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© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE Re: Etiology of Pancreatic Cancer, With a Hypothesis Concerning the Role of N-Nitroso Compounds and Excess Gastric Acidity
Harvey A. Risch, MD, PhD, Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College St., POB 208034, New Haven, CT 06520–8034 (e-mail: harvey.risch{at}yale.edu)
I thank Dr. Capurso and colleagues for their observations concerning the etiologic hypotheses I presented in my review of gastric pathophysiology, Helicobacter pylori, nitrite exposures, and pancreatic cancer. Studies in the literature provide a lot of suggestive evidence but are certainly not definitive for the hypotheses, and interpretations other than the ones I proposed are possible.
Capurso et al. mention two areas of potential controversy. The first concerns the relation between chronically increased gastric acid secretion and risk of pancreatic cancer. In support of this association, I cited studies of individuals with a history of duodenal ulcers, as well as studies of persons who had undergone gastrectomy for duodenal ulcer treatment. Capurso et al. are correct that gastrectomy usually decreases gastric acid output. Furthermore, duodenal ulcer patients treated with vagotomy and gastrojejunostomy or pyloroplasty can have elevated gastric nitrites and N-nitroso compounds that could be the reason for their increased risk of pancreatic cancer. However, as I noted in the review, a number of case–control studies examining only a history of duodenal ulcers, without considering gastrectomy, have shown an increased risk of pancreatic cancer.
Second, Capurso et al. state that pernicious anemia is associated with risk of pancreatic cancer. Although there have been two reports linking pernicious anemia and risk (1,2), most studies of this relation, in fact, have not shown appreciable association, unlike the known association with gastric cancer [reviewed in (2)]. Pernicious anemia is frequently the end result of H. pylori–induced corpus atrophic gastritis in hosts carrying inflammatory cytokine genetic variants that are associated with the suppression of gastric acid production. This syndrome favors the risk of gastric cancer rather than pancreatic cancer, and it must be distinguished from other causes of pernicious anemia to determine whether a relationship between those forms of pernicious anemia and pancreatic cancer exists.
Capurso et al. speculate that hypergastrinemia rather than excess gastric acidity might explain the various features of gastric pathology and the risk of pancreatic cancer. This hypothesis was originally proposed by Borch et al. (2). To start with, it seems unlikely that gastrin, which has sequence homology within the gastrin–cholecystokinin (CCK) family, would have relevant hormonal effects on pancreatic ductular epithelial cells. Gastrin receptors are apparently not present on normal ductular epithelium (3). Although not without some criticism, a case–control study did not find that serum levels of gastrin and CCK were associated with risk of pancreatic cancer (4). Associations with hypergastrinemia can be distinguished from those with hyperchlorhydria when parietal cell gastric acid production itself is suppressed, allowing negative feedback hypergastrinemia. This effect occurs in H. pylori–related and other types of corpus atrophic gastritis and with use of histamine-receptor antagonists and proton-pump inhibitors (5). At least in the rat azaserine acinar cell cancer model, proton-pump inhibitors have not been associated with increased tumor development (5). Further work in ductal carcinoma models is needed.
One last piece of evidence bearing upon the issue of hypergastrinemia versus hyperchlorhydria involves chronic aspirin use. Acute intravenous aspirin administration suppresses secretin-induced pancreatic bicarbonate and fluid output. However, long-term use or high levels of aspirin intake cause gastric inflammation, which disinhibits acid production while not increasing gastrin secretion (6). A recent report (7) from the Nurses’ Health Study found that extended periods of regular aspirin use were statistically significantly associated with dose–response increases in risk of pancreatic cancer. Thus, excess gastric acidity, rather than elevated gastrin secretion, appears to be responsible for increased risk of pancreatic cancer.
REFERENCES
1 Hsing AW, Hansson LE, McLaughlin JK, Nyren O, Blot WJ, Ekbom A, et al. Pernicious anemia and subsequent cancer. A population-based cohort study. Cancer 1993;71:745–50.[CrossRef][Web of Science][Medline]
2 Borch K, Kullman E, Hallhagen S, Ledin T, Ihse I. Increased incidence of pancreatic neoplasia in pernicious anemia. World J Surg 1988;12:866–70.[CrossRef][Web of Science][Medline]
3 McDonald JM, Longnecker DS, Bell RH Jr. Effect of hypergastrinemia on pancreatic carcinogenesis. Am J Surg 2002;183:441–4.[Medline]
4 Weinberg DS, Heyt GJ, Cavanagh M, Pitchon D, McGlynn KA, London WT. Cholecystokinin and gastrin levels are not elevated in human pancreatic adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2001;10:721–2.
5 Qvigstad G, Arnestad JS, Brenna E, Waldum HL. Treatment with proton pump inhibitors induces tolerance to histamine-2 receptor antagonists in Helicobacter pylori-negative patients. Scand J Gastroenterol 1998;33:1244–8.[CrossRef][Web of Science][Medline]
6 Hamlet A, Lindholm C, Nilsson O, Olbe L. Aspirin-induced gastritis, like Helicobacter pylori-induced gastritis disinhibits acid secretion in humans: relation to cytokine expression. Scand J Gastroenterol 1998;33:346–56.[Medline]
7 Schernhammer E, Kang JH, Chan AT, Michaud DS, Skinner HG, Giovannucci E, et al. A prospective study of aspirin use and risk of pancreatic cancer in women. Cancer Epidemiol Biomarkers Prev 2003;12:1292S.
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J Natl Cancer Inst 2003 95: 948-960.
J Natl Cancer Inst 2004 96: 75.
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