In our study, gastric ulcer was associated with an increase in risk of pancreatic cancer. The elevated risk persisted 10–19 years after gastric ulcer diagnosis. In contrast, duodenal ulcer was not associated with pancreatic cancer risk.
The positive relation between gastric ulcer and pancreatic cancer risk might be explained by excess nitrosamine formation associated with gastric ulcer. Nitrosamines induce pancreatic cancer in animals and are considered potential human pancreatic carcinogens 6
. Tobacco smoke, a strong risk factor of pancreatic cancer, contain high levels of nitrosamines 7
. Besides exogenous exposure from cigarette smoke, the main source of human exposure to nitrosamines comes from endogenous formation by a number of bacterial strains in the oral cavity and the gastrointestinal tract 30
. Periodontal disease and H. pylori
infection have been hypothesized to influence pancreatic carcinogenesis through greater endogenous nitrosation 3, 30
. Another piece of evidence supporting nitrosamine hypothesis comes from a strong association between gastrectomy and pancreatic cancer risk. Patients who had undergone partial gastric resection for benign conditions such as peptic ulcer disease have extremely high concentration of intragastric nitrosamines 10
, probably due to bacterial overgrowth secondary to postoperative hypochlorhydria; these individuals also have increased pancreatic cancer risk 20 or more years after the surgery 20, 31–33
. Gastric ulcer patients have low acid output 9
and the neutral pH allows for bacterial colonization and nitrosation 10, 34
which leads to elevated intragastric nitrosamine concentrations. It is possible that bacterially catalyzed nitrosamines are transported via the bloodstream to the organs (such as pancreas) where they could induce DNA damage, stimulate DNA synthesis and eventually cause tumor development 35, 36
. A previous analysis in the HPFS 3
, which demonstrated an increase risk of bladder cancer with gastric ulcer, also suggests that gastric ulcer might be a source of nitrosamines and hereby involved in carcinogenesis. In addition, we observed in the present study that high intakes of vitamin C and E, two blockers of nitrosamine formation, may have attenuated the positive association of gastric ulcer with pancreatic cancer.
An alternative explanation for the association between gastric ulcer and pancreatic cancer risk might be the inflammatory response related to H. pylori
infection and the ulcer healing process. Chronic inflammation involves generation of pro-inflammatory cytokines that can be delivered through the circulation , which might contribute to pancreatic carcinogenesis 37
. Since the majority of ulcer patients are infected with H. pylori
and ulcer healing is an inflammatory process 38
, gastric ulcers may lead to systemic inflammation by increasing secretion of inflammatory mediators and thereby increase risk of pancreatic cancer. However duodenal ulcer, also involving inflammation, was not associated with risk of pancreatic cancer in our study, but gastric ulcer and duodenal ulcer have different pathophysiologies 9 and therefore might have different inflammatory response patterns. Although no evidence so far showed differences in the inflammatory response between these two ulcers, we can not entirely rule out the possibility that inflammatory response is partly responsible for the increased risk with gastric ulcer, since there is not much research being conducted to examine differences in inflammatory response patterns of these two ulcers and there are still so many unanswered questions in terms of biological mechanisms.
Unlike gastric ulcer, duodenal ulcer is largely a disease of acid hypersecretion 9
. Because duodenal ulcer was not related to risk of pancreatic cancer in the present study, hyperacidity is not likely to play a crucial role in the initiation of pancreatic cancer.
Similar results were found in a large cohort study conducted in Sweden 11
. In that register-based study, gastric ulcer but not duodenal ulcer was associated with a modest increase in risk of pancreatic cancer. After a peak in risk during the first 2 years of follow-up (RR, 4.8; 95% CI, 4.2 – 5.5), gastric ulcer was associated with 20% (95% CI, 1.1 – 1.4) excess risk for pancreatic cancer during year 3–38 of follow-up. The risk increased with follow-up duration and reached 1.5 after 10 years (p value for trend test=0.03). However, they were not able to adjust for cigarette smoking, a potential confounding factor which could bias estimates upwards. Several case-control studies 12, 17, 20, 21
also had information on the types of ulcer and examined their associations with the risk. No associations were found with gastric ulcer 12, 17, 20, 21
and most observed null associations with duodenal ulcer 17, 20, 21
, with one exception 12
The strengths of the present study included a relatively large number of cases of pancreatic cancer, a long follow-up duration, the assessment of the time-dependent effect of ulcer occurrence, and extensive information on potential confounders. The repeated measurement on ulcer occurrence was an advantage because it allowed for the opportunity to account for changes in ulcer status over time. The cohort design and relatively complete follow-up minimized selection bias in this study.
One of the major concerns of the study was that ulcer diagnoses were self-reported. Misclassification of ulcer location (gastric versus duodenal) or confusion with other gastrointestinal diseases, such as gastritis and duodenitis, was possible. However, men in this cohort were health professionals and have been shown in this cohort to accurately report many medical conditions 3, 39
. Self- reporting of ulcer occurrence was reasonably accurate in the cohort: among men for whom we were able to retrieve medical records during 1988–2002, only 23% of the self-reported ulcers were rejected after medical record review. Conceptually, even if reported gastric ulcers were mixed with gastritis, the findings still support evidence for the inflammation and nitrosamine hypotheses, because gastritis is also accompanied by an inflammatory response and nitrosamine formation 40, 41
. In addition, the relative risk estimates for ulcers diagnosed between 1987–2002, which were confirmed by endoscopy, were similar to those in the primary analysis which combined self-reported baseline ulcers and confirmed follow-up ulcers. Furthermore, ulcer misclassification in this study is likely to be nondifferential given the prospective design, leading to underestimation of the true association given the binary exposure. Our misclassification analysis showed that the association with gastric ulcer was strengthened after correction for measurement error; therefore, misclassification of ulcer location is unlikely to explain the positive association with gastric ulcer we found in the primary analysis. Nonetheless, non-differential misclassification due to remote recall of ulcer occurrence and lack of endoscopic equipment at that time remained an alternative explanation for the lack of significant association among men who had gastric ulcer before 1974 or before age 40 or among men with gastric ulcer followed for more than 20 years.
Another concern is that by the time that peptic ulcers were diagnosed, pancreatic cancer might have had already existed given its insidious onset and non-specific early symptoms. It is also possible that peptic ulcers were an early symptom or consequence of pancreatic cancer. To rule out the reverse temporal relationship, we conducted a sensitivity analysis by excluding the first 2 years of follow-up because pancreatic cancer is a fast-growing malignancy with a median survival of less than 5 months. The results were not materially changed. In addition, the risk of pancreatic cancer remained significantly elevated 10–19 years after gastric ulcer diagnosis.
Antacids, H2 receptor antagonists and proton-pump inhibitors are the main treatment for peptic ulcers and may mediate the effects of ulcers on pancreatic cancer. In the primary analysis, we found no association of H2-blocker use with pancreatic cancer and the risk estimates remained unchanged after adjusting for H2-receptor antagonists, indicating that the ulcer effects are not mediated by these drugs. Although we cannot control for antacids due to lack of information, they would not be able to explain the divergent effects observed with two types of ulcers because antacids are used indiscriminately for gastric and duodenal ulcers. Proton-pump inhibitors were not introduced into clinical practice until 1988, thus they are not likely to be responsible for any associations found before baseline.
Because of the substantial overlap between gastric ulcer and duodenal ulcer among pancreatic cancer cases, we had very limited power to estimate the risk and examine the time-dependent effect for those with only gastric ulcer (11 pancreatic cancer cases) or for those with only duodenal ulcer (21 pancreatic cancer cases). For most analyses, the exposure was ever having gastric/duodenal ulcer, i.e., individuals with both ulcers (9 pancreatic cancer cases) were included in the gastric ulcer group and in the duodenal ulcer group. Although gastric ulcer and duodenal ulcer were mutually adjusted, it might not be enough and the observed associations could partially reflect greater exposure where both ulcers occurred.
Residual confounding is probably of minor importance because risk estimates were similar for age-adjusted models and multivariable models. Particularly, the observed positive association with gastric ulcer was not likely to be due to confounding by cigarette smoking because the association remained significantly elevated among never smokers. The association among ever smokers was weaker probably because of the high background level of nitrosamines from smoke in these individuals. Unmeasured confounding by potential risk factors for pancreatic cancer, including history of chronic pancreatitis, family history of pancreatic cancer and low socioeconomic status, cannot be completely ruled out. However, the prevalence of chronic pancreatitis in the general population is very low, ranging from 0.04 to 5% in different geographic regions 42
, and its relation with peptic ulcers remains unclear. Similarly, family history of pancreatic cancer is uncommon and no evidence has linked it to peptic ulcer disease. Although socioeconomic status may be related to both ulcer and pancreatic cancer, our cohort is relatively homogeneous with all the members being health professionals.
In conclusion, gastric ulcer was strongly associated with pancreatic cancer risk in our study, suggesting that intragastric N-nitrosamine formation might be an important mechanism in pancreatic carcinogenesis. Lack of association for duodenal ulcer, on the other hand, is consistent with a less crucial role of hyperacidity in the development of pancreatic cancer.