9 Helicobacter pylori as a risk factor for cancer

9 Helicobacter pylori as a risk factor for cancer PENELOPE M. WEBB DAVID FORMAN The final sentence of Marshall’s, now classic, letter to the Lancet in June 1983 (Marshall, 1983) suggests that the, then unidentified, curved bacilli found in human gastric epithelia ‘may have a part to play in poorly understood, gastritis associated diseases (i.e. peptic ulcer and gastric cancer)‘. Exactly eleven years later, in June 1994, the International Agency for Research on Cancer convened a Working Group which reviewed over 350 papers on the relationship between Helicobacter pylori and gastric cancer and came to the conclusion that this relationship was causal (International Agency for Research on Cancer, 1994). This conclusion was reached after considering a wealth of evidence concerning the epidemiology of H. pylori, specific studies of the association between infection and the risk of cancer and mechanistic evidence about the pathogenicity of the bacterium. It is extremely rare for such a body of evidence to accumulate in a short time period and permit a definitive judgment about the carcinogenicity of an environmental exposure. Marshall’s conjecture in 1983 has proven to be remarkably prophetic, so much so that H. pylori eradication is now envisaged as a method of cancer prevention. The objectives of this chapter are to review briefly the epidemiology of gastric cancer and then to summarize the evidence, both epidemiological and mechanistic, which shows that some considerable fraction of this lethal disease may be caused by infection with H. pylori. Finally the public health implications of this relationship are discussed.

THE

EPIDEMIOLOGY

OF GASTRIC

CANCER

Gastric cancer is the second most common cause of cancer mortality in the world, having caused an estimated 620000 deaths in 1985 (Pisani et al, 1993) while 775 000 new cases were diagnosed (Parkin et al, 1993). Because it is predominantly a disease of the elderly, these figures are expected to rise as people live longer and it has been calculated that, if the 1985 rates are maintained, there will be more than 870 000 gastric cancer deaths per year by the year 2000 (Pisani et al, 1993), even though the age corrected incidence is falling (see below). Baillike’s Clinical Gastroenterology563 Vol. 9, No. 3, September ISBN &7020-1961-5

1995

Copyright 0 1995, by Baillikre Tindall All rights of reproduction in any form reserved

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Geographic trends There is considerable geographic variation in the incidence of gastric cancer (Parkin et al, 1992). It is most common in Eastern Asia, the exUSSR and parts of South America, with age-standardized incidence rates in Japanese men of up to 90 per 100 000 per year. The lowest rates are found in North America and Australasia, with 15 or fewer cases per 100 000 males per year, and very low rates have also been reported for parts of Africa, although registration may be less complete there. Western European countries have rates between these two extremes. There can also be considerable variation between the rates in different parts of the same country. In the northern hemisphere there is a tendency towards a north-south gradient with higher rates observed in more northerly regions. This pattern can be seen in countries as far apart as Italy, where the incidence of gastric cancer is much lower in Sicily in the south (16/100 000 males) than in Florence further north (40/100 000) (Parkin et al, 1992), and in China where the cumulative mortality rate (O-64 years) ranges from 3 per 1000 in Guangdong province in the south, to 80-90 per 1000 in Gansu province in the north. Isolated pockets of very high rates have also been observed in China with cumulative mortality rates up to 133 per 1000 males (Chen et al, 1990). Demographic

and socio-economic

trends

Gastric cancer rarely occurs below the age of 30, but after this rates steadily increase with age and the highest rates are seen in the oldest age groups. In the younger age groups it occurs with a similar frequency in men and women, but in the older age groups the rates in men are about twice those in women (Howson et al, 1986). There is a two or three-fold difference between the rates seen in different socio-economic classes, with higher rates occurring in those of lower socio-economic status (Howson et al, 1986). A large variation is also seen between different racial groups living in the same area; in Los Angeles the age-standardized incidence rate of 7.4 per 100 000 white males in 1983-87 compares with rates of 14.8 in blacks, 29.7 in Japanese and 41.5 in Koreans (Parkin et al, 1992). Time trends The most striking feature of the epidemiology of gastric cancer is, however, the marked decline in mortality and incidence rates that has occurred over the last few decades (Howson et al, 1986). The earliest recorded fall began around 1926 in the United States when, over a period of three decades, gastric cancer declined from being the leading cause of cancer death in males to become only the sixth most common. Similar changes were observed in Europe from around 1940 onwards and, more recently, the rates in the high risk countries like Japan have also begun to fall. This decline has occurred in almost all populations studied (Coleman et al, 1993) suggesting that over the last 50 or 60 years there has been a dramatic

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decease in the worldwide prevalence of a risk factor(s) for gastric cancer and/or an increase in the prevalence of a protective factor(s).

TYPES

OF GASTRIC

CANCER

In 1965, Lauren (1965) described two major histological forms of gastric cancer: a well-differentiated ‘intestinal’ type that forms definite glandular structures that are intestinal in appearance and an undifferentiated ‘diffuse’ type characterized by a lack of cellular cohesiveness and diffuse infiltration of the gastric wall. These two types differ, not only in their morphology, but also in their epidemiological characteristics; intestinal-type gastric cancer is more common in males and in the older age groups, while diffuse-type gastric cancer is relatively more common in the younger age groups and has a male-to-female ratio closer to one. Areas with high rates of gastric cancer have a higher proportion of intestinal-type tumours than low-risk areas and it has been estimated that it is this excess of intestinal cancers that accounts for the overall high rates in these areas (Muiioz et al, 1968). The decline in gastric cancer rates has also been attributed primarily to a fall in the rates of intestinal cancer (Sipponen et al, 1987).

THE

MULTISTAGE

MODEL

OF GASTRIC

CARCINOGENESIS

In 1975, Correa and colleagues (1975) put forward a multistage model for the process of gastric carcinogenesis suggesting that the intestinal-type of gastric cancer developed, over several decades, as the end result of a progression of increasingly severe gastric lesions; from superficial to chronic gastritis, followed by the development of atrophy, intestinal metaplasia, dysplasia and finally cancer (Correa, 1988, 1992). They postulated an important role for gastric hypochlorhydria, subsequent to chronic atrophic gastritis and extensive degeneration of acid secreting cells. Loss of gastric acidity would create permissive pH conditions for general bacterial colonization by species which could reduce nitrate to nitrite and catalyse the formation of carcinogenic N-nitroso-compounds. At that time gastric irritants, such as aspirin and salt, were thought to be responsible for triggering this sequence of events (Correa et al, 1975). The multistage model is supported by the observation that patients with severe gastric lesions also have earlier stages in the progression of the disease in other regions of the stomach. In a cross-sectional study in Columbia, for instance, all 95 subjects with gastric dysplasia also had both intestinal metaplasia and chronic atrophic gastritis, while all 447 subjects with intestinal metaplasia also had chronic atrophy (Correa et al, 1990a). Follow-up studies have also concluded that gastric disease tends to progress, over time; from gastritis to chronic atrophy and intestinal metaplasia (Correa et al, 1990b; Villako et al, 1991) and from mild to moderate and severe dysplasia and finally cancer (Rugge et al, 1991).

566

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EVIDENCE FOR A ROLE FOR HELICOBACTER THE DEVELOPMENT OF GASTRIC CANCER

AND

D.

PYLORI

FORMAN

IN

An observation that, like other diseases with an infectious aetiology, the risk of gastric cancer was related to overcrowding in childhood, prompted suggestions that an infectious agent, such as H. pylori, might play a role in the process of gastric carcinogenesis (Barker et al, 1990). There is now considerable epidemiological evidence to support this hypothesis. Geographic

studies

Several groups have compared the prevalence of H. pylori infection in areas with differing rates of gastric cancer but one drawback of all of these studies is that H. pylori infection rates are compared with gastric cancer rates for the same time period. If, however, the organism is a cause of gastric cancer, then cancer rates would be determined by the prevalence of infection several decades earlier. Changes in the prevalence of H. pylori over time could, therefore, mask any potential association. Notwithstanding this problem, there is some evidence that areas with high rates of gastric cancer also have a high prevalence of H. pylori infection (Table 1). Significant associations were seen between gastric cancer mortality rates and the prevalence of H. pylori in two areas in Columbia (Correa et al, 199Oc), in three areas in China (Lin, 1989) and 46 rural counties in China (Forman et al, 1990). A notable observation in the latter study was the fact that, although several counties had a high seroprevalence of H. pylori but low gastric cancer rates, there were no counties with a low prevalence of H. pylori and a high gastric cancer rate. Finally, an international study that compared 17 populations from 13 different countries worldwide, chosen to reflect the global range in gastric cancer incidence, also found a significant association between the seroprevalence of H. pylori and the gastric cancer rates in these areas (The EuroGast Study Group, 1993a). In contrast, no difference was found between the seroprevalence in high and low risk areas of Costa Rica (Sierra et al, 1992) and Italy (Palli et al, 1993), while two groups failed to find an association between H. pyloriseropositivity and gastric cancer mortality in four (Fukao et al, 1993) and five (Tsugane et al, 1993) regions of Japan. In each of these latter studies, however, there was considerably less variation in gastric cancer rates than in those that did report an association. Another important exception to the general pattern is seen in Africa, where very low gastric cancer rates accompany a very high prevalence of H. pylori-seropositivity (Holcombe, 1992). Case-control studies Many groups have documented the seroprevalence of H. pylori in patients following the diagnosis of gastric cancer. There is, however, evidence that the bacterium cannot live on atrophic or metaplastic mucosa (Dixon, 1992) and that the infection may be lost following the development of

624 1882 3194

5 46 17

Japan China 13 Countries

of the association

26(F)-150(M/F) 20 & 49 16(F)-70(M) S-60 48-136(M)’ 40-l 17(F)’ 2.2-5.7%2 0.3-6.9%3 0.3%(F)-9.9%(M)’

Gastric cancer rates (per 100 000 or %)

studies

I Standardized mortality rate; ’ Cumulative mortality rate O-74 years; 3 Cumulative F, females; M, males; The sex is stated where the group with the highest or lowest

18 282 930 690 1815

No, Subjects

2 2 2 3 4

No. Areas

1. Geographic

Colombia Costa Rica Italy China Japan

Country

Table

63 & 93% 12 & 66% 44&45% 13-63% 5@60% 41-60% 63-86% 28-96% 8-89%

cancer.

P=O.Ol NS NS P < 0.01 NS NS NS P = 0.02 P = 0.002

Results

and gastric

Tsugane et al (1993) Forman et al (1990) EuroGast Study Group (1993)

Correa et al (199Oc) Sierra et al (1992) Palli et al (1993) Lin et al (1989) Fukao et al (1993)

Reference

mo&dity rate O-64 yeas; rate was only one sex. NS, not statistically significant.

cancer

pylori

of H. pylori

Helicobacter

Prevalence

between

568

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WEBB

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severe atrophy, intestinal metaplasia or cancer (Karnes et al, 1991). In one study, 4 out of 15 (27%) gastric cancer patients who were negative for H. pylori IgG by ELISA showed recognition of the H. pylori cytotoxin-associated 120 kDa protein by Western blotting, suggesting that they had previously been infected (Crabtree et al, 1993). Such ‘false negatives’ may reduce the observed prevalence of infection in patients with cancer and so lessen the chances of detecting an association with H. pylori infection. The results from retrospective case-control studies have, therefore, to be interpreted with caution. The results from eleven studies, that used serology to compare infection rates in gastric cancer patients and control groups of asymptomatic volunteers and patients without gastrointestinal conditions, are shown in Table 2. In six studies there was a significant association between H. pyloriseropositivity and either gastric cancer overall (Sipponen et al, 1992; Hansson et al, 1993; Asaka et al, 1994; Kikuchi et al, 1995) or specifically with non-cardia cancer (Talley et al, 1991; Blaser et al, 1993). In four studies there were no differences between the seroprevalence in cases and controls (Archimandritis et al, 1993; Kuipers et al, 1993; Lin et al, 1993; Fukuda et al, 1995) although, in the study of Fukuda et al (1995), an association was seen in the younger patients and those with early or small cancers who might be less likely to have chronic atrophy that could have led to spontaneous loss of H. pylori infection. In this study, a significant association was also seen between H. pylori infection and gastric cancer in the whole population after adjustment for the ratio of serum pepsinogen A and C levels, as an indicator of the presence of chronic atrophy. In the only study that reported a higher seroprevalence of H. pylori in controls than in gastric cancer cases (Estevens et al, 1993) 89% of patients with less advanced tumours were seropositive compared with only 67% of patients with more advanced tumours, suggesting that the development of more severe disease could have been accompanied by a loss of H. pylori infection. It is also notable that higher odds-ratios were seen in younger patients; 6.0 in those aged I70 years (Talley et al, 1991), 9.3 in those aged < 60 (Hansson et al, 1993) and 13.3 in those aged <40 (Kikuchi et al, 1995). Furthermore the Swedish study (Hansson et al, 1993) reported a trend towards increasing risk with decreasing age at diagnosis. Most studies that have been able to distinguish between intestinal and diffuse-type tumours have reported similar H. pylori-seroprevalence rates in both types although two studies (Parsonnet et al, 1991 b; Tatsuta et al, 1993) reported significantly higher rates in intestinal type cases (80-90% compared with about 30% in diffuse-type cancers). In contrast, cancers of the gastric cardia have not been associated with H. pylori infection with odds-ratios of 0.94 (95% CI, 0.34-2.6) (Talley et al, 1991) and 1.4 (95% CI, 0.44-4.8) (Hansson et al, 1993) in two case-control studies. Prospective

studies

The strongest evidence for an association between H. pylori infection and the subsequent development of gastric cancer has come from prospective

2 70 year

105

69 37 54 41 29 19 80 112 93 116 148 213 282

No.

’ After adjustment for PgA/C as a marker NS-not statistically significant.

Japan

Holland Taiwan Japan Japan

Portugal Sweden

Age c 40 year

All Non-cardia All Non-cardia All Non-cardia All All Non-cardia All All All All

USA

Finland Greece Japan

Cases

Country

of chronic

89%

52% 65% 70% 72% 83% 90% 70% 80% 93% 77% 62% 88% 76%

%+ve

Table

atrophy.

Hospital/Screening

GI patients Health check participants Asymptomatic Outpatients (cancer free)

Blood donors and outpatients Hospital patients

(non-cancer)

of Helicobacter

and patients

studies

Other cancers Healthy subjects Outpatients

Volunteers

Controls

2. Case-control

pylori

203

84 50 58 38 80 103 103 116 92 213 767

252

No.

cancer.

39%

51% 68% 67% 63% 82% 61% 61% 79% 62% 75% 74%

38%

%+ve

and gastric

1.6 (0.8-3.4) 2.7 (1.0-7.1) P < 0.05 1.2 (0.5-3.0) 2.1 (0.7-6.4) 6.0 (1.1-3.4) NS 2.6 (1.4-5.0) 3.1 (1.5-6.3) NS 1.0 (0.6-1.8) P < 0.01 1.0 (0.7-1.5) 1.71(1.0-2.8) 13 (5.3-36)

Odds ratio (95% Cl)

et al (199 1)

et al (1993) et al (1993)

Kikuchi

et al (1995)

Kuipers et al (1993) Lin et al (1993) Asaka et al (1994) Fukuda et al (1995)

Estevens Hansson

Sipponen et al (1992) Archimandritis et al (1993) Blaser et al (1993)

Talley

Reference

570

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studies (Table 3). Each of these made use of an established cohort to compare subjects who developed gastric cancer with a group of matched controls who did not. Specific anti-H. pyZuri antibodies were measured in blood samples collected up to 24 years prior to the diagnosis of cancer. Four groups have reported significantly elevated odds-ratios (between 1.8 and 6.0) for the development of gastric cancer following H. pyZoriseropositivity (Forman et al, 1991; Nomura et al, 1991; Parsonnet et al, 1991a; Hansen et al, 1994), while two studies from Taiwan and China, with a shorter follow-up period, have respectively reported a weaker nonsignificant association (Lin et al, 1995) and no association (Webb et al, 1995). On the basis of these studies it has been estimated that 35-55% (Forman et al, 1991) and 37-89% (Nomura et al, 1991) of gastric cancers could be attributable to H. pylori infection. When the data from the first three prospective studies (Forman et al, 1991; Nomura et al, 1991; Parsonnet et al, 1991a) were pooled, the risk of gastric cancer following H. pylori infection was found to increase significantly with the length of follow-up with an almost nine-fold risk observed after 15 or more years (Forman et al, 1994). This is consistent with the idea that gastric cancer patients test H. pylori negative shortly before the diagnosis of cancer although they were previously infected, and suggests that the strength of the H. pylori-gastric cancer association might be even greater than that reported from individual studies to date. Temporal

and socio-demographic

trends

Parallels between the epidemiology of gastric cancer and H. pylori infection are also compatible with a causal association. There is evidence that, like gastric cancer rates, H. pylori seroprevalence has fallen over the last few decades. In a study using sera stored from 1969, 1979 and 1989, the odds of being H. pylori-seropositive decreased by 26% per decade (Banatvala et al, 1993). Improvements in living conditions and trends towards a smaller family size could explain this reduction which could, in turn, help to explain the fall in gastric cancer rates. Similarly, the two or three-fold excess of gastric cancer seen in those of lower socio-economic status (Howson et al, 1986) is matched by a similar excess of H. pylori infection in these socioeconomic groups (Sitas et al, 1991; Webb et al, 1994; Feldman, this volume). An association with H. pylori infection cannot, however, explain the approximately two-fold excess of gastric cancer seen in males. Although one study of young adults in California found a significant association between male gender and H. pylori infection (Replogle et al, 1994) most groups have reported similar infection rates in males and females (Taylor and Blaser, 1991; The EuroGast Study Group, 199313). MECHANISMS

OF GASTRIC

CARCINOGENESIS

There are important experimental observations that lend additional support to the association and lay some foundations for understanding the

Male Both Male Both Both Male

United Kingdom California, USA Hawaii, USA Taiwan Norway China

I Median follow-up. * Not reported.

Sex

country

Table

6.0 14.2 13.5 3.1 12.4l 2.4

Follow-up (Mean/year)

3. Prospective

studies

29 109 109 29 201 52

No.

between

69% 84% 94% 69% NR2 58%

Cases H. pylori +ve

of the association

116 109 109 220 402 156

No.

Helicobacfer

47% 61% 76% 59% NR 55%

2.8 3.6 6.0 1.6 1.8 1.1

Odds ratio

and the development

Controls H. pylori +ve

pylon’

cancer.

1 .O-8.0 1.8-7.3 2.1-17 0.7-2.6 1.2-2.6 0.6-2.1

95% CI

of gastric

Forman et al (1991) Parsonnet et al (1991a) Nomura et al (199 1) Lin et al (1995) Hansen et al (1994) Webb et al (1995)

Reference

Y

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mechanistic basis of the relationship. Before reviewing this work it should be emphasized that there is no evidence that H. pylori infection is, in itself, directly genotoxic or mutagenic. Thus, unlike certain viral agents which can cause cancer, such as certain strains of the human papilloma virus, there does not appear to be any direct interaction between the bacteria and host DNA which gives rise to mutations and transformed cell phenotypes. A number of constitutive properties of H. pylori may be of relevance to cancer without being specifically carcinogenic. Thus, it has been suggested that ammonia, or ammonium-containing substances, abundantly produced as a result of H. pylori urease activity, may act as cancer promoters enhancing rates of cell division (Tsujii et al, 1992). H. pylori also produces phospholipases which may damage the phospholipid bilayer of the epithelial cell membrane (Marshall, 1991) and degrade the protective mucus layer (Goggin et al, 1991; Sidebotham et al, 1991). Some strains of H. pylori produce a vacuolating cytotoxin (Leunk et al, 1988) associated with increased pathogenic activity and ulcerogenesis (Figura et al, 1989). All of these activities may impair host defence and render the gastric epithelial cells prone to the activity of direct-acting carcinogens. Other important and potentially ‘carcinogenic’ properties of H. pylori infection result from the host’s immune response to the bacteria. A defining feature of gastritis is infiltration of the gastric epithelium by a variety of leukocyte cell types. Stimulation of such cells should, theoretically, lead to the activation of both specific and non-specific immune defence mechanisms that would eventually cause limitation and resolution of the infection. The immune response to infection is complex and is reviewed elsewhere in this volume (Calam, this volume). It is characterized by the up-regulation of several cytokines, especially IL-8 and the induction of proteolytic enzymes, adhesion molecules and reactive oxygen metabolites. What is of relevance, in the context of carcinogenesis, is that this intended bactericidal response is not short-lived but may continue indefinitely as the H. pylori infection avoids immune defences and becomes established. Thus the toxic response, may, over an extensive time period, cause structural and biochemical damage to the gastric epithelium of the host (Dixon, this volume). One example of this dysfunctional host defence response is the excessive production of reactive oxygen metabolites by stimulated neutrophil polymorphs and monocytes. These are highly reactive chemicals, often free radicals, and are capable of causing extensive DNA damage and molecular mutations (Davies, 1994a). It has been shown that H. pylori infected gastric epithelium has a significantly higher level of these compounds than normal epithelium (Davies et al, 1994b; Drake et al, 1994) and that eradication of the bacteria restores normal levels (Drake et al, 1995). Interestingly gastritis, in the absence of H. pylori, appears not to increase concentrations of oxidative metabolites (Davies et al, 1994b). Genetic damage by persistent inflammation may be mediated by other chemicals, such as oxides of nitrogen, which are synthesized by stimulated neutrophils and monocytes (Iyengar et al, 1987), and lead to the formation of N-nitroso-compounds (Grisham et al, 1992) and nitric oxide which can induce DNA damage (Wink et al, 199 1; Nguyen et al, 1992). The relative importance to carcinogenesis of the varied

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consequences of inflammation is currently unclear and, unless it can be demonstrated that there is a single predominant mechanism, it would be prudent to assume that several pathways lead to the same end result. There are two further responses to H. pylon infection that are likely to be of profound significance to carcinogenesis. Firstly, H. pyloriassociated gastritis is associated with a significant decrease in the concentration of ascorbic acid in gastric juice (Sobala et al, 1989; Webb et al, 1993; Banerjee et al, 1994; Rood et al, 1994). This effect is independent of dietary intake and plasma ascorbate concentrations and the underlying mechanism is unclear, although it is thought that active secretion of ascorbic acid from the circulation is disrupted (Schorah et al, 1991). Ascorbic acid is a critical antioxidant which has important functions as a scavenger of reactive oxygen species (Frei et al, 1989) and inhibits N-nitrosation (Mirvish, 1994). There is abundant evidence that high consumption of fresh fruits and vegetables protects against several types of cancer, including gastric cancer, (Steinmetz and Potter, 1991; Block et al, 1992) and it is believed that the antioxidant properties of ascorbic acid are central to this chemopreventive effect. Any process that reduces the effectiveness of ascorbic acid is, therefore, likely to increase the risk of cancer. The second general response to H. pylori infection is a substantial increase in gastric epithelial cell turnover rates. Studies in varied populations have shown an approximate doubling of cell turnover associated with H. pylori infection and a restitution of normal levels after successful eradication therapy (Brenes et al, 1993; Cahill et al, 1995; Lynch et al, 1995). As stated above, this may result from the effect of ammonia. Cell division is, of course, vital to the development of cancer (Preston-Martin et al, 1990) and an elevated rate of mitosis increases the likelihood of a somatic DNA mutation avoiding the surveillance of DNA repair enzymes and becoming fixed (Ames and Gold, 1990). There is no particular conflict between Correa’s model of gastric carcinogenesis discussed earlier and the understanding brought about by research into H. pylori. It is now known that H. pylori has evolved to colonize the normochlorhydric stomach and that the chronic degeneration of the gastric epithelium, resulting from infection, will eventually lead to necrosis and atrophy. Thus H. pylori can be regarded as a major (if not the major) environmental determinant for the first stage in the sequence of events leading to cancer. The physiological and biochemical changes associated with H. pylori infection, summarized above, may then enhance the progression through the subsequent stages (Villako et al, 1990; Kuipers et al, 1994). H. pylori’s role in cancer development must, however, be largely restricted to ‘early’ events as the bacterium will not colonize cancerous tissue or the common precursor, intestinal metaplasia (Dixon, 1992). Thus, events beyond the establishment of intestinal metaplasia are likely to be determined by other risk factors as proposed by Correa (Correa et al, 1975; Correa, 1988, 1992). The question of which stages in the development of gastric cancer are H. pylori-associated is of great importance if bacterial eradication is to be used

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as a cancer prevention measure, as discussed below. It is, however encouraging to note that most of the H. pylori-induced changes that may be of relevance to carcinogenesis, e.g. formation of reactive oxygen metabolites, suppression of secretion, ascorbic acid, stimulation of cell turnover, can all be reversed following successful eradication (Sobala et al, 1993; Brenes et al, 1993; Ruiz et al, 1994; Drake et al, 1995). In comparison with the high prevalence of H. pylori infection, gastric cancer is a very rare event but, as yet, it is unclear what additional factors are required for a bacterial gastritis to become malignant. Related to this is the question of why certain populations, notably in Africa (Holcombe, 1992), have low gastric cancer rates despite almost universal infection. Whether the host’s genetic background (Blaser, 1993), the age at acquisition of infection (Blaser et al, 1995) or the presence of other environmental co-factors are important requires clarification. One key issue concerns gastric acidity in that this is usually increased following infection (El-Omar et al, 1993) yet cancer is generally associated with a reduction in acidity. This apparent contradiction is further demonstrated in the observation that patients who have had a duodenal ulcer seem less likely to develop gastric cancer (Lee et al, 1990; Parsonnet et al, 1991a), despite the association of both diseases with H. pylori. A possible explanation that partly explains these discrepancies relates to the underlying level of gastric acid output (Dixon, 1993). This may be determined by both genetic and nutritional factors and, in those populations with high acid output, the corpus of the stomach (the site of acid-secreting cells) would be protected from H. pylori colonization and the development of corpus gastritis which is likely to become atrophic and lead to cancer. In contrast, individuals with low acid output would lack such protection. One particularly interesting question is whether toxogenic strains of H. pylori are specifically associated with gastric cancer. Such strains exhibit a more aggressive pathological behaviour together with enhanced upregulation of host cytokines (Calam, this volume). In particular, strains with the cytotoxin-associated gene cagA are found more frequently in duodenal ulcer patients than in asymptomatic H. pylori infected individuals (Crabtree et al, 1991). There is now evidence that cagA-positive strains are more prevalent, in cancer patients (Crabtree et al, 1993) and in patients with precursor lesions (Fox et al, 1992). One epidemiological study (Blaser et al, 1994) showed that gastric cancer patients with H. pylori infection had a significantly higher prevalence of antibodies to Cag-A protein than control subjects with H. pylori infection. THE ROLE NEOPLASIA

OF HELICOBACTER

PYLORI

IN OTHER

Gastric lymphoma There is increasing evidence that H. pylori infection might play a role in the development of some types of gastric lymphoma. The incidence of primary

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gastric lymphoma was several-fold higher in an area of north-eastern Italy with a high prevalence of H. pylori (89%) than in three similar communities in the UK with an average H. pylori prevalence rate of 50-60% (Doglioni et al, 1992). The prevalence of H. pylori infection in series of patients with primary gastric lymphoma is also very high; 101 of 110 (92%) patients with primary B-cell mucosa-associated lymphoid tissue (MALT) lymphoma in the United Kingdom had histological evidence of infection (Wotherspoon et al, 1991) while H. pylori colonization was found in 175 of 178 (98%) surgical specimens containing primary malignant B-cell lymphomas in Germany (Stolte and Eidt, 1993). In a prospective case-control study, patients with gastric non-Hodgkin’s lymphoma (NHL) were significantly more likely to have been infected with H. pylori, before they developed NHL, than controls (odds-ratios 6.3; 95% CI 2.0-20) (Parsonnet et al, 1994). There was, however, no association with the development of extra-gastric NHL (odds ratios 1.2; 0.5-3.0). Although the stomach does not normally contain lymphoid tissue, this is acquired in response to local infection by H. pylori. The organism can stimulate cellular proliferation of low-grade B-cell gastric MALT lymphomas in vitro (Hussell et al, 1993). Further evidence to support a role for H. pylori in the development of gastric lymphoma has come from two intervention studies where the regression of low-grade MALT lymphomas was observed following successful eradication of the organism in five of six patients (Wotherspoon et al, 1993) and after treatment in 12 of 16 patients (Stolte et al, 1993). Cancer at other anatomical

sites

There is no evidence to suggest that H. pylori infection is associated with the development of cancer at sites other than the stomach but this possibility has rarely been studied. In a geographic study in China, the seroprevalence of H. pylori in 46 counties was not significantly correlated with mortality rates from cancer at 12 sites other than the stomach, although an association with all types of lymphoma did reach borderline significance (Forman et al, 1990). One case-control study that compared gastric cancer patients with other cancer patients reported H. pylori seroprevalence rates of 51% in colorectal cancer, 49% in oesophageal cancer and 56% in lung cancer giving odds-ratios (adjusted for age and sex) of 1.8 (95% CI, 0.86-9.4), 1.4 (0.58-3.4) and 1.8 (0.91-3.6) respectively when compared with the cancer-free control group (Talley et al, 1991). CLINICAL

IMPLICATIONS

As discussed above, it has been estimated that more than one third and possibly as many as 90% of gastric cancers might be attributable to H. pylori and, therefore, would not occur in the absence of infection. Furthermore, if the maximum odds ratio of 8.7 observed for a follow-up of 15 years or more in the pooled cohort analysis (Forman et al, 1994) is an

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accurate estimate of the strength of the association, then an estimated 690 000 of the 750000 cases diagnosed in 1985 could potentially have been avoided. Therefore worldwide eradication of the organism could theoretically, have a major impact on the global burden of cancer. There are several possible ways in which the prevalence of H. pylori could be decreased in order to reduce gastric cancer rates. Transmission of infection could be prevented by reducing exposure to the bacteria or by vaccination against the organism. Alternatively, screening programmes could be implemented to identify infected subjects who could then be treated. Prevention

of infection

Of the two strategies for prevention of infection, effective vaccination (Lee, this volume) is unlikely to be a viable option in the foreseeable future. Any vaccination programme would have to be a very long-term strategy as infection is thought to be acquired early in life and vaccination would, therefore, have to be targeted at children. It would then be 50 years or more before any reduction was seen in the rates of gastric cancer, which is primarily a disease of the elderly. The second option, reducing exposure to the organism, is also likely to be impractical. If the apparent reduction in infection rates in developed countries over the last century (Banatvala et al, 1993) has resulted from improvements in living conditions, it is unlikely that further improvements will occur sufficiently quickly to bring rates much lower. Moreover, the developing countries that would benefit most from such improvements are probably least able to afford to implement them. Screening and treatment of infection With the exception of gastric MALT lymphoma there is, as yet, no evidence that eradication of H. pylori benefits patients who have already developed gastric cancer. Although eradication leads to healing of chronic gastritis (Rauws et al, 1988) the effects on more severe lesions are less well understood and, while there are reports that gastric atrophy (Borody et al, 1993), intestinal metaplasia (Hack et al, 1994) and dysplasia (Marrero et al, 1994) improve following successful H. pylori eradication, others have reported that while atrophy is improved, the type and degree of intestinal metaplasia remained unchanged two years following eradication (Onishi et al, 1994). It is, therefore, unclear at which stages of the disease process H. pylori eradication can reverse or halt the disease process and thus reduce the subsequent risk of cancer. In a pilot intervention trial in Venezuela, H. pylori eradication was achieved in only 6.5% of the treatment group compared with 2.0% of the placebo group (Buiatti et al, 1994) suggesting that either the therapy was ineffective or that re-infection rates were very high. From a public health perspective, therefore, we have the capability to identify and treat infected individuals, at least in developed populations, but there is as yet no clear indication as to who should be tested for

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infection or what should be done for those who test positive. It would clearly be impossible to treat the estimated 50% of the world population who carry this infection. Finally, it is worth noting that both gastric cancer and H. pylori infection rates are already declining and any measures designed to further reduce these rates would have to be very cost-effective to achieve more than is already occurring in the absence of any planned intervention.

SUMMARY In 1985, gastric cancer was the second most common cause of cancer death in the world. The rapid decline in gastric cancer rates over the last few decades has been attributed to a decline in the prevalence of environmental risk factors for gastric cancer and/or an increase in the prevalence of protective factors. One such risk factor could be the bacterium Helicobacter pylori. Epidemiological studies have shown that areas with high gastric cancer rates often have a correspondingly high prevalence of H. pylori and prospective studies have shown that subjects with serological evidence of H. pylori infection were significantly more likely to go on to develop gastric cancer than those who did not. Helicobacter pylori itself does not appear to be either genotoxic or mutagenic. Infection is, however, associated with increased cell turnover, a chronic immune response accompanied by increased levels of reactive oxygen metabolites and a reduction in gastric levels of ascorbic acid, all conditions that could favour the development of cancer. Nonetheless, the majority of those who are infected with H. pylori do not go on to develop gastric cancer and other factors, such as the strain of the infecting organism or consumption of dietary antioxidants including vitamin C, could also affect the risk of cancer. Finally, it has been estimated that more than one third, and possibly as many as 90% of gastric cancers might be attributable to infection with H. pylori. Prevention and treatment of infection are, therefore, possible approaches to reducing gastric cancer rates. It is, however, unclear what, if any, effect eradication of the infection would have on an individual’s risk of gastric cancer and, to date, anti-Helicobacter therapy has only been shown to be of potential benefit in the treatment of low grade gastric MALT lymphomas.

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