis and being of intestinal or diffuse subtype similar to non-cardia cancer, and one related to GORD and intestinal in subtype, similar to oesophageal adenocarcinoma. Gastric atrophy, GORD symptoms and histological subtype may distinguish between gastric versus oesophageal origin of cardia cancer. In the fourth study we investigated the relationship between gender and upper gastrointestinal adenocarcinoma. Male gender is a well-established risk factor for oesophageal adenocarcinoma. Male predominance of gastric cancer is related to the histological subtype of the tumour being more marked in the intestinal versus diffuse histological subtype. In addition, global data suggests that the male predominance of upper gastrointestinal cancer is related to the anatomical location, being higher for proximal and lower for distal tumours. However, the proportion of the intestinal histological subtype differs according to anatomical site and it is unclear whether it is the anatomical site or the histological subtype which is associated with the gender phenomenon. We have conducted a population-based study to investigate this. The study was based upon 3270 gastric and oesophageal cancers recorded in West of Scotland Cancer Registry between 1998 and 2002. The Lauren subtype of adenocarcinoma was determined by reviewing 1204 reports and 3241 slides in a sample of 812 cases. Logistic regression models were used to estimate relationship between male predominance and histological subtype, tumour location and age. We found that the crude incidence rate of intestinal subtype was higher in males (23.86/ 100,000 person-years) versus females (9.00/ 100,000 person-years), giving M/F of 2.65. M/F ratio of intestinal subtype cancer was 3.41 at age <50, reached a peak of 7.86 at age 50-59, and then showed a progressive decrease throughout the life. In contrast, the incidence rate of diffuse subtype adenocarcinoma was similar in both sexes (5.58 vs. 5.20 /100,000 person-years) yielding M/F of 1.07. Multivariate analyses including histological subtype, tumour location and age indicated that the male predominance was related to the histological type rather than anatomical location. Intestinal type tumour showed similar male predominance of incidence irrespective of its anatomical location (OR, 95% CI: 2.6, 1.78 – 3.9). Further analysis of the age-specific incidence curves indicated that the male predominance of intestinal subtype was due to a 17.2-year delay of development of this cancer in females.