Hematopoietic cancer and peptic ulcer: a multicenter case-control study

Paolo Vineis1,11, Paolo Crosignani2, Carlotta Sacerdote1, Arabella Fontana3, Giovanna Masala4,5, Lucia Miligi5, Oriana Nanni6, Valerio Ramazzotti7, Stefania Rodella8, Emanuele Stagnaro4, Rosario Tumino9, Clotilde Viganò2, Carla Vindigni10 and Adele Seniori Costantini5

1 Unit of Cancer Epidemiology, Ospedale S. Giovanni and CPO-Piemonte, via Santena 7, I-10126 Torino,
2 Unit of Epidemiology, National Cancer Institute, Milano,
3 Local Health Unit, Novara,
4 National Cancer Institute, Genova,
5 Unit of Epidemiology, Centre for Oncologic Prevention (CSPO), Firenze,
6 Istituto Oncologico Romagnolo, Forlì,
7 National Cancer Institute, Istituto Regina Elena, Roma,
8 Azienda Ospedaliera, Verona,
9 Cancer Registry, Ragusa and
10 Institute of Pathology, University of Siena, Italy


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Helicobacter pylori has been suggested as a cause of gastric carcinoma and gastric non-Hodgkin's lymphoma (NHL). In a previous cohort study, a relative risk of six for gastric NHL was reported among subjects who tested positive for anti-H.pylori antibodies. The association between peptic ulcer and NHL has been studied in a population-based case-control investigation on hemato-lymphopoietic malignancies in Italy, based on face-to-face interviews to 2671 cases and 1718 controls (refusal rates 10 and 19%, respectively). Subjects who reported a diagnosis of peptic ulcer had a relative risk of 5.6 [95% confidence interval (CI) 3.8–8.0] for gastric NHL, whereas the estimate for non-gastric NHL was 1.3 (1.0–1.6). The association with recent diagnosis of ulcer was stronger, but the odds ratio (OR) was as high as 2.1 (95% CI 1.1–4.2) after >=20 years since such diagnosis. After exclusion of the last 2 years before the diagnosis of NHL, and of ulcers diagnosed before 1978 (when gastroscopy became common in Italy), the OR was still 5.3 (95% CI 3.0–9.2). We found a strong effect modification by educational level, with ORs for ulcer more elevated in higher social groups. Gender was an effect modifier (OR = 4.1 in males, 9.2 in females; P = 0.03 for heterogeneity). The association with other gastrointestinal pathologies was much lower and statistically not significant. Almost all gastric lymphomas were B-cell NHLs of intermediate grade according to the working formulation; the majority belonged to the mucosa-associated lymphoid tissue (MALT) type. The association with ulcer was much stronger among MALT lymphomas, but only for recent ulcer diagnoses (2–10 years). Our study shows an increased risk for gastric NHL, very similar to the estimate reported in a previous cohort study. The risk was higher among more educated subjects.

Abbreviations: CI, confidence interval; CLL, chronic lymphocytic leukemia; HD, Hodgkin's disease; LL, lymphocytic leukemia; ML, myeloid leukemia; NHL, non-Hodgkin's lymphoma; OR, odds ratio


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Time trends show a considerable increase (3–4% per year) of the incidence rates for non-Hodgkin's lymphomas (NHLs) in all Western countries, whereas those for Hodgkin's disease (HD), leukemias and myelomas have remained stable (1,2). This rise cannot be explained by the AIDS epidemic because it is larger than can be justified by the strength of association with the HIV infection, and because it largely affects elderly people.

Helicobacter pylori is a recognized cause of peptic ulcer and is a suspected etiologic agent of gastric carcinoma (3). Infection with H.pylori has been reported as a risk factor for gastric NHL in the prospective study by Parsonnet et al. (4). In this investigation, the presence of H.pylori IgG antibodies was compared in 33 gastric NHL patients and 134 matched controls, within a cohort in the USA and one in Norway. The reported odds ratio (OR) for the presence of antibodies was 6.3 [95% confidence interval (CI) 2.0–20]. No differences in the relative risks were found when cases were stratified by age at diagnosis or time between blood sampling and diagnosis. For non-gastric NHL, the OR was 1.2 (95% CI 0.5–3.0) (3). The majority of gastric NHLs belong to the mucosa-associated lymphoid tissues (MALT) category. A study reported a stronger association with H.pylori among MALT lymphomas than in other categories (76 versus 48%, P < 0.001), and among patients with low-grade compared with high-grade disease, according to the working formulation (P < 0.05) (5).

We report on a large multicenter, population-based case-control study in Italy, in which we collected a detailed medical history.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Design
We have conducted a population-based case-control study in 12 Italian areas differing in their demographic and productive characteristics (town of Torino, provinces of Varese, Novara, Vercelli, Alessandria, Imperia, Ragusa, Siena, Latina, Forlì, Verona and Firenze). Overall, the study covered a population of ~7 million residents. The incidence rates for each of the pathologies investigated have been published (6).

Individuals possibly affected by leukemia, lymphoma or multiple myeloma were identified through periodical surveys taken at each hospital department where these diseases are diagnosed (ICD-9 codes 200–208). Only newly diagnosed cases occurring in the study period (late 1989–1992) were included (both sexes, aged 20–74 years, residents of the areas under study). In each hospital department a reference physician was identified and cooperated in case finding. Case ascertainment was based also on periodical surveys in the pathology departments and, where available, from the Cancer Registry archives. In addition, cancer institutes and departments of hematology and pathology located in Milano, Roma, Pavia, Bologna and Genova (external to the study areas), where relevant diagnoses among residents of the study areas could be posed, were periodically surveyed. Timely recruitment was necessary in order to keep the proportion of individuals still alive at interview as high as possible. After they were identified and interviewed, their case status was further evaluated.

A working group of consultant hematologists and pathologists was formed. Their tasks were: (i) to advise local pathologists and hematologists on diagnostic criteria; (ii) to review a 20% random sample of the cases, and to assess its diagnostic reproducibility; and (iii) to review the cases in which the original diagnosis disagreed with the judgement of the local hematologists or pathologists. Data on diagnostic agreement for NHL are in preparation. For case classification, based on immunocytochemical techniques, we used the Working Formulation proposed by the National Cancer Institute for NHLs (7) and the Rye classification for HD (8). A distinction between B and T cell origin was made.

The control group consisted of a random sample of the population resident in each of the areas and aged between 20 and 74 years. The sample was stratified according to 5 year age groups and sex, and its size was somewhat higher than the number of cases in the largest diagnostic group (NHL + CLL). Two types of procedures for control sampling were carried out. The procedure used in the provinces of Forlì and Ragusa and in the city of Firenze drew data from the computerized demographic files that are regularly updated. National law requires municipalities throughout Italy to maintain central population registries which serve varied purposes, such as voter registration, automobile insurance, school eligibility and pension entitlement. They are well-validated as epidemiologic data sources, are continually updated and highly accurate. The other sampling procedure was adopted in the areas where the demographic files were not accessible to the investigators. Here, data were collected from the National Health Service files, which are updated every 6 months and cover nearly the entire population.

Interviews
Information about the known or suspect risk factors for the pathologies under investigation was collected through person-to-person interviews carried out preferentially at the interviewee's home. The same procedures were followed for cases and controls, except for interviews with individuals affected by acute leukemia or with the seriously ill, which were mostly performed at the hospital. This choice represents a trade-off between the need to assure comparability between cases and controls (which would require home interviews for all the cases) and the need to interview as many living cases as possible. To ensure blind interviews, the following procedures were followed: (i) the personnel in charge of case ascertainment, or in any form aware of the identity of the cases and controls, were not involved in any of the procedures dealing with collection and treatment of information on exposures (interviews, coding, exposure assessment); (ii) each interviewer had a roughly equal proportion of interviewed cases to controls.

Among the techniques for motivating individuals to participate in the study was contacting general practitioners. In this way, the response rate was kept reasonably high.

The interview was conducted face-to-face and lasted ~1 h. In addition to an interviewer manual prepared for the study, the personnel in charge of the interviews received specific training on a residential 3 day course held at the Siena University. Both the course program and the manual are available on request. Accuracy and standardization of the interview procedures were periodically verified by the epidemiologist responsible for the study in each center.

We collected detailed information about smoking habits, beverage intake, residential history, hair dye use, the complete occupational history, non-occupational chemical exposures and medical history (including use of drugs and family history). All dates of onset were collected for relevant previous pathological conditions.

Response rates
Expected numbers of cases for each of the diseases included in the study were computed, based on Cancer Registries (data available on request). The observed:expected ratio was generally close to, or slightly less than 1. Observed:expected ratios less than 1 can be explained by the rather stringent criteria for inclusion into our study (e.g., Cancer Registries include a variable proportion of `death certificate only' cases).

We have completed the study in 10 of the 12 centres (two centers are excluded because material accidents have delayed completion of interviews). Table IGo gives detailed information on the numbers of cases and controls in each centre, divided into: eligible; interviewed; refusals; not traced or impossible to interview. The overall refusal rate totalled 10% for the cases and 19% for the controls. The overall response rate, considering individuals who were not traced or were too ill to be interviewed, was 82.5% among the cases and 74.2% among the controls.


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Table I. Response rates by center and case/control status
 
Data analyses
Data editing, checks of logical consistency and error correction were performed using ad hoc programs. Point estimates of ORs and the corresponding 95% CIs were computed according to both stratified and multivariate procedures, taking into account relevant potential confounders (age, social class, education) (9,10). Heterogeneity between ORs was evaluated with the Breslow–Day test (10). Logistic regression was performed using dummy variables for four educational groups and their interaction with peptic ulcer; age was treated as a continuous variable. All analyses were performed with SAS for personal computers. In some centers, myelomas or myeloid leukemias (MLs) were not recruited; these centers were excluded from the analyses when myelomas and MLs were considered.

Check on clinical records
Clinical records have been perused in one center (Torino) to check the reliability of interviews. Fifty-two records from patients with NHL or HD who declared a history of peptic ulcer (n = 30) or hepatitis (n = 22) have been identified. Twenty-two out of 30 records confirmed the interview data for peptic ulcer (20 NHL, 2 HD, endoscopically proven ulcer), and 13/22 for hepatitis. The same check could not be performed for the controls since these were a random sample of the general (healthy) population and no clinical record was available.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We have interviewed overall 2671 cases and 1718 controls in 10 centers. Table IIGo reports their relevant characteristics. There was a balanced distribution of education (years in school) and duration of interviews among cases and controls. Most interviews (95–96%) were conducted face-to-face, the rest by telephone. The majority of interviews took place at home; the higher proportion of interviews at hospital for the cases was related to long hospital stays with health-threatening conditions. The few controls interviewed at hospital in fact made appointments with the local epidemiology units.


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Table II. Selected characteristics of interviewed cases and controls
 
Peptic ulcer and NHL
Table IIIGo shows the distribution of cases and controls by a history of peptic ulcer. Chronic lymphocytic leukemias (CLLs) are included among lymphocytic leukemias (LLs). No diagnostic category, except NHL, shows an association with ulcer. The association is statistically significant for NHL. Table IVGo shows that the association is stronger among gastric lymphomas (n = 116; OR 5.6, 95% CI 3.9–8.0), with an OR of 1.3 for non-gastric NHL (n = 1253; 19 cases are excluded from the analysis because of missing information on age at onset of ulcer). The estimates were unchanged after adjustment by study area (center). The association with peptic ulcer is stronger in females, in young ages and after a relatively short time since the diagnosis of peptic ulcer, although the OR is still 2.1 after >=20 years since first diagnosis of ulcer. Twenty gastric and 32 non-gastric cases had ulcers diagnosed <2 years before NHL developed; Table IVGo shows the relationship with time since ulcer diagnosis after exclusion of these very short latencies.


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Table III. Peptic ulcer and hematopoietic cancers
 

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Table IV. Gastric and other NHLs
 
We further excluded ulcers diagnosed before 1978 (the approximate year of regular introduction of gastroscopy in Italy): the OR for ulcers diagnosed >=2 years before gastric NHL was 5.3 (3.0–9.2).

If we adopt a conservative approach, i.e. we only consider the ulcers reported in the clinical records of the one center where a check was made (20 ulcers in NHL patients), we still find an age-adjusted OR of 3.71 (1.44–9.57).

Effect modifiers
Females had a clearly higher risk of gastric NHL after peptic ulcer. The difference between the OR in the two genders (9.2 and 4.1, respectively) was statistically significant (Breslow–Day test for heterogeneity, P = 0.03). Curiously, males had a higher risk for non-gastric NHL associated with ulcer.

A rather unexpected finding was the effect modification exerted by educational level; the OR for peptic ulcer, in fact, was stronger for higher social groups (defined in terms of years in school, Table IVGo).

The vast majority of gastric lymphomas belonged to the MALT category and to the `intermediate' histologic grade category of the Working Formulation. CLL were included in the `low grade' category according to the working formulation. The association with peptic ulcer was stronger in MALT as opposed to non-MALT gastric lymphomas (Tables V and VIGoGo), but only for more recent ulcer diagnoses (2–10 years).


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Table V. Distribution of gastric and non-gastric NHL by Working Formulation and diagnosis of peptic ulcer
 

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Table VI. Distribution of gastric NHL by grand histologic categories and latency since diagnosis of ulcer
 
We also analyzed the distribution of gastric NHL by peptic ulcer and family history for lymphomas. A positive family history was found in seven gastric NHL cases and 49 controls; among these, two cases and seven controls, respectively, reported a history of peptic ulcer (OR for peptic ulcer was 2.4, 95% CI 0.4–14.9). Among the cases and controls without a family history, the OR was 6.7 (4.5–10). Therefore, if any interaction between family history and H.pylori infection could be suggested, it is a negative one. The {chi}2 for heterogeneity between the two categories of family history was 1.2 (P = 0.26; Breslow–Day test).

No interaction was found with previous tonsillectomy or adenoidectomy, or with a history of mononucleosis. Birth in the southern regions of Italy (which are poorer than northern regions) did not influence the association with peptic ulcer.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We have conducted a large population-based case-control study on hemato-lymphopoietic malignancies in Italy. Strengths of the study were the high response rate, the good overall quality of the interviews, and good case definition, including detailed histologic classification.

We have found that individuals who reported a diagnosis of peptic ulcer had a relative risk of 5.6 for gastric NHL, while the estimate for non-gastric lymphomas was 1.3. These figures are strictly comparable with those published by Parsonnet et al. (4) in their prospective investigation and suggest that H.pylori is a cause of gastric NHLs. Parsonnet et al. (4) did not find an association with time since blood collection (which, however, is a very imperfect proxy for latency since infection with H.pylori), whereas we found that the association was stronger with a recent history of ulcer. This finding could be interpreted as suggesting that the association may be due to a `detection bias', i.e. subjects with ulcer who undergo gastroscopy frequently would have a greater probability of NHL detection. However: (i) the association with other gastrointestinal pathologies was much lower and non-statistically significant (OR = 1.4; ulcerative colitis, Chron's disease and coeliac disease excluded); (ii) the OR was as high as 2.1 (95% CI 1.1–4.2) after >=20 years since diagnosis of ulcer.

We found a stronger association with ulcers in females than in males. H.pylori infection has a slightly higher prevalence among males; in a previous survey among 930 healthy Italians, 46% of males were positive for anti-H.pylori antibodies, versus 43% of females. In the present study, control males reported a lifetime prevalence of peptic ulcer of 15%, versus 6.5% among control females.

Almost all gastric lymphomas were B-cell intermediate grade NHLs, according to the working formulation; most belonged to the MALT type. The association with ulcers was much stronger among MALT lymphomas, but only for recent ulcer diagnoses (2–10 years).

A rather puzzling finding is the direct and strong association with level of education (years in school). This observation merits interest since evidence indicates that H.pylori infection occurs more frequently among lower social groups. In a previous survey in Italy, anti-H.pylori antibodies were found in 48% of individuals belonging to lower social class, 42% in those belonging to intermediate class and 38% in high-class individuals (11). In the present study, the lifetime prevalence of peptic ulcer was 14 (<6 years in school), 10 (6–8 years), 8 (9–13 years) and 6% (>=14 years). Table VIIGo shows the results of logistic regression in which peptic ulcer, schooling and an interactive term between education and ulcer have been introduced. Although there is an independent relationship between gastric lymphoma and ulcer (diagnosed >=2 years before NHL), the strongest association is with the interactive term between higher education and peptic ulcer. Some late event associated with higher social class could trigger the development of gastric NHL. One can speculate that early H.pylori infection creates some sort of local immunological protection, while late infection, more typical of higher social groups, would entail an increased risk of lymphoma, but this is pure speculation. In a previous Japanese study, early infection with H.pylori increased the risk of developing both gastric carcinoma and gastric ulcer but not duodenal ulcer (12). No information was available for NHL.


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Table VII. Logistic regression models
 
At least in Italy, social class differences in the access to health services are not so evident as to justify a class-related detection bias. Nor did a family history of lymphoma seem to interact with peptic ulcer. If any interaction can be supposed, our data suggest that familial lymphoma and H.pylori-induced NHL follow different pathogenetic patterns.


    Acknowledgments
 
We thank Professors Luigi Resegotti, Giorgio Palestro (Torino) and Luciano Fiore Donati (Verona) for suggestions and encouragement. We are indebted to David Forman and Domenico Palli for thoughtful comments on the manuscript. The kind cooperation of the clinical department staff involved in patient recruitment is acknowledged. The Italian multicenter study on hemato-lymphopoietic malignancies has been funded by the US National Cancer Institute (CA51086).


    Notes
 
11 To whom correspondence should be addressed Email: paolo.vineis{at}unito.it Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received June 29, 1998; revised March 9, 1999; accepted April 12, 1999.