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Helicobacter pylori and Gastric Cancer
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. Studies of H. pylori have not only provided insight into human migration and development patterns, but also have linked the organism to chronic inflammation of the stomach and peptic ulcer disease, as well as the development of certain forms of gastric cancer. H. pylori is responsible for most ulcers and many cases of chronic gastritis (inflammation of the lining of the stomach). The past 20 years has witnessed a growth in our understanding about the associations of H. pylori with gastric adenocarcinoma (cancer that involves the lining of the stomach) and lymphoma (cancer that begins in the immune system).
H. pylori are present in the stomachs of about half the world's population. This highly adapted organism possesses several features that enable it to evade the body's defenses. H. pylori attaches itself to the lining of the stomach and causes inflammation; over time, this persistent inflammation leads to cell changes that may predispose an individual to the development of dysplasia (abnormal cellular development that may progress to malignancy).
Gastric cancer, also known as stomach 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 nonHodgkin's lymphoma. Rates of stomach cancer are higher in developing countries, among members of lower socioeconomic groups, in people over age 40, and in men. 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. There has been a three- to six-fold decrease in gastric 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 (about 22,000 Americans are diagnosed with this malignancy each year). Parallel declines have been observed in other developed countries. Although overall rates of gastric cancer have declined, African-Americans, Hispanic-Americans, and Native Americans have twice the rates of Caucasians. The decreasing incidence of stomach cancer observed in developed countries has been attributed to improvements in living conditions, including the use of refrigeration (which eliminates the need for salting, drying, smoking, or pickling food in order to preserve it-a risk factor for gastric cancer) and the increased consumption of fruits and vegetables, as well as a decrease in the prevalence of H. pylori.
Gastric adenocarcinoma can be classified according to histology, as either intestinal or diffuse. It is thought that the intestinal type develops sequentially from superficial gastritis to chronic atrophic gastritis (where the normal stomach glands are either absent or decreased in number), intestinal metaplasia (abnormal replacement of one type of cells by another), dysplasia (abnormal growth or development of cells), and finally carcinoma. A parallel sequence has not been detected for the diffuse type 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. Smoking has been found to double the risk of transition from chronic atrophic gastritis to dysplasia, although no similar risk has been shown for alcohol use. Individuals with an increased genetic risk for gastric cancer include those with hereditary nonpolyposis colorectal cancer as well as those with familial polyposis coli.
In epidemiological studies, colonization with H. pylori has been demonstrated to be associated with an increased risk of noncardia (the cardia is the uppermost part of the stomach) gastric adenocarcinoma, especially in individuals who have harbored the organism for 10 or more years. A meta-analysis of these studies revealed that individuals with H. pylori colonization have more than twice the risk of gastric cancer than those who do not. But not everyone who has H. pylori will develop gastric cancer. Some of the factors that increase the risk for this malignancy in individuals affected with the bacterium include acquisition of H. pylori early in life, higher birth order, and colonization with certain strains of the organism. Those who acquire H. pylori 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 1,630 adults from the Fujian Province in China who were followed for 7.5 years, did not find a significant difference in the development of gastric cancer between the treated and the placebo groups. 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.
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; recent animal studies continue to support this relationship. Although H. pylori has been linked to gastric carcinoma and lymphoma, the percentage of colonized individuals who actually develop these malignancies remains small and the disease usually develops late in life. Eradication of H. pylori has not been demonstrated to significantly decrease the incidence of gastric cancer in medium-term follow up, but studies of individuals at very high risk have shown that treatment appears to be beneficial. The interplay between host, bacterial, and environmental factors may ultimately determine the risk of developing gastric cancer, as well as its natural history.
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