Cancer Causes and Control 13: 603–608, 2002. Ó 2002 Kluwer Academic Publishers. Printed in the Netherlands.
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Risk factors for myelodysplastic syndromes: a case–control study in Greece Maria Dalamaga1, Eleni Petridou1,2,* Francis E. Cook2 & Dimitrios Trichopoulos1,2 1 Department of Hygiene and Epidemiology, Athens University Medical School, Athens, Greece; 2Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Received 22 October 2001; accepted in revised form 17 March 2002
Key words: Greece, myelodysplastic syndromes, risk factor.
Abstract Objective: The etiology of most cases of myelodysplastic syndromes (MDS) has not been elucidated. We have undertaken an investigation in Greece to determine the risk profile of adult de-novo MDS. Methods: A case–control investigation was conducted in a large Veterans’ hospital over a five-year period, covering 84 MDS cases and 84 age- and gender-matched controls with minor non-neoplastic non-infectious conditions from the same study base. Cases and controls reported to the medically trained principal investigator lifestyle characteristics and medical histories, with emphasis on autoimmune disorders and allergic conditions. Results: Alcohol intake and tobacco smoking jointly increased significantly the risk of MDS (odd ratio contrasting ever smokers and regular drinkers of at least one glass per day to never smokers and drinkers of less than one glass per day: 9.54, 95% CI 3.52–25.82) whereas each of these factors alone had limited effect. There was also evidence that autoimmune conditions, but not allergic disorders, were positively associated with MDS risk, irrespective of their occurrence during the recent (less than ten years) or the remote (more than ten years) past (OR 3.34, 95% CI 1.15–9.74; OR 3.50, 95% CI 1.19–10.26, respectively). Conclusion: We found evidence that both exogenous and endogenous factors may play a role in the etiology of the so-called ‘‘de novo’’ myelodysplastic syndromes, but these findings need further confirmation.
Introduction The myelodysplastic syndromes (MDS), also referred to as preleukemic syndromes [1] or smoldering leukemia [2], are a heterogeneous group of acquired clonal disorders of the stem cell, characterized by ineffective hematopoiesis leading to one or more peripheral blood cytopenias associated typically with a normocellular or hypercellular bone marrow [3, 4]. These blood disorders, that evolve progressively and often transform into acute leukemia [5, 6], generally arise de novo (idiopathic or primary MDS), but may be seen after exposure to radiotherapy or cytotoxic chemotherapy – especially with melphalan and procarbazine [7]. The French– American–British (FAB) Cooperative Group proposed * Address correspondence to: Eleni Petridou MD, MPH, Department of Hygiene and Epidemiology, Athens University Medical School, 75 M. Asias str., Post Code 11527 Athens, Greece. Ph.: and fax: (301) 7773840 – (301) 9324300; E-mail:
[email protected]
a classification scheme with five morphologic subtypes of MDS, based upon bone marrow and peripheral blood findings [8]. Although the etiopathogenesis of de novo MDS is not well understood, the high incidence in the elderly implies that senescence of the hematopoietic system is important in the development of the disease [3]. A number of suggested and established risk factors have been considered, including genetic disorders such as Down’s syndrome, Fanconi’s anemia, ataxia–telangiectasia, Bloom’s syndrome, neurofibromatosis type 1, and congenital neutropenia; cancer treatment with radiotherapy and/or mutagenic chemotherapy; certain occupational exposures; splenectomy; aplastic anemia, polycythemia vera, and paroxysmal nocturnal hemoglobinuria. Tobacco smoking [9, 10] and alcohol consumption [11] have also been implicated. A variety of autoimmune conditions are characterized by an increase in the helper/suppressor ratio (CD4+/ CD8+), a decrease in suppressor CD8+ cells and a
604 polyclonal activation of B lymphocytes [12–15]. Abnormalities involving ratios and function of T lymphocytes may provide the basis for an increased risk of neoplastic conditions. MDS patients also present immunologic abnormalities involving T-cell subsets and NK cells [16]. Autoimmune disorders such as polymyalgia rheumatica, Raynaud and Sjøgren syndromes, relapsing polychondritis, vasculitis, pericarditis, pleural effusions, iritis, peripheral neuropathy, and inflammatory bowel disease are common in patients with MDS [17, 18] but it has not been established whether these disorders precede MDS or are part of the spectrum of the manifestations of these disorders. Asymptomatic immunologic abnormalities such as hypergammaglobulinemia, hypogammaglobulinemia, monoclonal gammopathy, and several types of positive antiglobulin tests are also common in patients with MDS [16]. The present case–control study was conducted at the large Veterans’ General Hospital in Athens, Greece. The aim of the study was to obtain evidence concerning the hypothesis that chronic immune stimulation of the hematopoietic system may affect the risk of developing primary MDS, and to ascertain the possible role of important lifestyle variables such as tobacco smoking and drinking of alcoholic beverages.
M. Dalamaga et al. graphic variables, notably age, sex, and year of diagnosis. The predominant histologic subtype of MDS in this series was refractory anemia with or without excess blasts in transformation (48 cases). Cytogenetic information was available for a minority of cases and was not systematically recorded. Selection of controls Controls were patients under age 85, admitted for acute non-neoplastic and non-infectious conditions to the Orthopedic Department of the same hospital and matched to cases on age (±5 years) and gender. The main diagnoses in the control group were injuries and, in particular, fractures not secondary to a disease. For every eligible case an attempt was made to randomly identify a control admitted to the Veterans’ Hospital as closely as possible in time to the corresponding case. A total of 119 potential controls were identified and of those 84 were interviewed. Among the latter, 47 were males and 37 females, aged 47–85 years (median age 74). As for cases, the main reason for nonparticipation was refusal on the part of the subject or his/her relatives, but responders and non-responders did not differ on demographic variables, notably age, sex, and year of diagnosis. Data collection
Materials and methods In this study both cases and controls were selected from patients hospitalized at the Veterans’ General Hospital of Athens. The study covered 84 cases and 84 controls under 85 years old, who were all of Greek nationality, permanent residents, and from the same study base. Records were abstracted and interviews were carried out to obtain information on prior immune-related conditions, such as autoimmune disorders, allergic manifestations, as well as demographic characteristics and lifestyle variables. Selection of cases Cases included newly diagnosed patients with histologically confirmed primary MDS, under age 85, consecutively admitted to the Internal Medicine Department of the Veterans’ hospital between 1 April, 1995 and 31 May, 2000. All cases were classified according to the FAB Cooperative Group scheme [8]. A total of 108 cases were identified and of those 84 cases (47 males and 37 females), aged 44–85 years (median age 74) were interviewed. The main reason for nonparticipation was refusal on the part of the subject or his/her relatives, but responders and non-responders did not differ on demo-
A precoded questionnaire comprising 23 items was administered to all cases and controls by the same interviewer (M.D.), who also reviewed the medical records. Sociodemographic and medical variables and lifestyle characteristics, including tobacco and alcohol consumption, were covered. Because most patients were elderly, questions were simple and straightforward, without undue attention to details that are difficult to ascertain and summarize. For example, a 75-year-old smoker is likely to have gone through periods of light or heavy smoking, of unfiltered or filtered cigarettes of variable tar content. This information, even when accurate, is difficult to summarize and utilize. Eventually, three categories of smoking status were examined: never smokers, ex-smokers (that is those who quit smoking more than three years before the interview), and current smokers. With respect to reported drinking of alcoholic beverages five categories were used: non-drinkers, occasional drinkers (two or less glasses per month), regular drinkers of less than seven glasses per week, regular drinkers of about one glass per day, and regular drinkers of more than one glass per day. The levels of alcohol drinking reported by the study subjects are medically and socially acceptable in Greece and they are not subject to changes over time as frequently as smoking habits are.
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Myelodysplastic syndromes in Greece Information on medical history was obtained based on an additional list of 30 frequent disorders reflecting autoimmune processes, chronic inflammatory conditions, or allergic disorders. A history of autoimmune disease, or chronic inflammatory disease, was defined as that covering at least one of the following: rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Reiter’s syndrome, Behc¸et’s syndrome, psoriatic arthritis, systemic sclerosis, Sjo¨gren’s syndrome, dermatomyositis–polymyositis, vasculitic syndromes, polymyalgia rheumatica syndrome, sarcoidosis, inflammatory bowel disease, psoriasis, pemphigus, autoimmune thyroiditis, pernicious anemia, myasthenia gravis, and multiple sclerosis. A history of allergic disorder was defined as that covering at least one of the following: asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, drug and food allergies, and reactions to insect stings. All collected exposure data referred to the time prior to the MDS diagnosis for cases and the corresponding period for controls. Information provided in the questionnaire was supplemented and validated by examination of medical records and pathology reports, which were available and usable for about 50% of cases and controls (Veterans are generally hospitalized in the hospital where our study was conducted). Medical records in the Veterans’ hospital are usually of acceptable quality, but their retrieval depends on manual methods. Statistical analysis Statistical analysis of the data was performed with SAS (SAS Institute, Cary, NC). Initially data were assessed through simple cross-tabulations. For exposures with three or more ordered categories a trend for proportions test (a variant of the Mantel extension test) was used [26]. Subsequently, statistical analysis was undertaken through multiple logistic regression [19]. Unconditional logistic regression can be used without loss of validity, if the matching factors are accounted for [19]. We have opted for unconditional rather than conditional analysis in order to use the same approach when investigating subtypes of MDS. In any case, the two approaches generated similar results for the total series of MDS cases.
Results Table 1 displays the distribution of the studied cases of myelodysplastic syndromes and their matched controls by sociodemographic factors; that is: gender, age, marital status, and educational level. Most cases were older than 65 years. Smoking status and alcohol drinking were significant risk factors for MDS in the
univariate analyses, as was timed history of an autoimmune disorder. The 75% non-smoking rate among the control group, confirmed by anecdotal reports from veteran facilities in Greece, reflects the high proportion of non-smokers amid officers, non-commissioned officers and their families (population admitted to this Veterans’ hospital) as opposed to the high proportion of smokers in the general population and soldiers doing their military service (not admitted to this hospital). Table 2 shows multiple logistic regression-derived, mutually adjusted odds ratios (OR) and 95% confidence intervals (CI) for an MDS in relation to the studied factors. Age and gender are matching factors and the apparently increased risk of MDS among never married individuals may reflect, at least in part, residual confounding by alcohol drinking and tobacco smoking, both conditions known to be more common among the never married. There is evidence for an interaction between tobacco smoking (ever smokers vs others) and alcohol drinking (one or more glasses per day vs others) in the causation of MDS. Ignoring interaction, and treating smoking and drinking as possible mutual confounders, indicates that alcohol drinking is probably more important than tobacco smoking in the causation of MDS. There is also strong and statistically significant evidence that autoimmune disorders are associated with increased risk of MDS. On the contrary, there is little evidence that allergic disorders play a role in the causation of the MDS (data not shown). Among autoimmune conditions Graves’ disease and Hashimoto’s thyroiditis appear to be most important. However, examination of individual autoimmune and allergic disorders is difficult to interpret, because of the multiple comparison process and the modest study size. Nevertheless, the similarity of the excess risk linking autoimmune disorders to MDS, irrespective of the time of first diagnosis of the autoimmune disorder, argues against information bias, because the latter tends to generate disproportional excesses during the recent rather than the remote past. Moreover, no difference was evident between cases and controls with respect to reproductive variables (women only), history of surgical operations of any type, and history of hospitalizations for any reason other than neoplastic (for which a small excess among cases could be explained in terms of the exclusion criteria for controls).
Discussion The precise incidence of primary MDS has not been accurately assessed by epidemiologic studies [8]. However, estimates indicate that the incidence varies around
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Table 1. Distribution of 84 cases of myelodysplastic syndromes and 84 age- and gender-matched controls by sociodemographic and lifestyle variables as well as timed history of autoimmune disorder(s) Variable
Gender Male Female Age (years)
