Cancer Prevention and Health Disparities Among Minorities

Helicobacter pylori and Gastric Cancer

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Martin J. Blaser,MD
Frederick H. King Professor of Internal Medicine
Chairman, Department of Medicine and Professor of Microbiology

Fritz Francois, MD
Senior Gastroenterology Fellow
Assistant Residency Program Director
Department of Medicine
New York University School of Medicine
VA New York Harbor Healthcare System
New York, New York

Although organisms were observed in the human stomach more than 100 years ago, it wasn't until 1982 that gram-negative spiral bacteria were identified, cultured, and later classified as Helicobacter pylori.(1,2) Studies of H. pylori have not only provided insight into human migration and development patterns,(3) but also have linked the organism to chronic inflammation of the stomach, peptic ulcer disease, as well as the development of certain forms of gastric cancer.(4) The past 20 years has witnessed a growth in our understanding about the associations of H. pylori with gastric adenocarcinoma and lymphoma.

Humans are essentially the only reservoir for Helicobacter pylori, which is estimated to colonize the stomach of about half the world's population. This highly adapted organism possesses several features, including flagella and urease, that enable it to evade host defenses, resulting in persistence.(5) Some strains of H. pylori contain genes encoding for CagA, a protein that is injected by the organism into host cells, resulting in cytokine production, and a growth factor-like response.(6,7) Although the bacteria generally do not invade the mucosa, attachment to the epithelium leads to an inflammatory reaction with neutrophils, lymphocytes, plasma cells, and macrophages.(8) Over time, the persistent inflammation leads to changes in the gastric mucosa that may predispose to the development of dysplasia.

Gastric cancer is one of the most common malignancies in the world, and is the second leading cause of cancer-related death worldwide, although regional variations in incidence exist. About 90% of diagnosed gastric cancers are adenocarcinomas, with a much smaller percentage classified as nonHodgkins lymphoma or leiomyosarcomas.(9) Rates of stomach cancer are higher in developing countries, among members of lower socioeconomic groups, in individuals older than age 40, and in men.(10) The highest incidence rates occur in Japan, China, South America, and Eastern Europe, while the US has one of the lowest rates of gastric cancer.(11) There has been a three- to six-fold decrease in stomach cancer in the US over the past 50 years, with current incidence rates estimated as 10 cases per 100,0000 in men, and 5 cases per 100,000 in women.(12, 13) Parallel declines have been observed in other developed countries.(14, 15) Although overall rates of gastric cancer have declined, African Americans, Hispanics, and Native Americans have twice those of Caucasians.(16,17) The decreasing incidence of stomach cancer observed in developed countries has been attributed to improvements in living conditions, including the use of refrigeration and an increased consumption of fruits and vegetables, as well as a decrease in the prevalence of H. pylori.(18-30)

Gastric adenocarcinoma can be classified according to histology, as either intestinal or diffuse types;(21) Table 1 lists the differentiating characteristics between these two types. It has been hypothesized that the intestinal type develops in sequential fashion from superficial gastritis, to chronic atrophic gastritis, intestinal metaplasia, dysplasia, and carcinoma.(22) A parallel sequence has not been detected for the diffuse type of gastric cancer.

Table 1. Differentiating Characteristics Between the Intestinal and Diffuse Types of Gastric Cancer

The development of gastric adenocarcinoma is associated with environmental as well as genetic factors. High dietary levels of nitrates, complex carbohydrates, and salted, pickled, or smoked foods have been linked to this malignancy.(24,25) A history of smoking has been found to double the risk of transition from chronic atrophic gastritis to dysplasia, although no similar risk has been shown with alcohol use.(26,27) Individuals with an increased genetic risk for gastric cancer include those with hereditary nonpolyposis colorectal cancer as well as those with familial polyposis coli.(28,29) Particular polymorphisms affecting expression of the cytokines IL-1 beta and its receptor, and TNF alpha have been associated with increased risk of gastric cancer.(30,31)

In epidemiological studies, colonization with H. pylori has been demonstrated to be associated with an increased risk of noncardia gastric adenocarcinoma, especially in individuals who have harbored the organism for 10 years or longer.(32,33) A meta-analysis of these studies revealed that H. pylori colonization is associated with more than twice the risk of gastric cancer development compared to noncolonized individuals.(34) Experimental H. pylori inoculation of Mongolian gerbils leads to pre-malignant gastric lesions(35,36) and ultimately to adenocarcinoma.(37) In humans, determinants of gastric malignancy development in the setting of H. pylori colonization include presumed acquisition of the organism early in life, higher birth order, and colonization with cagA+ strains of the organism.(38-40) Individuals who become colonized later in life may be at increased risk for peptic ulcer disease but not for gastric cancer. A recent prospective, randomized, placebo-controlled H. pylori eradication study involving 1630 adults from the Fujian Province in China followed for 7.5 years, did not find a significant difference in the development of gastric cancer between the treated and the placebo groups.(41) Further studies with longer follow-up are needed to clarify the effect of H. pylori eradication on the incidence of gastric cancer development, based on the presence or absence of precancerous lesions at baseline.

Primary gastric lymphoma accounts for about 3% of cancers in the stomach.(42) These lesions arising from the mucosa also are known as mucosa-associated lymphoid tissue tumors (MALToma), and are B-cell tumors. H. pylori-induced gastric inflammation leads to an accumulation of CD4+ lymphocytes and B cells in the lamina propria, which does not contain significant lymphoid tissue in the absence of H. pylori. Numerous studies have reported an association between H. pylori colonization and the development of MALToma.(43-45) There is no clear association with cagA+ strains. Further evidence for the link between H. pylori and MALToma comes from the observation that remission of the tumor often, but not always, occurs with eradication of the organism.(46,47) The tumors that do not regress following H. pylori eradication, are either advanced in stage or carry a chromosomal translocation.(48)

In conclusion, H. pylori is a colonizer of the human stomach that has been associated with the development of chronic gastric inflammation, peptic ulcer disease, as well as gastric cancer. Based on epidemiological evidence, in 1994 H. pylori was classified as a carcinogen;(49) recent animal studies continue to support this relationship.(50) Although H. pylori has been linked to gastric carcinoma and lymphoma, the percentage of colonized individuals who actually develop these malignancies remains small and presentation usually is late in life. Eradication of H. pylori has not been demonstrated to significantly decrease the incidence of gastric cancer in medium-term follow up,(41) but studies of individuals at very high risk have shown that treatment appears to be beneficial.(51) The interplay between host, bacterial, and environmental factors may ultimately determine the risk of developing gastric cancer, as well as its natural history.

References

1. Marshall, BJ. History of the discovery of C. pylori. In: Campylobacter Pylori in Gastritis and Peptic Ulcer Disease, Blaser, MJ (Ed), Igaku-Shoin, New York; 1989.
2. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1:1311.
3. Falush D, Wirth T, Linz B, et al. Traces of human migrations in Helicobacter pylori populations. Science. 2003;299:1582.
4. Peek RM Jr, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002;2:28.
5. Weeks DL, Eskandari S, Scott DR, Sachs G. A H+-gated urea channel: the link between Helicobacter pylori urease and gastric colonization. Science 2000;287:482.
6. Tummuru MK, Cover TL, Blaser MJ. Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect Immun. 1993;61:1799.
7. Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287:1497.
8. Goodwin CS, Armstrong JA, Marshall BJ. Campylobacter pyloridis, gastritis, and peptic ulceration. J Clin Pathol. 1986;39:353.
9. Rotterdam H. Carcinoma of the stomach. In: Rotterdam H, Enterline HT. Pathology of the stomach and duodenum. New York: Springer-Verlag, 1989:142-204.
10. Howson CP, Hiyama T, Wynder EL. The decline in gastric cancer: epidemiology of an unplanned triumph. Epidemiol Rev. 1986;8:1.
11. Terry MB, Gaudet MM, Gammon MD. The epidemiology of gastric cancer. Semin Radiat Oncol. 2002;12:111.
12. Wingo PA, Cardinez CJ, Landis SH, et al. Long-term trends in cancer mortality in the United States, 1930-1998. Cancer. 2003;97:3133.
13. National Cancer Institute. Annual cancer statistics review: 1973-1991. Bethesda, Md.: Department of Health and Human Services, 1994. (DHHS publication no. (NIH) 942789.
14. Popiela T, Kulig J, Kolodziejczyk P, et al. Changing patterns of gastric carcinoma over the past two decades in a single institution: clinicopathological findings in 1557 patients. Scand J Gastroenterol. 2002;37:561.
15. Kocher HM, Linklater K, Patel S, et al. Epidemiological study of oesophageal and gastric cancer in south-east England. Br J Surg. 2001;88:1249.
16. Wiggins CL, Becker TM, Key CR, Samet JM.Stomach cancer among New Mexico's American Indians, Hispanic whites, and non-Hispanic whites. Cancer Res. 1989;49:1595.
17. Parker SL, Tong T, Bolden S, et al. Cancer statistics, 1996. CA Cancer J Clin. 1996;46:5-27.
18. Kobayashi M, Tsubono Y, Sasazuki S, et al. JPHC Study Group. Vegetables, fruit and risk of gastric cancer in Japan: a 10-year follow-up of the JPHC Study Cohort I. Int J Cancer. 2002;102:39.
19. Rehnberg-Laiho L, Rautelin H, Koskela P, et al. Decreasing prevalence of helicobacter antibodies in Finland, with reference to the decreasing incidence of gastric cancer. Epidemiol Infect. 2001;126:37.
20. Ekstrom AM, Hansson LE, Signorello LB, et al. Decreasing incidence of both major histologic subtypes of gastric adenocarcinoma--a population-based study in Sweden. Br J Cancer. 2000;83:391.
21. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand. 1965;64:31.
22. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52:6735.
23. Adachi Y, Yasuda K, Inomata M, et al. Pathology and prognosis of gastric carcinoma: well versus poorly differentiated type. Cancer. 2000;89:1418.
24. Ngoan LT, Mizoue T, Fujino Y, Tokui N, Yoshimura T. Dietary factors and stomach cancer mortality. Br J Cancer. 2002;87:37.
25. Mirvish SS. The etiology of gastric cancer. Intragastric nitrosamide formation and other theories. J Natl Cancer Inst. 1983;71:629.
26. Kneller RW, You WC, Chang YS, et al. Cigarette smoking and other risk factors for progression of precancerous stomach lesions. J Natl Cancer Inst. 1992;84:1261.
27. Nomura A, Grove JS, Stemmermann GN, et al. A prospective study of stomach cancer and its relation to diet, cigarettes, and alcohol consumption. Cancer Res. 1990;50:627.
28. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology. 1993;104:1535.
29. Watanabe H, Enjoji M, Yao T, et al. Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. Hum Pathol. 1978;9:269.
30. El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000; 404(6776):398.
31. Machado JC, Figueiredo C, Canedo P, et al. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology. 2003; 125:364.
32. Nomura A, Stemmermann GN, Chyou PH, et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991;325:1132.
33. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut. 2001;49:347.
34. Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998;114:1169.
35. Peek RM Jr, Wirth HP, Moss SF, et al. Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils. Gastroenterology. 2000;118:48.
36. Konturek PC, Brzozowski T, Konturek SJ, et al. Functional and morphological aspects of Helicobacter pylori-induced gastric cancer in Mongolian gerbils. Eur J Gastroenterol Hepatol. 2003;15:745.
37. Watanabe T, Tada M, Nagai H, et al. Helicobacter pylori infection induces gastric cancer in Mongolian gerbils. Gastroenterology. 1998;115:642.
38. Blaser MJ, Chyou PH, Nomura A. Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer, and duodenal ulcer risk. Cancer Res. 1995;55:562.
39. Blaser MJ, Perez-Perez GI, Kleanthous H, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res. 1995;55:2111.
40. Nomura AM, Lee J, Stemmermann GN, et al. Helicobacter pylori CagA seropositivity and gastric carcinoma risk in a Japanese American population. J Infect Dis. 2002;186:1138.
41. Wong B, Lam S, Wong W, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004;291:187.
42. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972;29:252.
43. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med. 1994;330:1267.
44. Yamasaki R, Yokota K, Okada H, et al. Immune response in Helicobacter pylori-induced low-grade gastric-mucosa-associated lymphoid tissue (MALT) lymphoma. J Med Microbiol. 2004;53:21.
45. Ohara T, Kanoh Y, Higuchi K, et al. Eradication therapy of Helicobacter pylori directly induces apoptosis in inflammation-related immunocytes in the gastric mucosa--possible mechanism for cure of peptic ulcer disease and MALT lymphoma with a low-grade malignancy. Hepatogastroenterolog. 2003;50:607.
46. Alsolaiman MM, Bakis G, Nazeer T, et al. Five years of complete remission of gastric diffuse large B cell lymphoma after eradication of Helicobacter pylori infection. Gut. 2003;52:507.
47. Fischbach W, Goebeler-Kolve ME, Dragosics B, et al. Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: experience from a large prospective series. Gut. 2004;53:34.
48. Parsonnet J, Isaacson PG. Bacterial Infection and MALT Lymphoma. N Engl J Med. 2004;350:213.
49. International Agency for Research on Cancer. Schistosomes, liver flukes and Helicobacter pylori. IARC. 1994;61:1.
50. Touati E, Michel V, Thiberge JM, et al. Chronic Helicobacter pylori infections induce gastric mutations in mice. Gastroenterology. 2003;124:1408.
51. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784.