PEDIATRICS Vol. 107 No. 2 February 2001, pp. 373-380

REVIEW ARTICLE:
Is Helicobacter pylori Infection in Childhood a Risk Factor for Gastric Cancer?

Cameron Imrie, FRACP, Marion Rowland, MB, Billy Bourke, MD, and Brendan Drumm, MD

From the Department of Paediatrics, University College Dublin and The Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland.

	ABSTRACT

Top Abstract References

Helicobacter pylori infection is associated with chronic gastritis and peptic ulcer disease. Furthermore, the World Health Organization has classified this organism as a carcinogen for gastric cancer. H pylori infection is mainly acquired in childhood. Children with H pylori infection are asymptomatic except for a very small number that develop peptic ulcer disease. However, if H pylori gastritis is associated with gastric cancer, do pediatricians need to screen children for this infection and treat those who are infected? In an attempt to determine the significance of the association between H pylori and gastric cancer, we have reviewed all of the English language literature on this topic. H pylori infection seems to be associated with an increased risk of developing gastric cancer. However, only a small number of infected individuals (~1%) will develop gastric cancer. Furthermore, there are potential cofactors other than H pylori that could be equally important. The effect of the eradication of H pylori alone on the development of gastric cancer is unknown. Based on our knowledge to date, we suggest that it is not indicated to treat all children with H pylori infection because of the risk of developing gastric cancer or to institute a screening and treatment program.

Helicobacter pylori is a Gram-negative spiral organism which colonizes the gastric mucosa causing chronic gastritis.^1-4 H pylori-associated gastritis is present in almost all adults and children with duodenal ulceration.^2-6 Eradication of H pylori from the gastric mucosa results in long-term healing of duodenal ulcers.^7-10

H pylori gastritis in the absence of duodenal ulcer disease seems to be an asymptomatic condition in most, if not all, children.^11-14 Therefore, there has been no indication to treat the great majority of infected children. However, in 1994 H pylori was classified as a group 1 carcinogen for gastric cancer by the International Agency for Research on Cancer.¹⁵ This statement is reinforced by our knowledge that early life exposures are critical in the development of gastric cancer.¹⁶

If H pylori is a carcinogen, should pediatricians treat this infection whenever it is identified? Should consideration be given to the establishment of a screening program for H pylori infection? European and Canadian consensus reports, including those on H pylori infection in childhood, do not make recommendations in relation to the association between H pylori infection in children and the development of gastric cancer.^17-20 In this review we explore the controversies surrounding the association between H pylori infection, which is usually acquired in childhood, and the development of gastric cancer in adult life.

	EPIDEMIOLOGY OF H PYLORI

H pylori infection is almost always acquired in childhood^21-23 and usually persists for life unless specifically treated.²⁴ The incidence of infection in adults is very low with rates of infection <1% per year.^22,24-26 The mode of transmission of H pylori infection is not known but person to person transmission seems to be the most likely route.^27,28

The major risk factor for acquiring H pylori infection is poor socioeconomic conditions during childhood.^14,29-32 In developing countries, therefore, the prevalence of infection can be >80% in children <10 years old.^33-38 In developed countries, while the overall prevalence of H pylori in children is often <10%, up to 50% of children living in poor socioeconomic circumstances may harbor the infection.¹⁴

The prevalence of H pylori infection in developed countries ranges from 10% in children to 60% in 60 year olds. However, the increasing prevalence of H pylori infection with increasing age seems to be attributable to a cohort effect. Present day adults acquired H pylori infection frequently in childhood because socioeconomic conditions in their countries were worse then than those pertaining now.²¹

	GASTRIC CANCER

Morphology

Adenocarcinomas are the most common malignant tumors of the stomach comprising 97% of all gastric cancers with the remaining 3% being lymphomas or leiomyosarcomas.³⁹ Primary gastric adenocarcinomas are classified by anatomic location as being either proximal in the cardia or distal to the cardia. Infection with H pylori has not been associated with proximal gastric carcinoma. The purpose of this review is to discuss the relationship between H pylori and noncardia (distal) adenocarcinoma of the stomach.

Distal to the cardia gastric adenocarcinoma can be further classified by the Lauren classification into 2 histologic types-intestinal and diffuse.⁴⁰ Intestinal-type gastric cancer consists of cohesively grouped neoplastic cells which form distinct polarized gland-like tubular structures with well-defined lumina. These are predominantly found in the prepyloric antrum.^40,41 Diffuse-type gastric cancer, in which cell cohesion is missing, generally arises in the fundus and consists of individually infiltrating neoplastic cells that thicken the stomach wall without forming glandular structures or a discrete mass.^40,41 It should be noted that gastric tumors may be heterogeneous with both intestinal- and diffuse-type morphology, and also that some tumors do not conform to either category.^39,40 Intestinal-type tumors are more common than diffuse-type tumors,⁴⁰ especially in regions with a high incidence of gastric cancer.⁴¹

Epidemiology of Gastric Cancer

Before 1940, gastric cancer was the leading cause of cancer- related death in American males and the third leading cause after breast and cervical cancer in women.³⁹ Since 1950, there has been a progressive and unexplained decrease in the incidence of gastric cancer in developed countries.³⁹ Gastric cancer mortality rates fell by 67% in the United States between 1950 and 1980³⁹ despite the fact that survival has not improved for those who develop gastric cancer. However, the worldwide prevalence of gastric cancer is increasing as the incidence of gastric cancer increases with age and lifespans worldwide are increasing. Gastric cancer is now the second most common cancer worldwide after lung cancer in men.⁴² It accounts for 12% of all cancers in men and 7.5% in women.⁴³ There are estimated to be over a million new cases of gastric cancer worldwide each year.⁴⁴ Gastric cancer rates vary widely between different geographic regions. Age standardized rates in males are high (>35/100 000) in Japan, China, Korea and Columbia. Rates are low (<15/100 000) in North American whites, Australia, some western European countries, and most African countries.^44-46

Tumors located distal to the cardia have historically accounted for the majority of gastric adenocarcinomas.^41,47 Although the incidence of distal gastric cancer has declined steadily in developed countries, there has been an unexplained increase in adenocarcinoma of the gastric cardia and esophagus over the last 3 decades in developed countries.^48-56 An association between H pylori infection and adenocarcinoma of the gastric cardia or esophagus has not been shown.⁵⁷ In fact, it has been suggested that eradication of H pylori may result in an increased incidence of proximal gastric or esophageal adenocarcinoma.⁵⁸ It is speculated that eradication of H pylori infection may result in an increase in gastric acidity and therefore promote the development of reflux esophagitis,⁵⁹ which in turn, might increase the risk of developing esophageal adenocarcinoma.

The cause of gastric cancer is thought to be multifactorial, including both environmental and genetic risk factors. Gastric cancer is associated with socioeconomic status^39,60 with those from lower socioeconomic groups having double the risk of those from higher socioeconomic groups.³⁹ Diets high in salt, nitrates, and preserved foods may predispose to gastric cancer, and diets low in fresh fruit and vegetables also increase the risk of gastric cancer.⁶¹

Migration studies have shown that early life environmental exposures are important in the development of gastric cancer. First generation migrants have similar gastric cancer mortality rates to those in their country of origin.^16,62-64 The same has been shown for intracountry migration in Columbia.⁶⁵ Second generation migrants however, have gastric cancer mortality rates similar to those in their adopted country.^66,67

Environmental exposures are thought to be more important in the cause of intestinal-type gastric cancer than diffuse-type gastric cancer.³⁹ Intestinal-type gastric cancers are the more common type in areas of high gastric cancer risk.^40,41 Furthermore, the decline in the incidence of gastric cancer in developed countries is attributable primarily to a decreasing incidence of intestinal type gastric cancer.^41,68

Conversely, genetic factors are thought to play an important role in the cause of diffuse-type gastric cancer. Diffuse gastric cancer has a similar incidence in males and females and is associated with blood group A. It is relatively more frequent in younger age groups.⁶⁸

	H PYLORI AND GASTRIC CANCER

Evidence in Favor of an Association

There are 3 possible long-term outcomes for H pylori-associated gastritis. The first is spontaneous resolution, which occurs in a very small number of cases.^26,69 In the majority of patients, there is persistence of a diffuse but predominantly antral gastritis. Up to 15% of patients with H pylori-associated diffuse antral gastritis subsequently develop a duodenal ulcer.^26,70

The third possible outcome is the development of gastric atrophy, also called multifocal atrophic gastritis. This involves loss of gastric mucosal glands and hence altered gastric secretion. These individuals are therefore very unlikely to develop ulcer disease. Previously, the development of gastric atrophy was considered to be associated with increasing age.⁷¹ It now seems that colonization with H pylori rather than age is the vital factor in developing gastric atrophy in susceptible individuals.⁷² The reasons for this progression to gastric atrophy in some but not all H pylori-infected individuals are unknown. However, the evolution of gastric atrophy may be the first step towards the development of gastric cancer. In fact, before the discovery of H pylori, Correa^65,73,74 proposed that gastric cancer evolved sequentially from chronic gastritis to atrophic gastritis and intestinal metaplasia, and ultimately to dysplasia and carcinoma in situ.

Histopathological follow-up studies lend support to a stepwise progression from chronic gastritis to atrophic gastritis.^71-73 An association between H pylori infection and intestinal metaplasia has been suggested.^26,72 However, it has not been proven that H pylori infection can cause intestinal metaplasia. There are significant methodological problems involved in such studies as atrophy and intestinal metaplasia are patchy and can therefore easily be missed when only a small number of biopsies are collected.

The strongest epidemiologic evidence linking H pylori infection with gastric cancer comes from 3 nested case-control studies published in 1991.^75-77 These studies (Table 1) using stored serum demonstrated that H pylori-infected people are more likely to develop gastric cancer. A combined analysis of these 3 studies showed that the relative risk of cancer is 2.1 to 8.7 times greater in infected adults compared with uninfected controls.⁷⁸

There are, in addition, a large number of other studies indicating that people with gastric cancer are more likely to have been infected with H pylori than matched controls without gastric cancer (Table 1).^79-87 Hansson et al⁸⁰ have shown that the strength of this association is higher for men (odds ratio [OR] 4.27; 95% confidence interval [CI]: 1.75-10.62) with H pylori as compared with women. A number of studies have shown that the strength of this association is higher still in younger individuals with gastric cancer than in older people.^80,82,88,89

Case-control studies based on serologic evidence of infection may underestimate the association between H pylori and gastric cancer⁷⁸ because H pylori colonization of the gastric mucosa decreases in association with the development of gastric atrophy.^79,90 Crabtree et al⁹¹ showed that 25% of gastric cancer patients who were seronegative on enzyme-linked immunosorbent assay (ELISA) testing were positive on Western blotting, suggesting that ELISA testing is underestimating the prevalence of H pylori infection. There are also difficulties with retrospective studies based on histologic evidence of H pylori infection. H pylori colonization does not occur in gastric tumor tissue.⁹² Therefore, reports based on the histologic diagnosis of infection from tumor biopsies may also underestimate the true prevalence of infection. The true relative risk of gastric cancer in patients with H pylori infection is thus likely to be higher than has been suggested. The authors of a combined analysis of the 3 nested case control studies suggest that a nine-fold relative risk of gastric cancer in infected adults might be a more accurate estimate.⁷⁸

In the last few decades there has been a progressive decline both in the incidence of gastric cancer and in the incidence of H pylori-associated chronic gastritis in developed countries.⁹³ The decreasing prevalence of H pylori infection is probably the result of improving socioeconomic conditions. Sipponen⁹⁴ has shown that the prevalence rates of H pylori gastritis for specific birth cohorts determines the subsequent incidence rates of gastric cancer at fixed ages.

A number of groups have demonstrated a higher prevalence of H pylori infection in intestinal-type gastric cancer compared with diffuse-type gastric cancer.^80,95-97 Other groups have demonstrated a significant association between H pylori and both subtypes.^{76,77,79,81,82,87,98,99} A recent metanalysis found that each subtype is significantly associated with H pylori infection.⁵⁷

There is evidence that host genetic factors increase the risk of developing gastric cancer. Familial gastric cancer has been recognized for many years.^41,100,101 Brenner et al¹⁰² recently demonstrated a higher prevalence of H pylori infection in the offspring of gastric cancer patients than in the offspring of patients without gastric cancer. The prevalence of H pylori in the offspring of gastric cancer patients may have been even higher if the analysis had been restricted to noncardia gastric cancer rather than all gastric cancers. El-Omar et al¹⁰³ have shown that H pylori-infected first degree relatives of gastric cancer patients have higher rates of gastric atrophy than controls with no family history of gastric cancer. A further host genetic factor may be the absence of the DQA1*0102 allele, which could be a risk factor for H pylori-associated atrophic gastritis and intestinal type gastric cancer.¹⁰⁴

Until recently there was no animal model which demonstrated a definite association between Helicobacter infection and gastric carcinoma. However, Watanabe et al¹⁰⁵ have recently demonstrated a relationship between H pylori infection and gastric adenocarcinoma in Mongolian gerbils. They also demonstrated the development of chronic gastritis and intestinal metaplasia in H pylori-infected gerbils.¹⁰⁵ The tumors were shown to develop within areas of intestinal metaplasia.¹⁰⁵ Helicobacter mustelae is another member of the Helicobacter genus that naturally infects ferrets. Fox et al^106,107 have shown that Helicobacter mustelae-infected ferrets with chronic gastritis may develop duodenal ulceration, and can develop multifocal atrophic gastritis. They have reported gastric adenocarcinoma occurring in two ferrets naturally infected with H mustelae.¹⁰⁸

It has been proposed that specific bacterial virulence factors may play a role in the development of gastric cancer. Strains of H pylori can be differentiated based on whether they contain the cytotoxin associated gene (cag). Cag is a marker for the presence of a pathogenicity island in the H pylori genome and may be a marker for a more virulent type of H pylori. Although a number of studies have suggested that infection with cag A positive strains of H pylori is associated with an increased risk of gastric cancer,^91,109-111 other studies have not confirmed this association.^112-114

Evidence Against the Association

The strongest evidence against an association between H pylori and gastric cancer is the finding that some regions with a high prevalence of H pylori infection have a relatively low prevalence of gastric cancer. The prevalence of H pylori infection is similar in regions of China with high and low prevalences of gastric cancer.¹¹⁵ Likewise, cross-sectional studies in Italy,¹¹⁶ Costa Rica,¹¹⁷ and Japan^118,119 did not show a higher prevalence of infection among people living in regions with a high prevalence of gastric cancer.

In African countries there is a high prevalence of H pylori infection. Half of the children <5 years' old are seropositive for H pylori in northern Nigeria¹²⁰ and the Gambia.¹²¹ In Ethiopia 60% of 4-year-olds are infected.³⁴ However, the estimated rates of gastric cancer are low in Africa.^122-125 These findings suggest that there are at least other environmental or genetic risk factors which have a role in the development of gastric cancer. Some potential cofactors for the development of gastric cancer such as a high salt intake or low vitamin C intake may not be present in all populations.

The prevalence of H pylori infection is the same in males and females,^126-128 whereas the prevalence of gastric cancer in males is higher than in females. The ratio of males to females among gastric cancer patients is 2.2:1 in patients <60 years of age. This falls to 1.4:1 in those >60 years of age.³⁹ This also suggests that there must be additional risk factors other than H pylori in young men or some protective factor in young women.

Two recent nested-case control studies have failed to show an increased risk of gastric cancer in H pylori-infected participants (Table 2).^129,130 However, the average intervals between serum collection and gastric cancer diagnosis were only 3.1 and 2.4 years. Because H pylori may disappear when gastric atrophy develops, these studies probably significantly underestimated the presence of H pylori infection. Additional case-control studies which have not shown an association between H pylori infection and gastric cancer are included in Table 2.^88,131-135

	H PYLORI AND GASTRIC LYMPHOMA

Gastric B-cell lymphomas, known as MALT (mucosa associated lymphoid tissue) lymphomas, are epidemiologically linked to H pylori infection.^136,137 These lymphomas are rare, with only 0.71 cases/100 000 population per year in the United States.¹³⁸ MALT lymphomas are extremely rare in children. Treatment of the infection usually leads to regression of gastric MALT lymphomas in adults.^139-142 Regression was also recently seen in a 14-year-old girl after treatment of H pylori infection.¹⁴³ H pylori eradication therapy is now indicated for low-grade gastric MALT lymphoma.²⁰

	IMPLICATIONS FOR H PYLORI-INFECTED CHILDREN

As outlined above, there is evidence suggesting an association between H pylori infection, which is almost always acquired in childhood, and gastric cancer occurring in adulthood. This association is specific to gastric cancer occurring distal to the cardia. However, we have to remember that only ~1% of H pylori-infected children will develop gastric cancer.¹⁴⁴ Furthermore, infection alone may not be sufficient to cause cancer,¹⁴⁵ and a number of other factors have been associated with an increased risk of gastric cancer. These include blood group A,¹⁴⁶ poor dietary intake of vitamin C¹⁴⁷ or carotenoids,¹⁴⁸ as well as increased intake of salted¹⁴⁹ and smoked foods.¹⁵⁰ Whether the eradication of H pylori can prevent the development of a significant number of cases of gastric cancer despite the persistence of other risk factors remains unknown.

Treatment studies are underway in Columbia, Venezuela, Europe (Prevention Intervention Study of Neoplastic Changes in the Stomach), China (National Cancer Institute¹⁵¹ and South China Intervention Study), and Japan (Japanese Intervention Trial of Helicobacter pylori) to determine if eradication of H pylori in adulthood will decrease the incidence of gastric cancer.^152,153 However, there is concern that such studies are too small to determine if eradication of infection will reduce the risk of gastric cancer. Five of the current studies should eventually randomize 27 000 H pylori infected individuals with a mean follow up of 10 years, but Danesh has suggested that 100 000 infected individuals would have to be followed for 20 years.^152,154 Furthermore, adults have usually been infected since childhood and progression to gastric atrophy and intestinal metaplasia may have already commenced in susceptible individuals.

Parsonnet et al¹⁵⁵ suggest that screening and treatment for H pylori infection is potentially cost-effective. Their model is based on screening for H pylori at age 50 and assumes that there will be no progression to gastric cancer after successful eradication therapy. However, precancerous lesions may be irreversible at this age.^156,157 It would seem more logical to treat H pylori-infected children before the development of precancerous lesions occurs. This approach would not be cost-effective because of the long time delay between treatment in childhood and possible prevention of gastric cancer in middle or old age. There is no data available on the proportion of gastric cancer that can be prevented by eradication of H pylori infection during childhood. The size and duration of studies are likely to render such studies in children impractical. Ethical considerations may also make it difficult to perform such studies.¹⁵⁸

Although definitive studies on the role of H pylori in gastric cancer may therefore never be achieved, or will at least take many years to carry out, a consensus as to the significance of H pylori infection in childhood in relation to the risk of gastric cancer is urgently required. The major question that arises for clinicians is how to respond to H pylori infection when it is identified at endoscopy or by noninvasive methods such as 13C-urea breath testing. We suggest that at present the association with gastric cancer is not an indication to treat such children. A decision to treat all infected children to reduce their risk of developing gastric cancer implies that community screening for this infection in childhood should be undertaken to identify and treat all infected children. Nevertheless, parents of children undergoing investigation will have to be informed when this infection is identified. Reports in the lay press describing an association between H pylori infection and gastric cancer will often result in parents asking for treatment for the infection. Furthermore, the recent findings of Brenner et al¹⁰² and El-Omar et al^100,103 suggest that we should treat infected children who have a family history of gastric cancer.

As only ~1% of patients infected with H pylori will develop gastric cancer, it will be difficult to justify screening and widespread treatment of infected individuals. A H pylori screening and treatment program would be especially difficult to justify in developing countries where health resources are scarce. An alternative strategy is to try to prevent H pylori infection by vaccination. Potential vaccines are presently being evaluated, but there is no direct evidence that vaccination can prevent infection in humans.^159-162 Furthermore, because of the relatively low prevalence of gastric cancer in infected individuals, a vaccine would have to be extremely inexpensive if it is to be cost-effective.

The most effective approach to reducing the prevalence of gastric adenocarcinoma is likely to be the prevention of childhood H pylori infection. It is therefore vital that we try to determine the age at which children become infected, the risk factors for infection, and the precise mode of transmission. Armed with this epidemiologic knowledge, it may be possible to develop effective intervention strategies to reduce the prevalence of infection.

	FOOTNOTES

Received for publication Jan 3, 2000; accepted Jun 6, 2000.

Address correspondence to Dr Marion Rowland, Professorial Unit, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland. E-mail: paediatrics{at}ucd.ie

	ABBREVIATIONS

OR, odds ratio; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay.

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