Our results suggested that allergic conditions are risk factors for hematological malignancies, and gave support to the antigenic stimulation hypothesis. Thus, the results are in concordance with most previous cohort studies [6, 15, 18, 19].
A major strength of the present cohort study is that information about allergic conditions and confounding factors has been collected prospectively. Therefore the exposure is not subject to differential misclassification, which is in contrast to retrospective case-control studies where recall bias may be a problem [2, 3, 9] and where separating the effects of prior allergic conditions from the effect of malignancy per se on the immune system may be difficult. This study has focused specifically on how allergy influences the risk of developing hematological malignancies.
Another strength is that the study is based on the Swedish Twin Registry, which is a unique resource allowing for an unusually long period of follow-up. In our study, 31 years of follow-up was possible. The cohort has been followed continuously in the Population Registry and the Cause of Death Registry during the study period, and therefore loss to follow-up is unlikely to be a problem. The Swedish Twin Registry is considered a study base representative of the general population of Sweden and has been used in many epidemiological studies [25–27]. Another strength is the completeness of the Swedish Cancer Registry, to which it is required by law to report all incident cancer cases in Sweden. New cases of cancer are reported by physicians in hospitals and other establishments as well as by pathologists. The two independent notifications systems ensure a high coverage. In addition, we could adjust for more confounding factors than in previous cohort studies [6, 13–19].
One limitation of the study is the small number of exposed cases, and therefore random variation cannot be excluded as an explanation for our findings and for the same reason no stratification for calendar time was performed. Another limitation in the study is that there may be non-differential misclassification of the malignancies. The study period covers 31 years, and during this time diagnostic practices may have changed. In particular, some cases previously diagnosed as HD are now likely to be classified as NHL [28]. This type of error would bias the effect estimates towards unity.
Differential misclassification of exposure is unlikely as there is no reason to believe that reporting exposure should differ between subjects subsequently (years later) diagnosed with a cancer, and those who are not. Non-differential misclassification of exposure is likely to affect the results, but cannot explain increased risks since it would dilute the effect estimates towards unity. The allergic conditions are self-reported and not diagnosed by a physician. However, these self-reported conditions have been used in an earlier study of brain tumors, where some support for the postulated hypothesis that allergic conditions are associated with a decreased risk of developing glioma was found [29]. Also, the validity of the allergic conditions has been investigated in a group of subjects from the Swedish Twin Registry [30]. In general, a good agreement was found between the self-reported conditions and an allergologist's diagnosis. Follow-up starts in 1969 and continues until the end of 1999. During 31 years it is possible to develop an allergic condition, but these individuals will still be considered as unexposed members of the cohort. However, the youngest individuals in our cohort were 42 years old when the questionnaire was sent out, which means that this bias have not at all affected childhood eczema, and hay fever and allergic asthma only to a small extent, as these conditions usually present earlier in life.
We found an increased risk of NHL among individuals with eczema during childhood. In the literature, there are only few studies concerning an association between eczema and NHL. In one study, a history of eczema was associated with an increased risk of NHL [10]. In several studies, elevated risks for different hematological malignancies among persons with eczema have been found, e.g. [7, 11]. On the other hand, eczema has also been observed to decrease the risk of NHL in two studies [3, 9]. Comparisons between these other studies and our study are difficult, however, since the other studies have investigated general eczema while we have focused on eczema of allergic origin (i.e. allergic eczema and eczema during childhood). When using the general definition for eczema many non-allergic forms will be included and while these may influence the risk of developing malignancies, the mechanisms involved are probably different from the ones active in allergic conditions. Thus, these eczemas are not included in the present study.
In our material subjects with hives showed an increased risk of leukemia, especially after exclusion of CLL. Several other studies have also found an increased risk of AML [12] and other hematological malignancies associated with hives [6, 9, 18]. In contrast, some other studies did not show this association [8]. A number of studies have found a protective effect of asthma on the risk of developing lymphatic leukemia and leukemia, respectively [16, 17]. This relationship between asthma and leukemia was not confirmed in our study. If anything, our results support the antigenic stimulation hypothesis. In a recent cohort study, an increased risk of leukemia was indicated [19]. On the other hand, most studies of hematological malignancies in relation to a history of asthma have shown risks close to unity [8, 9].
Clearly, these conflicting results indicate that this area needs to be investigated further. Allergic conditions, like asthma and hay fever, are increasing and it is of great importance to clarify if and how they are connected to hematological malignancies. The contradictory findings may have many explanations, e.g. that different immunological mechanisms may be involved in different types of asthma, that the pathogenesis is likely to be different even in seemingly similar hematological malignancies, and that new forms of pharmacological therapy may influence not only the outcome of asthma but also the risk of developing cancer. To solve these problems, large prospective epidemiological studies on individuals with clinically strictly defined allergic conditions, including data on pharmacological treatment and severity of disease, need to be combined with information about morphologically defined hematological malignancies, including subtyping with techniques from modern molecular biology.
