Helicobacter pylori (H. pylori) and Cancer

Question 1

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What is Helicobacter pylori?

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Helicobacter pylori (H. pylori) is a spiral-shaped bacterium that grows in the mucus layer that coats the inside of the human stomach. Although many bacteria cannot survive the stomach\u2019s acid environment, H. pylori is able to neutralize the acidity of its local environment in the stomach, though not the stomach as a whole. This local neutralization helps the bacterium survive.

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Another way H. pylori survives in the stomach\u2019s acidic environment is by burrowing into the mucus layer and attaching to the cells that line its inner surface. This also helps it avoid immune destruction, because even though immune cells that normally recognize and attack invading bacteria accumulate near sites of H. pylori infection, they are unable to reach the stomach lining.

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H. pylori also interferes with local immune responses, making them ineffective in eliminating this bacterium (1, 2).

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Infection with H. pylori is common, especially in low- and middle-income countries. The Centers for Disease Control and Prevention estimates that about two-thirds of the world\u2019s population harbors the bacterium. In the United States, the prevalence of H. pylori varies across racial and ethnic groups. For example, in 1999\u20132000, about 21% of non-Hispanic Whites, 52% of non-Hispanic Blacks, and 64% of Mexican Americans harbored the bacterium (3).

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H. pylori mainly spreads from person to person through oral contact with stool (fecal\u2013oral), saliva (oral\u2013oral), or vomit (gastric\u2013oral) (4). In most populations, the bacterium is first acquired during childhood. Infection is more likely in children living in poverty, in crowded conditions, and in areas with poor sanitation.

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Question 2

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Does H. pylori cause cancer or other diseases?

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Yes. Although H. pylori infection does not itself cause illness, chronic infection causes long-lasting inflammation in the stomach (called non-atrophic gastritis) in most people. This inflammation can lead to several possible conditions, including atrophic gastritis (thinning of the stomach lining caused by long-term inflammation) and certain types of stomach (gastric) cancer, particularly gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, which is a rare type of non-Hodgkin lymphoma.

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Because of its role in causing stomach cancer, in 1994 H. pylori was classified as a human carcinogen, or cancer-causing agent, by the World Health Organization\u2019s International Agency for Research on Cancer (5). In 2021, the National Toxicology Program\u2019s 15th Report on Carcinogens added chronic infection with H. pylori to its list of substances that are known or reasonably anticipated to cause cancer in humans.

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It remains unclear whether chronic H. pylori infection is associated with an increased risk of other cancers. Although some studies have found a possible association between H. pylori infection and an increased risk of pancreatic cancer, a 2023 meta-analysis of observational studies found insufficient evidence to support such an association (6). Growing evidence suggests a link between H. pylori infection and an increased risk of colorectal cancer (7\u20139).

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However, infection with H. pylori is also associated with a reduced risk of esophageal adenocarcinoma, a type of esophageal cancer that is associated with Barrett esophagus and gastroesophageal reflux disease.

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Chronic H. pylori infection can also cause peptic ulcers (ulcers of the stomach and upper small intestine). More information about peptic ulcers is available from the National Institute of Diabetes and Digestive and Kidney Diseases.

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Question 3

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What is the evidence that H. pylori causes stomach cancer?

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Many studies have provided consistent evidence that chronic H. pylori infection causes gastric adenocarcinoma and gastric MALT lymphoma.

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Gastric adenocarcinoma: Epidemiologic studies have shown that people who have chronic H. pylori infections have an increased risk of developing non-cardia gastric adenocarcinoma\u2014that is, cancer in the main part of the stomach, excluding the part closest to the esophagus (10\u201317).

Epidemiologic studies have also shown that in geographic areas where stomach cancer is common, especially in Asia, people with chronic H. pylori infections have an increased risk of developing gastric cardia cancer\u2014that is, cancer in the part of the stomach that is closest to the esophagus (18, 19).

In addition, studies have shown that treatment to eradicate H. pylori infection reduces the risk of gastric cancer in asymptomatic individuals (20), in individuals at increased risk due to family history (21), and in those who have had surgery for early gastric cancer (22).
Gastric MALT lymphoma: Nearly all patients with gastric MALT lymphoma show signs of H. pylori infection, and the risk of developing this cancer is substantially greater in infected people than in uninfected people (23, 24).

The strongest evidence linking H. pylori infection with gastric MALT lymphoma comes from studies showing that when people with gastric MALT lymphoma are treated with antibiotics to eliminate H. pylori, their tumors shrink (25, 26).

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Question 4

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How common are cancers linked to chronic infection with H. pylori?

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In the United States, gastric (stomach) cancer represents 1.4% of all new cancers diagnosed and mainly affects racial and ethnic minority groups. In 2023, an estimated 26,500 people in the United States will be diagnosed with gastric cancer and 11,130 people will die of this cancer (27).

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Gastric cancer is more common in countries in Eastern Asia, Eastern Europe, and Central and South America than in the United States and other Western countries.

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Globally, gastric cancer is the fifth most common cancer (28, 29). It is the fourth most common cause of cancer-related deaths in the world, killing about 769,000 people in 2020 (28).

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Gastric cancer incidence is declining in most of the world (30, 31). In the United States, the decline in gastric cancer incidence is mainly among people older than 64 years and for non-cardia gastric cancer (31). However, an unexplained increase in incidence of non-cardia gastric cancer has been observed in young non-Hispanic White and Hispanic individuals (32). Worldwide, the incidence of gastric cardia cancer, which was once very uncommon, has risen in recent decades (31, 33).

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In the United States, gastric MALT lymphoma is rare; during 1999\u20132003, the annual incidence of gastric MALT lymphoma was about one case for every 100,000 persons. It accounts for only 2%\u20138% of all cases of stomach cancers and represents about 12% of the extranodal (outside of lymph nodes) non-Hodgkin lymphoma that occurs among men and about 18% of extranodal non-Hodgkin lymphoma among women (34).

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The majority of cases of gastric adenocarcinoma and gastric MALT lymphoma are attributed to H. pylori infection (35).

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Question 5

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What is the evidence that H. pylori may reduce the risk of some cancers?

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Multiple epidemiologic studies have shown a reduced risk of esophageal adenocarcinoma (but not of esophageal squamous cell carcinoma, the other main type of esophageal cancer) in H. pylori\u2013infected individuals (36\u201338).

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For example, in large case\u2013control studies carried out in Sweden and Australia, H. pylori infection was strongly associated with a reduced risk of esophageal adenocarcinoma (39, 40).

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Supporting evidence that H. pylori infection plays a role in reducing the risk of esophageal adenocarcinoma comes from the finding that the rate of this cancer has increased dramatically in several Western countries over the last century as H. pylori infection rates have declined with improved hygiene and widespread antibiotic use.

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Question 6

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How might H. pylori infection decrease the risk of some cancers but increase the risk of other cancers?

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Although it is not known for certain how H. pylori infection causes stomach cancer, some researchers speculate that the long-term presence of an inflammatory response predisposes cells in the stomach lining to become cancer (41). This idea is supported by the finding that increased expression of a single cytokine (interleukin-1-beta) in the stomach of transgenic mice causes sporadic gastric inflammation and cancer (42). The increased cell turnover resulting from ongoing cellular damage could increase the likelihood that cells will develop harmful mutations.

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The reduced risk of esophageal cancer in H. pylori\u2013infected individuals may relate to the decline in stomach acidity that is often seen after decades of H. pylori colonization (15). This decline would reduce acid reflux into the esophagus, which is a major risk factor for adenocarcinomas affecting the esophagus.

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Question 7

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What factors increase the likelihood that H. pylori infections will be harmful?

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Several factors affect the likelihood that an infection with H. pylori will cause cancer. Some of these factors are features of the bacterium itself. For example, some strains of H. pylori make a toxin called CagA that gets injected into the junctions where cells of the stomach lining meet. Once inside cells, CagA can cause them to become cancerous by removing controls on cell growth and enhancing cell motility (43). Long-term exposure of cells to the toxin causes chronic inflammation. Epidemiology studies suggest that CagA-positive strains have a stronger association with non-cardia gastric cancer than CagA-negative strains (44).

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Some evidence also suggests that certain lifestyle exposures may modify H. pylori\u2013induced stomach cancer risk. For example, H. pylori\u2013infected individuals who smoke have a higher risk of stomach cancer than H. pylori\u2013infected individuals who do not smoke (45). Also, a high intake of salt and processed meat is associated with an increased risk of stomach cancer (29), possibly by increasing the risk that H. pylori will colonize the stomach or that CagA will enter gastric cells (46, 47).

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Question 8

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Does treatment of H. pylori infection reduce the risk of gastric cancer?

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Yes. Long-term follow-up data from a randomized clinical trial carried out in Shandong, China\u2014an area where rates of gastric cancer are very high\u2014showed that 2 weeks of treatment with antibiotics to eradicate H. pylori significantly reduced the incidence of gastric cancer by nearly 50% over 22 years of follow-up after treatment (20). Other studies in Asian populations have similarly found that eradicating H. pylori reduces the incidence of gastric cancer in healthy asymptomatic infected individuals (48, 49).

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Another randomized clinical trial, carried out among patients undergoing surgery for early gastric cancer, found that those who received H. pylori eradication treatment were half as likely to develop additional gastric cancer lesions (called metachronous gastric cancer) as those who received placebo (50). Importantly, a nationwide population-based cohort study in Sweden found no evidence of an increase in esophageal adenocarcinoma after eradication treatment for H. pylori (51).

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Question 9

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Who should be tested and treated for an H. pylori infection?

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According to the Centers for Disease Control and Prevention, people with an active gastric or duodenal ulcers or a documented history of ulcers should be tested for H. pylori, and, if they have an infection, should be treated. Testing for and treating H. pylori infection is also recommended after surgery for early gastric cancer or low-grade gastric MALT lymphoma (52\u201354). However, most experts agree that the available evidence does not support widespread testing for and eradication of H. pylori infection (52, 55). Unnecessary or inappropriate eradication treatment may be contributing to the increase in H. pylori resistance to several antibiotics in the United States (56).

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