1. Exposure Data

1.3. Epidemiology of infection

H. pylori infection is long-standing and only rarely resolves spontaneously; it may occasionally be influenced by concomitant antimicrobiological treatment. Thus, it is the prevalence of this infection rather than its incidence that is usually estimated in epidemiological studies (Langenberg et al., 1988; Kuipers et al., 1993a).

1.3.1. Prevalence

The prevalence of H, pylori infection has been estimated in all the continents on the basis of the results of serological tests on populations such as blood donors, individuals presenting themselves to health centres and volunteers recruited in different ways.

In developing countries, the prevalence of infection increases rapidly during childhood and adulthood and is usually 80–90%. The prevalence is substantially lower in developed countries, especially in childhood (see section 1.3.2). These findings are illustrated in a study in which the same ELISA technique was used in subjects from four countries with different geographical and socioeconomic status (Mégraud et al., 1989) (Figure 1). Similar results were reported in the EuroGast study, in which defined populations of two age groups, 25–34 and 55–64 years, from 17 geographical areas, mainly European, were studied by the same protocol (EuroGast Study Group, 1993a,b; Table 1).

Figure 1.

Distribution of seropositivity for Helicobacter pylori immunoglobulin G antibodies by age and country of origin

Table 1.

Prevalence of seropositivity to Helicobacter pylori in 17 populations.

1.3.2. Risk factors for infection

The difference in prevalence between developed and developing countries seems to be linked to socioeconomic factors rather than to ethnicity. In most developed countries, the poorest people also have the highest prevalence. A low level of education and poor housing conditions have been associated with infection (Al Moagel et al., 1990; Fiedorek et al., 1991; Sitas et al., 1991; EuroGast Study Group, 1993a).

No difference in seroprevalence has been found between men and women (Mégraud et al., 1989), and no consistent association has been found with smoking or drinking habits (EuroGast Study Group, 1993a) or any particular diet (Hansson et al., 1993a; Palli et al., 1993). One study in Japan showed a positive association between eating salty food and infection with H. pylori (Tsugane et al., 1994). No sexual transmission has been observed (Polish et al., 1991). In cross-sectional studies, an association is always observed between prevalence of infection and age (see Figure 1 and Table 1). Two mechanisms may contribute to this age pattern of prevalence: an age effect, i.e. the progressive acquisition of infection throughout adult life (Graham et al., 1991), and a cohort effect, i.e. a progressive reduction of the rate of infection early in life of people in successive birth cohorts. The extent to which these two effects contribute to the cross-sectional association of age with prevalence of infection may vary between populations. The following observations indicate the relative importance of a cohort effect:

• - Infection is more strongly correlated to risk factors present during childhood (crowding, size of the family, sharing a bed) than to current risk factors (Mendall et al., 1992; Mitchell et al., 1992; Whitaker et al., 1993; Webb et al., 1994).
• - Among adults in developed countries, new cases of infection are uncommon (Mégraud et al., 1989; Rautelin et al., 1990).
• - Crude rates of seroconversion from negative to positive have been estimated to be around 0.3–0.5% per year (Parsonnet et al., 1992; Kuipers et al., 1993a); recurrence of infection after eradication therapy may reflect recrudescence of the treated infection rather than true reinfection.
• - The cohort effect has been demonstrated in a cohort in the USA (Parsonnet et al., 1992) and in a cohort in the Netherlands (Kuipers et al., 1993a) as well as in a study performed in the United Kingdom. In the last study, sera collected from the same area in 1969, 1979 and 1989, tested for H. pylori antibodies by immunoblot and plotted by age group showed that at a given age the prevalence had decreased over the two decades (26% per decade) (Banatvala et al., 1993).

In some populations, a decrease in seroprevalence has been observed in older people. This finding has been attributed to the disappearance of H. pylori from the gastric mucosa (loss of H. pylori infection) when atrophy develops as a result of long-standing gastritis. Such loss has been observed in some populations (Karnes et al., 1991; Kuipers et al., 1994b) but not in another (Guarner et al., 1993). Furthermore, it is still unclear whether a gradual decrease in H. pylori colonization also leads to negative seroconversion. Negative seroconversion was claimed in one retrospective study (Crabtree et al., 1993a) but not in two prospective studies (Parsonnet et al., 1992; Kuipers et al., 1994a).

The prevalence of infection is consistently higher in institutionalized children than in control groups from the surrounding area (Berkowitz & Lee, 1987; Pérez-Pérez et al., 1990).

For a long time, the stomach was thought to be sterile, and precautions such as the use of gloves were not taken in performing endoscopies. A higher prevalence of H. pylori infection has now been found among gastroenterologists who perform endoscopies than among other physicians or dentists (Mitchell et al., 1989). In countries with a high prevalence of infection, endoscopists have, nevertheless, a lower prevalence than the general population, probably due to the fact that they come from the middle and upper classes (Matysiak-Budnik et al., 1994).

1.3.3. Routes of transmission

Reservoirs of H. pylori are the digestive tracts of humans and some primates. Transmission from reservoirs is considered to be person-to-person. This assumption is supported by the finding of clustering of similar strains within families, as shown by molecular fingerprinting (Bamford et al., 1993) and by the consistent demonstration of close interpersonal contact as a risk factor for infection. The H. pylori status of mothers of H. pylori-positive children is significantly different from that of mothers of H. pylori-negative children, indicating that the intimate contact between mother and child could be a cause of transmission (Drumm et al., 1990). Transmission can exist between couples: 68% of spouses of H. pylori-infected people were infected, whereas 9% of spouses of uninfected people were infected (Malaty et al., 1991). In another study, the association disappeared in a multiple logistic regression analysis (Pérez-Pérez et al., 1991). Two modes of transmission have been proposed: oral-oral and faecal-oral transmission.

(a) Evidence for faecal-oral transmission

H. pylori is eliminated in faeces after turnover of the gastric mucosa. It has been detected by PCR (Mapstone et al., 1993) and by culture (Thomas et al., 1992). Consumption of raw vegetables fertilized with human faeces was found to be a risk factor for infection in Santiago, Chile (Hopkins et al., 1993), and consumption of municipal water was found to be a risk factor in children in Lima, Peru (Klein et al., 1991). H. pylori has been detected by PCR in sewage water in Peru (Westblom et al., 1993b).

(b) Evidence for oral-oral transmission

H. pylori has been detected in the oral cavity (Mapstone et al., 1993) and in the saliva of one person (Ferguson et al., 1993). Several claims have been made of the detection of H. pylori by PCR in dental plaque (Krajden et al., 1989; Majmudar et al., 1990). When gnotobiotic puppies infected with H. felis were put together with uninfected litter-mates in a germ-free isolator, with continual oral-oral contact, the agent was transmitted. Transmission did not occur between germ-free mice, which are coprophageous, under the same conditions (Lee et al., 1991).

2. Studies of Cancer in Humans

2.1. Descriptive studies

2.1.1. Geographical correlations

(a) Gastric carcinoma

Table 2 lists eight studies in which the prevalences of H. pylori infection were compared in geographical regions with different gastric cancer rates. The presence of infection was determined in most studies by ELISA for IgG antibodies to H. pylori in serum. In all studies, infection rates were compared with cancer rates in contemporaneous time periods, although a more appropriate comparison would be between infection prevalence rates and cancer rates several years or even decades later. Such a comparison would reflect the time sequence involved if there were a causal relationship between infection and cancer.

Table 2.

Geographical correlation studies of the prevalence of Helicobacter pylori infection and incidence or mortality rates for gastric cancer.

Four of the studies were comparisons of regions of high and low risk for gastric cancer within a single country; two showed a significant difference between H. pylori prevalence rates, with an increase in the high-risk region (in Colombia, Correa et al., 1990a; and in China, Lin et al., 1989), while the other two showed no significant difference between the two regions (in Italy, Palli et al., 1993; and in Costa Rica, Sierra et al., 1992). Two studies from Japan (Fukao et al., 1993; Tsugane et al., 1993) compared populations within five and four areas, respectively; neither showed a significant association between H. pylori seropositivity and gastric cancer mortality.

Forman et al. (1990) examined the prevalence of H. pylori IgG antibodies in 1882 residents of 46 rural counties in China and compared them with the gastric cancer mortality rates in the same counties. The correlation between H. pylori antibody prevalence rate and gastric cancer mortality rate was 0.34 (p = 0.02). The significant positive correlation remained after adjustment for dietary factors associated with risk for gastric cancer (Kneller et al., 1992).

The EuroGast Study Group (1993b) examined the seroprevalence of H. pylori IgG antibodies in 3194 randomly selected subjects resident in 17 centres in 13 countries, chosen to reflect the global range in gastric cancer incidence. In regression analyses, in which the two sexes were combined, there were significant relationships between the prevalence of H. pylori antibodies and both log-transformed gastric cancer cumulative mortality (p = 0.002) and incidence (p = 0.001)rates. Exclusion of the regions with highest and lowest mortality rates (Japan and the USA, respectively) reduced the strength of the relationship with mortality from gastric cancer to a nonsignificant (β = 0.62; p = 0.3) level (Forman et al., 1993).

It has been noted (Holcombe, 1992) in Nigeria and other African countries (e.g. Sudan, Uganda and Zimbabwe) that gastric cancer rates are relatively low (< 2–3 % of all malignant tumours) despite a very high prevalence of H. pylori infection. The populations of other developing countries with low incidence rates of gastric cancer, but for which no estimates of the prevalence of infection are available, include Kuwaitis, non-Jews in Israel, Malays in Singapore and those of Ahmedabad, Bangalore, Madras and Bombay in India. Gastric cancer incidence rates in the three population-based cancer registries in Africa (Sétif, Algeria; Bamako, Mali; and the Gambia) range from 3.9 to 19.4 per 100 000 in males and from 1.5 to 10.3 per 100 000 in females (Parkin et al., 1992). These rates are substantially below those in high-risk regions of the world (e.g. Costa Rica: 46.9 in males and 21.3 in females) and are comparable to the rates in US blacks (12.4 in males and 5.6 in females) and in England and Wales (16.9 in males and 6.8 in females).

(b) Gastric lymphoma

Doglioni et al. (1992) compared the incidence of primary gastric lymphoma, determined from endoscopy clinic records, in an area of northeastern Italy with that in three communities in the United Kingdom. In the Italian city of Feltre, the estimated incidence rate for gastric lymphomas was 66/100 000 per five years for the period 1986–90 (37 cases). In three districts in the United Kingdom, the comparable rates were 6/100 000 (six cases), 4/100 000 (seven cases) and 6/100 000 (20 cases). The H. pylori infection rate of all patients undergoing endoscopic biopsy was 87% in Feltre in 1991 and 50–60% in the United Kingdom. [The Working Group noted that this was a hospital-based study with no information about the referral patterns to the local endoscopy units. There is, therefore, uncertainty about the denominator populations used in this study.]

(c) Other cancers

In the study of Forman et al. (1990) (see above), correlation coefficients were calculated for associations between H. pylori IgG antibody prevalence and mortality rates from cancers at 12 sites other than the stomach. None was significant. The correlation with lymphoma (all types) was 0.32 and of borderline significance.

2.1.2. Time trends

Gastric cancer incidence and mortality rates have been declining rapidly in nearly all developed countries for several years. There are few data for developing countries, but the same trend has generally been observed (Coleman et al., 1993). Secular trends in the prevalence of H. pylori infection have not been investigated extensively, but the one serological study that has been conducted in the United Kingdom (Banatvala et al., 1993) indicated that the prevalence has decreased in recent decades. If H. pylori is acquired predominantly in childhood (see section 1.3.2), then data on age prevalence (section 1.3.1) can be interpreted as indicating a declining prevalence rate over much of the 20th century. This is also consistent with observed secular trends in duodenal ulcer disease in the USA (Sonnenberg, 1993), the United Kingdom (Susser & Stein, 1962) and Europe (La Vecchia et al., 1993), a disease strongly associated with H. pylori infection. Data from Japan (Blaser, 1993) indicate that mortality from gastric cancer in that country has decreased over the past 50–80 years, an effect consistent with a secular decrease in exposure to an environmental agent. The prevalence of gastric cancer of the cardia, in contrast to that of more distal sites within the stomach, has been shown to be increasing in a number of populations (Powell & McConkey, 1990; Blot et al., 1991; Hansson et al., 1993b). Gastric cancer of the cardia has been shown in some studies (Talley et al., 1991a; Hansson et al., 1993b) not to be associated with H. pylori infection (see sections 2.3 and 2.4).

2.1.3. Socioeconomic trends

Gastric cancer has been shown consistently in several countries to be commoner in poorer socioeconomic groups (Howson et al., 1986; Buiatti et al., 1989b; Logan, 1982). The same association has been observed consistently for H. pylori infection (see section 1.3.2).

2.2. Case series

2.2.1. Gastric carcinoma

The presence of H. pylori infection has been determined in numerous series of gastric cancer patients, usually by histological examination of biopsy and/or gastrectomy samples but also by microbiological culture; in some studies, serological tests were used to determine the presence of specific IgG antibodies to H. pylori. A number of studies were designed specifically to estimate the prevalence of H. pylori infection in gastric cancer patients; the majority, however, were broader surveys of patients with upper gastrointestinal disease and included a small subgroup of patients with gastric cancer. In the latter studies, it is unclear whether adequate mucosa was available to evaluate the presence of H. pylori; there was also frequently a subgroup of patients who had dyspeptic symptoms but no lesions in their stomachs and who were used as a control series. In a few studies, the control series were healthy volunteers who had undergone endoscopy. Serologically based studies in which data from matched case and control series were available are summarized in sections 2.3 and 2.4.

Table 3 lists the 11 largest case series. The percentage of gastric cancer patients who had H. pylori infection varied from 43 to 83%. Particular interest has focused on the Laurén histological classification of gastric adenocarcinoma into cancers of the intestinal (glandular) type and cancers of the diffuse type (Laurén, 1965). It has been reported that the incidence of the former varies between populations whereas that of the latter remains relatively constant (Laurén, 1965; Muñoz et al., 1968; Muñoz & Asvall, 1971; Correa et al., 1973). Environmental exposures are thought to be more important in the etiology of intestinal-type than of diffuse-type cancers (Howson et al., 1986). Table 4 lists eight series in which the cancer cases were classified into intestinal and diffuse histological categories. In some of these studies, an increased prevalence of H. pylori infection was seen in association with intestinal-type cancers (Parsonnet et al., 1991a; Tatsuta et al., 1993), but this difference was not observed consistently.

Table 3.

Prevalence of Helicobacter pylori in series of gastric cancer cases.

Table 4.

Prevalence of Helicobacter pylori infection in gastric cancer case series by histological type (Laurén classification).

2.2.2. Gastric lymphoma

Wotherspoon et al. (1991) examined 110 patients in the United Kingdom with gastric B-cell mucosa-associated lymphoid tissue lymphomas, a subset of primary gastric lymphomas. In this group, 101/110 patients (92%) had histological evidence of H. pylori infection.

A total of 205 surgical specimens containing primary malignant B-cell lymphomas were investigated in Germany. H. pylori colonization was found in 175/178 (98%) cases in which the mucosa some distance from the tumour could be evaluated (Stolte et al., 1994).

2.3. Cohort studies

2.3.1. Gastric carcinoma

Four prospective studies have been reported in which the relationship between H. pylori infection and the subsequent risk of gastric cancer has been assessed. All were case–control comparisons nested in prospective cohort studies in which blood samples had been taken from cancer-free individuals and stored. Specific antibodies to H. pylori were then measured in blood samples from individuals who subsequently developed gastric cancer, and the proportion of individuals with antibodies was compared with that in a matched control group.

Forman et al. (1991) compared 29 gastric cancer patients with 116 age-matched controls for the presence of IgG antibodies to H. pylori using a previously described ELISA (Steer et al., 1987) with a reported sensitivity of 93% and a specificity of 96% (Talley et al., 1991b). The subjects were all men taking part in one of two cohort studies: in one study, 20 179 men, aged 35–64 and living in south-east England, provided blood between 1975 and 1982 during a health check-up. In the other study, 2512 men, aged 45–59 and living in Caerphilly, Wales, provided blood between 1979 and 1982 as part of a population study of cardiovascular disease. Cancers or deaths among cohort participants were notified to the study organizers routinely; 23 men with gastric cancer were identified from the first cohort and six from the second. Cancers were diagnosed between 1980 and 1989, with a mean interval between blood sampling and diagnosis of six years (range, four months to 13 years seven months). The mean age of the cancer patients was 54 years (range, 41–63 years) at blood sampling and 60 years (range, 47–76 years) at diagnosis. Four controls were selected for each case by matching on cohort, date of birth (within one year), date of blood sampling (within one year) and number of freeze–thaw cycles the blood sample had undergone. Twenty of the 29 (69%) gastric cancer patients and 54 of the 116 (47%) controls had antibodies to H. pylori, resulting in a matched odds ratio of 2.8 (95% confidence interval [CI], 1.0–8.0). Stratifying the cases and corresponding controls into those diagnosed within five years of blood sampling and those diagnosed five or more years after sampling did not result in a significant difference in the resulting odds ratios. No information was available on site of cancer within the stomach or on histological subtype.

Parsonnet et al. (1991b) compared 109 gastric patients with 109 age-, sex- and race-matched controls for the presence of IgG antibodies to H. pylori using a previously described ELISA (Evans et al., 1989) with a reported sensitivity of 91% and a specificity of 98%. The subjects were taking part in a cohort study in which 128 992 participants living in California, USA, provided blood between 1964 and 1969 during a health check-up. A total of 246 gastric cancer registrations and/or hospitalizations for gastric cancer among cohort participants were notified to the study organizers routinely, and 200 of these were randomly selected. Availability of blood samples resulted in final inclusion of 186 patients with gastric cancer. Cancers were diagnosed between 1964 and 1989, with a mean interval between blood sampling and diagnosis of 14.2 years (range, 1–24 years). One control was selected for each case by matching on age at blood sampling (within one year), sex, race, date of blood sampling (within 0.5 year) and site of the health check-up. Of the 186 patients, 109 had histologically confirmed adenocarcinoma of the stomach; of these, 92 (84%) had antibodies to H. pylori, as did 66 of the 109 (61%) controls, resulting in a matched odds ratio of 3.6 (95% CI, 1.8–7.3). When the cases and controls were stratified by sex, the odds ratio for women was nonsignificantly higher than that for men; when they were stratified by race, the odds ratio for blacks was nonsignificantly higher than that for whites. Eighty-one patients had the intestinal type of adenocarcinoma (Laurén classification), and 67 (83%) of these were seropositive (odds ratio, 3.1; 95% CI, 1.5–6.6); 28 patients had a diffuse type, and 25 (89%) of these were seropositive (odds ratio, 8.0; 95% CI, 1.0–64). Four patients had an adenocarcinoma at a site in the cardia; one was seropositive, as was one of the four matched controls. An additional 27 patients had adenocarcinoma of the gastroesophageal junction (not included in the main analyses above); of these, 17 (63%) were seropositive, as were 19 (70%) controls (odds ratio, 0.8; 95% CI, 0.3–2.1).

Nomura et al. (1991) compared 109 patients with gastric carcinoma with 109 age-matched controls for the presence of IgG antibodies to H. pylori using a commercial ELISA. The subjects were all men taking part in a cohort study in which 7498 Japanese-Americans living in Oahu, Hawaii, USA, provided blood between 1967 and 1970 as part of a population study of heart disease. A total of 137 gastric cancer registrations and/or hospital discharges for gastric cancer among cohort participants were notified to the study organizers routinely, all with histologically confirmed gastric cancer. As insufficient serum was available from 26 men and the results of the ELISA were indeterminate for two, a total of 109 were included in the study. Cancers were diagnosed between 1968 and 1989, with a mean interval between blood sampling and diagnosis of 13 years (standard deviation, five years). The mean age of the cancer patients at recruitment was 59 years. One control was selected for each case by matching for age at recruitment and date of blood collection. Excluded from the control series were men who had had a gastrectomy before blood sampling or who had had a diagnosis of peptic ulcer at any time. The exclusion criteria reduced the pool of available controls by 13%. [The Working Group noted that the exclusion criteria would be likely to reduce the prevalence of H. pylori infection in the control group and, hence, bias the estimated odds ratio upwards.] Also excluded were men with cardiovascular disease or any other type of cancer diagnosed at any time. These exclusions reduced the control pool by 33%. Controls had to be alive when the cancer cases with which they were matched were diagnosed. Of the 109 gastric cancer patients, 103 (94%) had antibodies to H. pylori, as did 83 of the 109 (76%) controls, resulting in a matched odds ratio of 6.0 (95% CI, 2.1–17). Stratification of the cases into three groups (26, 40 and 43 pairs) on the basis of time between blood sampling and cancer diagnosis resulted in odds ratios of 1.5 (95% CI, 0.3–9.0) for less than 10 years, 6.0 (1.3–27) for 10–14 years and indeterminate (1.7–97) for 15 years or more. Stratification into two birth cohorts resulted in odds ratios of 3.0 (0.8–11) for those born in 1900–09 and 15 (2.0–114) for those born in 1910–19. Eighty-one patients had an intestinal type of carcinoma, and 75 (93%) of these were seropositive (odds ratio, 4.5; 95% CI, 1.5–13); 23 patients had a diffuse type, and all were seropositive (odds ratio, indeterminate; 1.1–64). Five patients had cancer at the cardia, and two were seropositive; after exclusion of these patients, the overall odds ratio was 12 (95% CI, 2.8–51). In this study, a trend was observed (p = 0.0009) of an increasing odds ratio with an increase in the quantitative antibody level. [The Working Group estimated that, had the exclusion criteria relating to controls with a history of gastrectomy or peptic ulcer not been used, the prevalence of H. pylori infection in the controls would have been increased by approximately 4% and the overall odds ratio would have been decreased by about 20%, i.e. from 6.0 to 4.8.]

In a combined analysis of the three nested case–control studies described above, Forman et al. (1994) showed that, overall, 215/247 (87%) gastric cancer patients and 203/334 (61%) controls were seropositive for IgG antibodies to H. pylori, resulting in a matched odds ratio of 3.8 (95% CI, 2.3–6.2). When these results were stratified by time between sample collection and cancer diagnosis into four periods—fewer than five years, 5–9 years, 10–14 years and 15 years or more—there was a significant trend (p = 0.049) towards an increased odds ratio with increasing time interval. The odds ratio changed from 2.1 (95% CI, 0.6–8.7) to 2.3 (0.9–6.5), 4.4 (1.8–13) and 8.7 (2.7–45) over the four periods, respectively. There were 20/25 (80%), 37/46 (80%), 70/78 (90%) and 88/98 (90%) seropositive cases and 34/58 (59%), 46/85 (54%), 58/93 (62%) and 65/98 (66%) seropositive controls in the four strata, respectively. This trend was interpreted by the authors as indicating that false-negative assessments of H. pylori status may have occurred more frequently among cancer cases than among matched controls, especially among those diagnosed soon after providing blood. False-negative assessments were believed to derive from the precancerous conditions, severe atrophic gastritis and intestinal metaplasia, from loss of H. pylori colonization and loss of seropositivity.

Lin et al. (1993a [abstract]) compared 29 gastric cancer patients in Taiwan, China, with 220 controls matched by age, sex and area of residence, for the presence of H. pylori IgG antibodies by an ELISA. The subjects were participants in a cohort study in which 9777 people in Taiwan had provided blood since 1984. The mean interval between blood sampling and diagnosis of cancer was 3.1 years. Sixty-nine percent of the gastric cancer patients and 59% of the controls were seropositive for antibodies to H. pylori, resulting in an odds ratio of 1.6 (95% CI, 0.68–2.6).

The four prospective studies are summarized in Table 5.

Table 5.

Helicobacter pylori seroprevalence rates in gastric cancer patients and matched controls: prospective studies.

2.3.2. Gastric lymphoma

Parsonnet et al. (1994) compared 33 patients with gastric non-Hodgkin's lymphoma with 134 age- and sex-matched controls for the presence of H. pylori IgG antibodies using an ELISA with a reported sensitivity of 96% and a specificity of 76% for active gastric infection. The subjects were taking part in one of two cohort studies, one in California, USA, described above (Parsonnet et al., 1991b), and the other of 170 000 participants living in Norway who provided blood between 1973 and 1991 during blood donation and health screening programmes. Cancer registrations between 1973 and 1990 among the Norwegian cohort were notified to the study organizers. Twenty gastric lymphomas were identified from the US cohort and 13 from the Norwegian cohort, with median intervals between blood sampling and diagnosis of 14 and 13 years, respectively. The median ages of the lymphoma patients at diagnosis were 66 and 55 years, and 40 and 69% patients in the two cohorts were men, respectively. Four cancer-free controls were selected for each case and matched on cohort, date of birth, age (five-year groups in the USA; within six months in Norway), sex, date and location of blood collection and ethnic group (only in the USA). Twenty-eight of the 33 (85%) gastric lymphoma patients were seropositive for antibodies to H. pylori, as were 74 of the 134 (55%) controls, resulting in a matched odds ratio of 6.3 (95% CI, 2.0–20). There was no significant difference between odds ratios when the cases and corresponding controls were stratified on the basis of cohort, sex, age at diagnosis (< 65 or ≥ 65 years) or time between blood sampling and diagnosis (< 14 or ≥ 14 years). In a separate analysis of 31 patients with non-gastric non-Hodgkin's lymphoma and 61 matched controls, 20 patients (65%) and 36 controls (59%) were seropositive, resulting in a matched odds ratio of 1.2 (95% CI, 0.5–3.0).

2.4. Case–control studies

2.4.1. Gastric carcinoma

Nine case–control studies have been carried out in which serological assessment of infection was done retrospectively in cancer patients after diagnosis.

Talley et al. (1991a) compared 69 patients with gastric adenocarcinoma with 252 controls for the presence of IgG antibodies to H. pylori using a previously described ELISA (Pérez-Pérez et al., 1988) with a reported sensitivity of 96% and a specificity of 94% (Talley et al., 1991b). The cases of cancer had been confirmed histologically and diagnosed between 1982 and 1989 at a single hospital in Minnesota, USA. The median age of the patients was 63 years (25th and 75th percentiles, 56.5 and 71 years), and 52% were men. The controls comprised 76 asymptomatic volunteers with no history of gastrointestinal disease and 176 patients who were treated between 1976 and 1989 at the same hospital as the cancer patients for a variety of non-malignant conditions: 67 for benign musculoskeletal problems, 52 for benign oesophageal disease and 57 for benign lung diseases. The median age of the controls was 61 years (25th and 75th percentiles, 54 and 67 years), and 50% were men. Of the 69 gastric cancer patients, 36 (52%) had antibodies to H. pylori, as did 96 (38%) of the controls. The odds ratio, after adjustment for age and sex, was 1.6 (99% CI, 0.79–3.4). Adjustment for length of storage of the blood samples had no substantial effect on the results. The odds ratio for gastric cancers at sites other than the cardia (n = 37) was 2.7 (99% CI, 1.0–7.1), while that for cancers at sites in the cardia (n = 32) was 0.94 (99% CI, 0.34–2.6). For the intestinal type of gastric cancer, according to the Lauren classification (n = 32), the odds ratio was 1.9 (99% CI, 0.67–5.1), while for cancers of the diffuse histological type (n = 22) it was 2.5 (99% CI, 0.73–8.2). After the cancers of the cardia had been excluded, the odds ratios were 4.6 (99% CI, 0.78–27) for the intestinal type (n = 13) and 2.3 (99% CI, 0.63–8.1) for the diffuse type (n = 19). There were five additional groups of patients in this study. The proportions with antibodies to H. pylori were 44% of nine with benign gastric lesions, 89% of nine with gastric cancers other than adenocarcinoma, 51% of 80 with colorectal cancer, 49% of 41 with oesophageal cancer and 56% of 79 with lung cancer. In comparisons with the cancer-free control group, as used in the study of gastric adenocarcinoma, the odds ratios, after adjustment for age and sex, were 1.5 (99% CI, 0.23–9.1) for benign gastric neoplasms, 13 (99% CI, 0.77–203) for other gastric cancers, 1.8 (99% CI, 0.86–3.4) for colorectal cancer, 1.4 (99% CI, 0.58–3.4) for oesophageal cancer and 1.8 (99% CI, 0.91–3.6) for lung cancer.

Sipponen et al. (1992) compared 54 patients with gastric adenocarcinoma with 84 controls for the presence of IgG, IgA and IgM antibodies to H. pylori using a previously described ELISA (Kosunen et al., 1989). The cases of gastric cancer were confirmed histologically and occurred in a consecutive series of patients diagnosed in 1988 and 1989 at a single hospital in Finland. Patients with cancers of the region of the cardia were excluded, as were patients who had previously undergone gastric surgery. The mean age of the patients who were included was 65 years (SD, 16 years), and 48% were men. The controls were 35 patients with cancers at gastrointestinal sites other than the stomach (6 in the oesophagus, 7 in the pancreas and 22 in the colon) and 48 patients with cancers at sites other than the gastrointestinal tract. The mean ages of these two groups of controls were 65 years (SD, 12 years) and 66 years (SD, 12 years), respectively, and 57 and 71%, respectively, were men. IgG antibodies to H. pylori were found in 38/54 (70%) of the gastric cancer patients and 43/84 (51%) of the patients with other cancers. [The unadjusted odds ratio was calculated by the Working Group to be 2.3 (95% CI, 1.0–5.0).] IgA antibodies to H. pylori were found in 76% of the gastric cancer patients and 58% of the controls [the unadjusted odds ratio was 2.3 (95% CI, 1.1–4.8]; IgM antibodies were found in 6% of the cases and 5% of the controls. When the gastric cancer patients were stratified into three age groups, IgG antibodies were found in 8/10 (80%) aged 30–49 years, 13/19 (68%) of those aged 50–69 years and 17/25 (68%) of those aged 70 years or more. For the patients with other cancers, the respective proportions were 5/9 (56%), 22/38 (58%) and 16/37 (43%), resulting in odds ratios for the three strata of [3.2 (95% CI, 0.3–45.4)], [1.6 (0.4–6.2)] and [2.8 (0.9–9.4)], respectively. Thirty-one gastric cancer patients had tumours of the intestinal type, and 22 (71%) of them were seropositive; 21 gastric cancer patients had tumours of the diffuse type, and 15 (71%) of them were seropositive.

Kang and Chung (1992) compared 28 patients with gastric adenocarcinoma in the Republic of Korea with 30 age- and sex-matched controls for the presence of IgG antibodies to H. pylori, using a commercial ELISA kit. The gastric cancer patients had all undergone resection, had histological confirmation of their disease and had been diagnosed in 1991. The mean age of the cases was 50 years (range, 29–67 years), and 66% were men. Controls were hospital patients with a variety of diagnoses other than gastrointestinal disease and included nine patients with non-gastrointestinal cancer. The mean age of the controls was 52 years (range, 28–69 years), and 67% were men. Twenty-five (89%) of the gastric cancer patients had antibodies to H. pylori, as did 20 (67%) of the control patients. A matched analysis resulted in an odds ratio of 4.2 (95% CI, 1.0–17). Ten of the patients had intestinal-type cancers, and eight (80%) of these were seropositive; 18 patients had diffuse-type cancers, and 17 (94%) of these were seropositive. All nine gastric cancer patients who had ‘early gastric cancer’ were seropositive; of the 19 who had advanced cancer, 16 (84%) were seropositive.

Hansson et al. (1993a) compared 112 gastric adenocarcinoma patients with 103 controls for the presence of IgG antibodies to H. pylori using a commercial ELISA kit with a reported sensitivity of 98.7% and a specificity of 100% (Evans et al., 1989). The cases were confirmed histologically and occurred in a consecutive series of patients diagnosed between 1989 and 1991 at eight hospitals in central and northern Sweden. Patients over 79 years of age and with advanced disease (20% of study base) were excluded, as were patients who refused (3%) or were unable (14%) to give blood. The mean age of the gastric cancer patients was 67 years, and 63% were men. Controls were patients admitted to the same hospitals with a variety of non-gastrointestinal diseases, who were frequency matched to the cases by 10-year age group, sex and hospital. The mean age of the controls was 67 years, and 66% were men. Antibodies to H. pylori were found in 90/112 (80%) of the gastric cancer patients and 63/103 (61%) of the controls (odds ratio, 2.6; 95% CI, 1.4–5.0). When the analysis was stratified into three age groups, the odds ratios were 9.3 (1.4–101) for patients aged less than 60 years, 4.3 (1.3–15) for those 60–69 years and 1.2 (0.44–3.0) for those aged 70 or more. The interaction between age and H. pylori seropositivity was significant. There was a higher odds ratio in men than in women, but the effect was of borderline significance. The multivariate odds ratio for H. pylori seropositivity, estimated in a multiple regression model with adjustment for occupation, diet, smoking and alcohol consumption (multivariate odds ratio, 2.7; 95% CI, 1.3–5.8) showed little difference from the univariate odds ratio. Of patients with gastric cancers at sites other than the cardia, 77/93 (83%) were seropositive (odds ratio, 3.1; 1.5–6.3), while 13/19 (68%) patients with cancers of the cardia were seropositive (1.4; 0.44–4.8). Of patients with intestinal-type gastric cancer, 60/75 (80%) were seropositive (2.5; 1.2–5.4), while 22/28 (79%) of patients with diffuse-type cancer were seropositive (2.3; 0.82–7.6).

Blaser et al. (1993) compared 29 gastric adenocarcinoma patients with 58 age- (within one year) and sex-matched controls for the presence of IgG antibodies to H. pylori, using a previously described ELISA (Pérez-Pérez et al., 1988) with a reported sensitivity of 96% and a specificity of 94% (Talley et al., 1991b). The cases were confirmed histologically and had been diagnosed between 1990 and 1992 in one city, Ichikawa, in Japan. The median age of patients was 63 years (range, 46–82 years), and 62% were men. Controls were out-patients attending the same hospital as the gastric cancer patients for a variety of illnesses, excluding ‘known stomach disease’ and chronic liver disease. Twenty-four of the 29 (83%) gastric cancer patients and 39/58 (67%) controls had antibodies to H. pylori (matched odds ratio, 2.1; 95% CI, 0.72–6.4). Exclusion of the three gastric cancer patients with cancers of the cardia and the corresponding controls, justified because of the previously identified specificity of association with cancer other than of the cardia (Nomura et al., 1991; Talley et al., 1991a), resulted in an odds ratio of 2.8 (95% CI, 0.82–9.6) for the patients with cancers at sites other than the cardia. Exclusion of non-cardia gastric cancer patients aged 70 years or over (and corresponding controls), justified because of the previously identified reduced association in the elderly (Nomura et al., 1991), resulted in an odds ratio of 6.0 (95% CI, 1.1–34). Comparisons of cases on the basis of stage or severity of pathological lesions were reported not to affect the odds ratio. [The Working Group noted that the exclusion of patients with known stomach disease from the control group would be likely to reduce the prevalence of H. pylori infection in the group and, hence, bias the estimated odds ratio upwards.]

Lin et al. (1993b,c) compared 148 gastric adenocarcinoma patients with two series of controls (n = 92 and 823) for the presence of IgG antibodies to H. pylori, using a commercial ELISA kit with a reported sensitivity of 96% and a specificity of 93%. The cases were confirmed histologically and occurred in a consecutive series of patients diagnosed in 1992 at a single hospital in Taiwan, China. The mean age was 59 years (range, 24–87 years), and 61 % were men. The first control series were part of a group of asymptomatic subjects who had had an endoscopic examination with negative results during a routine health check in 1992. Their mean age was 52 years (range, 22–77 years), and 59% were men. The second control series were randomly selected from household registry files in one precinct and three townships in Taiwan. The subjects included people of all ages, from < 10 years to ≥ 70 years, and 50% were men. [The Working Group noted that the two reports of the study had slightly different numbers of cases: 148 (Lin et al., 1993b) and 143 (Lin et al., 1993c). In the results reported below, the larger number was used, except where stated. The Working Group also noted that the selection of controls for the first series, excluding volunteers who did not have endoscopically normal stomachs, would be likely to reduce the estimated prevalence of H. pylori infection in the control group and, hence, bias the estimated odds ratio upwards.] Ninety-two of the 148 (62%) gastric cancer patients and 57/92 (62%) controls in the first series had antibodies to H. pylori (age- and sex-adjusted odds ratio, 1.0; 95% CI, 0.59–1.8), as did 448/823 (54%) controls in the second series [unadjusted odds ratio, 1.4 (95% CI, 1.0–2.0); after exclusion of controls from the second series who were aged less than 20 years, 347/527 (65%) were seropositive, giving a calculated unadjusted odds ratio of 0.85 (95% CI, 0.58–1.2)]. Among subjects below the age of 60 years, 44/64 (69%) of gastric cancer cases, 40/66 (61%) of the first series of controls and 280/436 (64%) of the second series of controls (20–59 years) were seropositive; among those 60 years of age or more, 48/84 (57%) of the cancer patients, 17/26 (65%) of the first series of controls and 67/91 (74%) of the second series of controls were seropositive. Twenty-six of the cancer patients had their tumour in the region of the cardia, and 17 of these (65%) were seropositive; 114 cancer patients had their tumour in regions other than the cardia, and 71 of these (62%) were seropositive. Of the 52 patients who had cancers of the intestinal type, 31 (60%) were seropositive, whereas of 96 patients with cancers of the diffuse type, 61 (64%) were seropositive. Of 26 ‘early’ gastric cancer patients, 16 (62%) were seropositive, and of 122 patients with advanced cancers, 76 (62%) were seropositive.

Kuipers et al. (1993c) compared 116 gastric adenocarcinoma patients with 116 age- and sex-matched controls for the presence of IgG antibodies to H. pylori using a previously described ELISA (Peña et al., 1989). The cases were confirmed histologically; the patients were resident in the Netherlands and had a median age of 67 years (range, 23–92 years); 56% were men. Controls were subjects undergoing upper gastrointestinal investigations, excluding those with endoscopic and histological abnormalities such as peptic ulcer, atrophic gastritis and intestinal metaplasia. Antibodies to H. pylori were found in 89/116 (77%) gastric cancer patients and 92/116 (79%) controls [resulting in an unadjusted and unmatched odds ratio of 0.86 (95% CI, 0.44–1.7)]. Stratification into five age groups (< 50, 50–59, 60–69, 70–79 and > 79 years) did not significantly change the odds ratios for gastric cancer within any strata [figures not available]. Of the 67 gastric cancer patients who had tumours of the intestinal type, 51 (76%) were seropositive; of the 36 patients with tumours of the diffuse type, 28 (78%) were seropositive. [The Working Group noted that, despite the exclusions from the control series, the use of symptomatic gastrointestinal disease patients would be likely to increase the estimated prevalence of H. pylori infection among the controls and, hence, bias the odds ratio downwards.]

Estevens et al. (1993) compared 80 gastric adenocarcinoma patients with 80 age- and sex-matched controls for the presence of IgG antibodies to H. pylori using an ELISA developed in their laboratory on the basis of a previously described assay (Evans et al., 1989). The cases were confirmed histologically and occurred in a consecutive series diagnosed in 1990–91 at a single hospital in Lisbon, Portugal. The mean age was 66 years (SD, 11.9 years), and 58% were men. Controls were blood donors and hospital out-patients attending trauma and orthopaedic clinics. Antibodies to H. pylori were found in 56/80 (70%) gastric cancer patients and 65/80 (82%) controls, resulting in an odds ratio of [0.54 (95% CI, 0.24–1.2)]. Of the gastric cancer patients with tumours of the cardia, 67% were seropositive; of the patients with tumours at other sites, 70% were seropositive. Of the patients with tumours of the intestinal type, 64% were seropositive, whereas of those with tumours of the diffuse type, 50% were seropositive.

Archimandritis et al. (1993) compared 47 gastric adenocarcinoma patients with 50 controls, matched for age, sex, socioeconomic status and area of residence. The presence of IgG antibodies to H. pylori was assessed using a commercial ELISA kit. The cases were confirmed histologically; patients with tumours of the cardia were excluded. Patients were from all over Greece, their mean age was 62 years (SD, 12.6 years) and 62% were men. Controls were healthy people from all over Greece with ‘no evidence of peptic ulcer or non-ulcer dyspepsia’; their mean age was 62 years (SD, 14.1 years), and 54% were men. Of the 47 gastric cancer patients, 34 (72%) were seropositive for H. pylori antibodies, as were 34/50 (68%) controls (odds ratio, 1.2; 95% CI, 0.51–3.0). When the analysis was stratified by age, the odds ratio for subjects aged < 60 years was 1.5 (0.42–5.0) and that for subjects > 60 was 0.87 (0.23–3.3). Of the 31 gastric cancer patients with tumours of the intestinal type, 22 (71%) were seropositive (1.2; 0.43–3.1); of nine patients with tumours of the diffuse type, seven (78%) were seropositive (0.83; 0.13–5.3). [The Working Group noted that the information provided about control selection was inadequate to allow a judgement about the adequacy of the control group. The exclusion of controls with peptic ulcer or non-ulcer dyspepsia would be likely to reduce the prevalence of H. pylori infection in the control group and, hence, bias the esimated odds ratio upwards.]

The studies are summarized in Table 6.

Table 6.

Seroprevalence for Helicobacter pylori in gastric cancer patients and matched controls: retrospective studies.

2.4.2. Other cancers

No case–control studies of cancers other than gastric cancer have been reported, although the study of Talley et al. (1991a) (see above) compared patients with lung, oesophageal and large bowel cancers.

3. Studies of Cancer in Experimental animals

4. Other Data Relevant for Evaluation of Carcinogenicity and its Mechanisms

5. Summary of Data Reported and Evaluation

6. References

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