Affiliations of authors: Department of Medical Epidemiology and Biostatistics (WY, MH, JL, LE, ON), Microbiolgy and Tumor Biology Center (LE), Karolinska Institutet, Stockholm, Sweden; International Epidemiology Institute, Rockville, MD (WJB, JKM); Department of Surgery, Karolinska Hospital, Stockholm (JL); Swedish Institute for Infectious Disease Control, Stockholm (LE); Department of Medicine, Vanderbilt University, Nashville, TN (WJB, JKM).
Correspondence to: Weimin Ye, MD, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE171 77, Stockholm, Sweden (e-mail: weimin.ye{at}meb.ki.se)
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ABSTRACT |
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INTRODUCTION |
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An H. pylori infection may also increase the risk of cancers such as esophageal squamous-cell carcinoma (15) by stimulating the production of nitrosamines. Mortality from esophageal cancer (predominantly squamous-cell carcinoma) was statistically significantly correlated with endogenous nitrosation ability in an ecologic study in China (16). Atrophic gastritis induced by H. pylori may form a milieu that favors bacterial overgrowth which, in turn, may increase intragastric nitrosation (17). Thus, infection with H. pylori, especially CagA-positive strains, may be a risk factor for esophageal squamous-cell carcinoma. However, only one study has investigated the relationship between a CagA-positive H. pylori infection and the risk of esophageal squamous-cell carcinoma; a nested case-control study (18) from China found a borderline statistically significantly increased risk for esophageal squamous-cell carcinoma associated with the presence of serum CagA antibodies.
In this article, we investigated whether H. pylori infection was associated with the risk for esophageal adenocarcinoma, esophageal squamous-cell carcinoma, and gastric cardia adenocarcinoma in a Swedish nationwide population-based case- control study. We paid special attention to the role of serum antibodies against CagA. After H. pylori has been eradicated, CagA antibodies appear to persist longer than antibodies against H. pylori cell-surface antigens (HP-CSAs). Thus, use of CagA antibodies may lead to less misclassification of previous H. pylori infections. We therefore used both serologic methods to detect relevant exposure to H. pylori (19). We evaluated whether gastric atrophy, with its associated reduction of the gastric acid output, is in the causal pathway between H. pylori infection and esophageal adenocarcinoma development. We also reasoned that if H. pylori and gastric atrophy are both in the causal chain, then 1) their associations with esophageal adenocarcinoma should be in the same direction, 2) the inverse association between H. pylori infection and the risk of esophageal adenocarcinoma should be confined to subjects with gastric atrophy, and 3) the risk for esophageal adenocarcinoma should be lower among subjects infected with H. pylori who have gastroesophageal reflux symptoms than among those who do not have reflux. Results of similar tests for the first two points can also be used to assess whether gastric atrophy is in the causal pathway between CagA-positive H. pylori infection and esophageal squamous-cell carcinoma risk.
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PATIENTS AND METHODS |
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Study methods have been described in detail elsewhere (20). Briefly, eligible case patients were all of the newly diagnosed patients with adenocarcinoma of the esophagus or gastric cardia and half of the patients with squamous-cell carcinoma of the esophagus (i.e., those born on even-numbered days) from 1995 through 1997 in the entire native Swedish population who were younger than 80 years. Considerable efforts, including establishment of a comprehensive organization with contact persons at all 195 departments of general surgery, thoracic surgery, otorhinolaryngology, oncology, and pathology in Sweden and continuous collaboration with the six regional tumor registries, were made to ensure that every eligible case patient throughout the country was identified shortly after diagnosis. All tumors were uniformly classified histologically and topographically, and almost all (97%) biopsy and surgical specimens were reviewed by a single pathologist. Biopsy specimens were also obtained from nontumorous mucosa in and around the gastroesophageal junction. Endoscopists, surgeons, and pathologists gave standardized, detailed descriptions of the location of the tumors. Cancer of the gastric cardia was defined as a tumor with its center within 2 cm proximal or 3 cm distal of the gastroesophageal junction and without evidence of Barrett's esophagus. To allay concerns about misclassification of gastric cardia adenocarcinoma, we also used a more stringent definition, i.e., a tumor within 1 cm proximal or distal to the gastroesophageal junction. Alternatively, we subdivided the gastric cardia adenocarcinoma tumors according to the location of tumor center, i.e., above or on or below the gastroesophageal junction. Squamous-cell carcinomas were classified as esophageal, even if the location was seemingly in the gastric cardia. If Barrett's esophagus was detected adjacent to gastric cardia adenocarcinoma, the tumors were classified as esophageal. Control subjects were randomly selected from the continuously updated Swedish Population Register and frequency-matched to resemble the age (in 10-year strata) and sex distributions of case patients with esophageal adenocarcinoma.
Interview
The 618 case patients and 820 control subjects were interviewed face-to-face by specially trained professional interviewers from Statistics Sweden. The participation rates were 88%, 73%, 84%, and 73% among case patients with esophageal adenocarcinoma, case patients with esophageal squamous-cell carcinoma, case patients with gastric cardia adenocarcinoma, and population control subjects, respectively. The questions covered demographic characteristics, living conditions during childhood and adolescence (e.g., number of siblings and access to a refrigerator during childhood), gastroesophageal reflux symptoms, anthropometric measures, smoking status, alcohol consumption, dietary history, history of medication use, and occupational history. The interviewers could not be kept blinded to case-control status but were trained to treat both groups in a strictly equal manner.
Serologic Data
Interviewed subjects were asked to provide a venous blood sample, which was drawn from case patients during the initial hospital stay and from control subjects at their local health centers. After centrifugation, all serum samples were stored at -20 °C and transported to our laboratory for further storage at -70 °C until analyses were performed. In total, serum was collected from 97 patients with incident esophageal adenocarcinoma, 85 patients with incident esophageal squamous-cell carcinoma, 133 patients with incident gastric cardia adenocarcinoma, and 499 randomly selected control subjects. To increase the number of case patients with squamous-cell carcinoma, we also collected blood samples from patients born on odd-numbered days, 1 year after the initiation of the study. These patients were not interviewed (21).
Serum immunoglobulin G (IgG) antibodies against HP-CSAs were measured with an enzyme-linked immunosorbent assay (ELISA) (Pyloriset EIA-G; Orion Diagnostica, Espoo, Finland) with a sensitivity of 98% and a specificity of 85% (22). We detected antibodies to CagA with an immunoblot assay (Helicoblot 2.1; Genelabs Diagnostics, Singapore). Tests with ambiguous results were repeated to arrive at a definite classification. A low value of serum pepsinogen I is an indication of gastric atrophy. Serum pepsinogen I was measured by an immunoenzymometric assay (Gastroset PGI; Orion Diagnostica). The recommended normal range of pepsinogen I in serum is 28158 µg/L. When pepsinogen I at 28 µg/L was used as the cut point, its sensitivity and specificity for detecting moderate and severe atrophic corpus gastritis were reported to be 81% and 99%, respectively (23). All persons involved in the analyses were blinded to case-control status of the subjects.
Statistical Analyses
We modeled the data by use of logistic regression to estimate relative risks in the form of odds ratios (ORs) with 95% confidence intervals (CIs). The confidence intervals were not adjusted for multiple comparisons. In multivariable modeling, our basic model included the frequency-matching variables of age (six categories) and sex. We further considered years of education (categorized into three classes), consumption of fruits and vegetables (categorized into three classes), body mass index (in quartiles), tobacco smoking status (2 years before interview, classified as never smoker, previous smoker, and current smoker of any tobacco), and alcohol consumption (total amount consumed of all types of alcoholic beverages and categorized into four classes) as potential confounding factors. Terms for confounders, as well as important risk factors for the outcome, were included in the regression model. Because gastric atrophy may be an intermediate step between H. pylori infection and esophageal cancer, we did not adjust for atrophy in the main analyses. The small number of subjects with gastric atrophy, defined as a serum pepsinogen I level of less than 28 µg/L, prevented meaningful comparisons of H. pylori effects in atrophic and nonatrophic strata. Because the sensitivity was only moderate when the recommended cutoff value of serum pepsinogen I (28 µg/L) was used to define gastric atrophy (23), we used a higher cutoff value (78 µg/L, the median value among control subjects), which gave a cleaner nonatrophic stratum and permitted more robust comparisons between the strata, when we performed stratified analyses by gastric atrophy status. All statistical analyses were performed with SAS, release 8.2 (SAS Institute, Cary, NC); PROC GENMOD was used for the logistic regression model. All statistical tests were two-sided.
Ethical Considerations
The study was approved by all regional ethics committees in Sweden. Individual written informed consent was obtained from study participants before the initial interview.
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RESULTS |
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The study included only those interviewed case patients and control subjects who provided serum samples. There were 97 case patients with esophageal adenocarcinoma, 85 with esophageal squamous-cell carcinoma, and 133 with gastric cardia adenocarcinoma. They constituted about 50% of all interviewed case patients. In addition, 499 control subjects were included, constituting approximately 60% of those interviewed. The main reason for nonparticipation among case patients was that the clinicians forgot to collect serum, whereas the main reason for nonparticipation among control subjects was failure to appear at the local health center. The median ages among participants included in the current study (both sexes) were 69 years for case patients with esophageal adenocarcinoma, 64 years for case patients with esophageal squamous-cell carcinoma, 65 years for case patients with gastric cardia adenocarcinoma, and 69 years for control subjects. The distributions of participants by sex, smoking status, alcohol consumption, and educational level are listed in Table 1. Consumption of fresh fruits and vegetables was lower among case patients with any of the three types of cancer under study than among control subjects (Table 1). Among case patients with esophageal adenocarcinoma, esophageal squamous-cell carcinoma, or gastric cardia adenocarcinoma, 54%, 9%, or 26%, respectively, reported reflux symptoms, and among control subjects, 17% reported reflux symptoms. No substantial differences in reflux symptoms, body mass index, and the number of siblingsa potential indicator of H. pylori infection (24)were observed between those who provided serum and those who did not provide serum (Table 1).
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The prevalence of H. pylori antibodies was lower among case patients with esophageal adenocarcinoma than among control subjects; 19% versus 40%, respectively, were positive for HP-CSAs, and 43% versus 59% were positive for CagA (Table 3). In multivariable analyses adjusted for age, sex, and other possible confounders including years of education, body mass index, tobacco smoking status, and consumption of fruit and vegetables, H. pylori infection determined by HP-CSA antibodies was associated with a statistically significantly reduced risk of esophageal adenocarcinoma (OR = 0.3, 95% CI = 0.2 to 0.6) (Table 3). Among subjects without gastric atrophy (pepsinogen I level 78 µg/L), the association was similar (OR = 0.3, 95% CI = 0.2 to 0.7). Likewise, no dramatic differences in the risk for esophageal adenocarcinoma emerged when we stratified subjects by the presence or absence of symptomatic reflux (OR = 0.4 [95% CI = 0.2 to 1.1] versus OR = 0.2 [95% CI = 0.1 to 0.6] for those with and without symptomatic reflux, respectively; P for interaction = .20). When H. pylori infection status was determined only by serum CagA antibody status, the overall relative risk for esophageal adenocarcinoma associated with H. pylori infection was also reduced (OR = 0.5, 95% CI = 0.3 to 0.8) (Table 3). Among subjects without gastric atrophy (pepsinogen I level
78 µg/L), the association was similar (OR = 0.4, 95% CI = 0.2 to 0.8). Likewise, no dramatic differences in the risk for esophageal adenocarcinoma were detected in analyses stratified by symptomatic reflux (P for interaction = .55).
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Patients with esophageal squamous-cell carcinoma (born on even-numbered days) compared with control subjects had a similar prevalence of HP-CSA antibodies (38% versus 40%) and had a higher prevalence of CagA antibodies (74% versus 59%) (Table 3). After controlling for age, sex, years of education, smoking status, alcohol consumption, and consumption of fruits and vegetables, H. pylori infection status assessed by measuring HP-CSA antibodies alone was not associated with risk for esophageal squamous-cell carcinoma (OR = 0.9, 95% CI = 0.5 to 1.6). However, H. pylori infection status assessed by measuring antibodies to CagA was associated with a statistically significantly increased risk for esophageal squamous-cell carcinoma (OR = 2.1, 95% CI = 1.1 to 4.0). This effect was stronger in those with gastric atrophy (pepsinogen I level <78 µg/L) (OR = 3.3, 95% CI = 1.3 to 8.7) than in those without gastric atrophy (OR = 1.1, 95% CI = 0.4 to 3.1) (P for interaction = .07). When we combined the results from the HP-CSA and CagA assays as a measure of H. pylori infection status, the relative risk for esophageal squamous-cell carcinoma was higher for the group that was seropositive for CagA but seronegative for HP-CSAs (OR = 3.0, 95% CI = 1.4 to 6.2) than for other groups, using those seronegative for both tests as the referent (Table 3). When we used the overall model to assess associations with gastric atrophy status, we found that gastric atrophy status was strongly associated with the risk of esophageal squamous-cell carcinoma (OR = 4.3, 95% CI = 1.9 to 9.6) (Table 4).
In a separate analysis of the 61 patients with esophageal squamous-cell carcinoma born on odd-numbered days that was adjusted for age and sex, the risks for esophageal squamous-cell carcinoma associated with serum antibodies against both HP-CSAs and CagA and gastric atrophy were consistent with the results for those born on even-numbered days (OR = 1.0, 95% CI = 0.6 to 1.8; OR = 2.0, 95% CI = 1.1 to 3.6; and OR = 3.9, 95% CI = 1.9 to 7.8, respectively).
Gastric Cardia Adenocarcinoma
Patients with gastric cardia adenocarcinoma had a somewhat lower overall prevalence of HP-CSA antibodies than control subjects (34% versus 40%), but they had a similar prevalence of CagA antibodies (60% versus 59%) (Table 3). H. pylori infection, measured with either antibody, was not associated with risk for gastric cardia adenocarcinoma (for HP-CSA antibodies, OR = 0.8, 95% CI = 0.5 to 1.2; for CagA antibodies, OR = 1.0, 95% CI = 0.7 to 1.6). Essentially no association emerged in any stratum when the results of the two assays were combined. However, gastric atrophy, as indicated by low serum pepsinogen I concentration (<28 µg/L), was associated with a statistically significantly increased risk for gastric cardia adenocarcinoma (OR = 4.5, 95% CI = 2.5 to 7.8) (Table 4). Interestingly, the risk for gastric cardia adenocarcinoma was higher among those with a high level (>158 µg/L) of serum pepsinogen I (OR = 2.9, 95% CI = 1.6 to 5.2) than among those with a normal level (28158 µg/L) of pepsinogen I.
In total, 44 patients had the center of their cardia adenocarcinomas within 1 cm of the gastroesophageal junction. In a subanalysis of this group, the point estimates for H. pylori seroprevalence remained essentially unchanged (for HP-CSA antibodies, OR = 0.8, 95% CI = 0.4 to 1.7; for CagA antibodies, OR = 1.1, 95% CI = 0.5 to 2.1). When we compared subjects by level of pepsinogen I, as a measure of gastric atrophy, higher risks for gastric cardia adenocarcinoma were found for those with low (<28 µg/L) or high levels (>158 µg/L) of pepsinogen I than for those with normal levels (28158 µg/L), although point estimates were lower than those in the main study (for low levels, OR = 1.9, 95% CI = 0.7 to 5.0; for high levels, OR = 2.6, 95% CI = 1.1 to 6.2). We also subdivided patients with gastric cardia adenocarcinoma into two groups: the 69 case patients with the tumor above or on the gastroesophageal junction and the 64 case patients with the tumor below the gastroesophageal junction. H. pylori seroprevalence was not associated with risk for gastric cardia adenocarcinoma in any of these groups (for the tumor above or on the gastroesophageal junction: for HP-CSA antibodies, OR = 0.9, 95% CI = 0.5 to 1.6; for CagA antibodies, OR = 0.8, 95% CI = 0.5 to 1.4; for the tumor below the gastroesophageal junction: for HP-CSA antibodies, OR = 0.6, 95% CI = 0.3 to 1.2; for CagA antibodies, OR = 1.4, 95% CI = 0.8 to 2.6). However, risk for gastric cardia adenocarcinoma above the gastroesophageal junction was higher for individuals with a high level of pepsinogen I (>158 µg/L) (OR = 3.8, 95% CI = 1.9 to 7.6) than for those with a normal level of pepsinogen I, although the odds ratio for such tumors among subjects with a low pepsinogen I level (<28 µg/L) was close to unity. In contrast, a low pepsinogen I level was associated with a more than 10-fold increased risk for gastric cardia adenocarcinoma below the gastroesophageal junction (OR = 10.9, 95% CI = 5.4 to 22.2), whereas the increased risk associated with high pepsinogen I levels was modest.
Sensitivity Analysis
To demonstrate consistency, we reanalyzed our data by using HP-CSA antibody results determined by immunoblotting. The associations between H. pylori infection and the risks of the three types of cancer were remarkably similar to those observed with HP-CSA antibody results determined by ELISA (data not shown). For instance, for esophageal adenocarcinoma, the presence of H. pylori determined by using HP-CSA antibodies was statistically significantly associated with a reduced risk (OR = 0.4, 95% CI = 0.2 to 0.6), and the reduced risk was still confined to the HP-CSA-positive and CagA-positive stratum (OR = 0.3, 95% CI = 0.2 to 0.6).
The interpretation of weak CagA bands in the immunoblot assays is controversial. Because we postulated that previous infections might result in only a faint response, in our main analyses, we classified even a faint CagA band as positive. In a sensitivity analysis, we reanalyzed our data by using a higher cutoff value for CagA, as recommended by the manufacturer, and found it had little impact on our results. As in the original analysis, the risk for esophageal adenocarcinoma among the CagA-positive subjects compared with the CagA-negative subjects was statistically significantly reduced (OR = 0.4, 95% CI = 0.2 to 0.6), and the risk reduction was essentially confined to subjects who were HP-CSA-positive and CagA-positive (OR = 0.2, 95% CI = 0.1 to 0.5). Also consistent with the original analysis was the increased risk of esophageal squamous-cell carcinoma among CagA-positive subjects, particularly among those without a concomitant HP-CSA seroresponse (OR = 3.0, 95% CI = 1.4 to 6.5).
Risk Factors for Symptomatic Gastroesophageal Reflux
H. pylori infection (assessed by HP-CSA antibodies, CagA antibodies, or the two combined) was not associated with occurrence of symptomatic reflux. Gastric atrophy, as indicated by low levels of pepsinogen I (<28 µg/L), was not associated with a reduced risk of symptomatic reflux, but high levels of pepsinogen I (158 µg/L) increased the risk for symptomatic reflux (OR = 1.9, 95% CI = 1.2 to 3.0). These results were similar regardless of whether the entire group of case patients and control subjects was analyzed or whether the analysis was confined to control subjects only (data not shown).
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DISCUSSION |
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Strengths of our study include the population-based design, the almost complete case patient ascertainment, the efforts made to minimize misclassification of case patients, and the high participation rate in the interview phase (20). Detailed interview data enabled us to control for a range of conceivable confounding factors. However, selection bias resulting from nonparticipation might have distorted our study findings in an unknown direction. Patients with the most aggressive or end-stage disease were possibly less likely to be recruited to the interview. The relatively low proportion of interviewed case patients and control subjects who provided serum may further raise concerns about the internal validity of the study. Our results could have been biased if characteristics of the subjects who did and did not provide serum differed. Although the similar distribution of demographic and exposure variables obtained at interview among participating and nonparticipating case patients and control subjects suggests that selection bias is unlikely to have substantially influenced our results, further studies, preferably with prospective design and complete follow-up, will be needed to confirm our findings. Another limitation of our study is the relatively small size of the groups; this problem resulted in limited statistical power for some of the subgroup analyses and prevented stratified analyses by sex and some other possible risk modifiers. Moreover, we had to rely on serologic methods to determine H. pylori infection status, including CagA status, and the presence of gastric atrophy. Misclassification of these variables could have distorted our study findings. The misclassification is likely to be non-differential, which might bias our results toward no association. Although cancer status may theoretically influence the antibody levels, the differential associations with the three types of cancers suggest that our findings are not explained by this effect.
Our study confirms and expands on a study by Chow et al. (7), who also found an inverse, albeit weaker, association between CagA-positive H. pylori infection and the risk of esophageal adenocarcinoma. Our data might also indicate areas in which to search for underlying mechanisms. A prevailing hypothesis postulates that the apparent protection associated with H. pylori infection is mediated via gastric atrophy and a reduced load of esophageal acid (12). This hypothesis finds some support in a number of clinical cross-sectional studies (13) that have reported an inverse association between H. pylori infection and risk of gastroesophageal reflux, including esophagitis, hiatal hernia, and Barrett's esophagus. However, in these studies, possible confounding was generally not taken into account, and selection bias may explain the observed results because control subjects for endoscopy are more likely to be H. pylori-positive. Moreover, although an earlier study (25) found that eradication of H. pylori provokes reflux, recent studies (2633) have found conflicting results. The lack of association between gastric atrophy and a decreased risk of esophageal adenocarcinoma in our study and the absence of risk modification for the relationship between H. pylori and adenocarcinoma by gastric atrophy status or reflux status further challenge the hypothesized mechanism. Doubt is also cast on this mechanism by the slightly increasedinstead of decreasedrisk of esophageal adenocarcinoma among patients with pernicious anemia and achlorhydria, noted in a recent cohort study (14), and by the lack of association of esophageal and gastric cardia adenocarcinoma with proinflammatory genotypes (which enhance gastric acid inhibition and promote the development of atrophic gastritis) (34). The relative unimportance of hydrochloric acid in esophageal carcinogenesis is also corroborated in studies that use animal models (35). Hence, the mechanism by which CagA-positive H. pylori is associated with a reduced risk for esophageal adenocarcinoma clearly warrants further investigation and might provide important clues to the unexplained increase in esophageal adenocarcinoma in Western populations.
To our surprise, we found that a high level of serum pepsinogen I was associated with an increased risk for esophageal and gastric cardia adenocarcinoma. The underlying mechanism for this finding is not clear. It was reported that duodenal ulcer and treatment with omeprazole may increase the level of serum pepsinogen I (36). Because gastroesophageal reflux is a strong risk factor for esophageal and cardia adenocarcinoma and because the use of inhibiters of gastric acid secretion, such as omeprazole, is obviously overrepresented in patients with adenocarcinoma in the gastroesophageal junction, our findings may be influenced by confounding or reversed causation.
Previous studies (18,37) using HP-CSA antibodies as the only marker of H. pylori infection found no association between H. pylori and esophageal squamous-cell carcinoma. Our results are consistent with these observations. However, similar to a recent nested case-control study in a high-risk area of China (18), we found an increased risk for esophageal squamous-cell carcinoma among CagA-seropositive subjects. This increased risk was not observed in the stratum of subjects who were presumably free of gastric atrophy. Furthermore, a closer look revealed that this positive association was most pronounced among CagA-positive subjects who were H. pylori-negative as assessed by HP-CSA antibodies. In our validation study, this category consisted of individuals who frequently lacked an H. pylori infection, as determined by culture and histologic examination, but who also frequently had gastric atrophy, paralleling that seen among CagA-positive and HP-CSA-positive patients (Ye W, Held M, Enroth H, Kraaz W, Engstrand L, Nyrén O: unpublished results). In this study, hypopepsinogenemia was associated with a statistically significantly elevated risk for esophageal squamous-cell carcinoma. Confounding by other factors is an unlikely explanation because the results remained unchanged after control for possible confounders, including smoking status (38,39) and alcohol consumption (40). These observations suggest that CagA-positive H. pylori infection may increase the risk of esophageal squamous-cell carcinoma by a pathway involving gastric atrophy. N-Nitrosoamines appear to be an important environmental risk factor for this tumor type (15) because O6-methyldeoxyguanosine adducts, a product of DNA alkylation by nitrosamines and other alkylation substances, were found in subjects living in a high-risk area for esophageal squamous-cell carcinoma (41). Severe atrophic gastritis induced by H. pylori infection forms a milieu that favors overgrowth of anaerobic bacteria capable of increasing intragastric nitrosation (17). Gastric nitrosamines can conceivably reach the esophageal mucosa through reflux or the superficial gastroesophageal venous plexus. Cytochrome P450 isoforms, abundant in the esophagus, can activate nitrosamines into carcinogenic substances (42). Thus, endogenous nitrosamines may be involved in the etiology of esophageal squamous-cell carcinoma, as shown by the results of an ecologic study (16) in China in which mortality from esophageal cancer in 69 counties was statistically significantly correlated with endogenous nitrosation ability, measured by an N-nitrosoproline test. Moreover, in a cohort of pernicious anemia patients with long-term achlorhydria, we observed a statistically significantly increased risk of esophageal squamous-cell carcinoma (14). Further studies are needed to clarify the role of atrophic gastritis and endogenous nitrosamines in the carcinogenesis of squamous-cell carcinoma.
In patients with an H. pylori infection, colonization in the cardia is common (43). Although evidence is accumulating that H. pylori colonization may be linked to carditis and intestinal metaplasia in the cardia (44), results in previous studies (37,4547) and in this article do not support an important role of H. pylori infection in the development of gastric cardia adenocarcinoma.
In this population-based study from Sweden, infection with CagA-positive strains of H. pylori was strongly and inversely related to the risk of esophageal adenocarcinoma through a mechanism that does not appear to involve gastric atrophy and hypoacidity. However, CagA seropositivity, particularly that accompanied by HP-CSA seronegativity, was associated with an increased risk of esophageal squamous-cell carcinoma. The presence of gastric atrophy was also a statistically significant risk factor for esophageal squamous-cell carcinoma and, in the absence of atrophy, CagA-positive H. pylori infection was unrelated to the risk of esophageal squamous-cell carcinoma. Hence, atrophy may be an important mediator of the observed association between CagA seropositivity and esophageal squamous-cell carcinoma. Further studies are warranted to explore the mechanism by which CagA-positive H. pylori is inversely associated with the risk of esophageal adenocarcinoma, to confirm the positive association between CagA-positive H. pylori and esophageal squamous-cell carcinoma, and to elucidate the possible role of gastric atrophy and intragastric nitrosation in this putative carcinogenic pathway.
Note added in proof. A preliminary report of some of the results in this article has been published (48).
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NOTES |
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Manuscript received July 10, 2003; revised December 9, 2003; accepted January 5, 2004.
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