Affiliations of authors: Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark (HH, KR, NMN, LM, MM); National Institute of Public Health, Copenhagen (SR); The Danish Multiple Sclerosis Registry, Copenhagen (SR, NKH); Department of Neurology, Aarhus University Hospital in Aalborg, Aalborg, Denmark (NKH); Department of Cancer Prevention and Documentation, Danish Cancer Society, Copenhagen (HHS).
Correspondence to: Henrik Hjalgrim, MD, Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark (e-mail: hhj{at}ssi.dk)
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ABSTRACT |
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INTRODUCTION |
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Few studies provide information relevant to the hypothesized connection between Hodgkin lymphoma and multiple sclerosis. No geographical correlation between incidence of multiple sclerosis and that of Hodgkin lymphoma was observed in a Danish ecologic study (2). No increase in the co-occurrence of Hodgkin lymphoma and multiple sclerosis in individual patients has been reported in follow-up studies with cancer mortality [e.g., see (35)] or incident cancers (6,7) as outcomes. Finally, no clustering of Hodgkin lymphoma and multiple sclerosis was observed in two casecontrol studies (8,9), although accumulation of the two conditions within families (including conjugal relatives) was suggested in one study (8). However, inherent methodologic limitations and, in particular, modest numbers of patients in the previous studies make it difficult to rule out the suggested etiologic relationship between Hodgkin lymphoma and multiple sclerosis.
If Hodgkin lymphoma and multiple sclerosis share risk factors, then we would expect both diseases to be found at increased frequency in individuals, in their families, or in both. To investigate this possibility, we took advantage of two unique Danish population-based registers containing information on incident cases of cancer and multiple sclerosis to study the risk of Hodgkin lymphoma in patients with multiple sclerosis and their first-degree relatives and the risk of multiple sclerosis in patients with Hodgkin lymphoma and their first-degree relatives.
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MATERIALS AND METHODS |
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Cohorts of Patients With Multiple Sclerosis and Their Relatives
The Danish Multiple Sclerosis Registry was officially established in 1956 but actually started operating in 1949 with a nationwide survey of prevalent cases of multiple sclerosis (12). The registration and validation procedures used have ensured high degrees of completeness (>90%) and diagnostic validity (94%) (12). For this study, we identified all persons registered in the Danish Multiple Sclerosis Registry as of December 31, 1997 (most recent year with complete data). We subsequently used the personal identification numbers of all of the patients to identify all their first-degree relatives (parents, siblings, and offspring) recorded in the Danish Civil Registration System.
We followed the cohorts of patients with multiple sclerosis (total = 11 790 patients) and their relatives (total = 19 599 relatives) for diagnoses of Hodgkin lymphoma and (for comparative purposes) for diagnoses of other hematopoietic or lymphatic cancers by linking with the Danish Cancer Registry. Follow-up was from July 1 of the year that multiple sclerosis was diagnosed, date of birth (for patients relatives), or April 1, 1968, whichever came later, until the date of multiple sclerosis diagnosis (in the relatives), death, emigration, disappearance, or December 31, 1997 (most recent year of complete cancer registration), whichever came first.
Cohorts of Patients With Hodgkin Lymphoma and Their Relatives
The population-based Danish Cancer Registry has been in operation since 1943 (11). The procedures used have ensured that registration is essentially 100% complete for most types of cancer (11). We identified all persons registered with Hodgkin lymphoma in the Danish Cancer Registry between April 1, 1968, and December 31, 1997, and we used their personal identification numbers to identify all their first-degree relatives (parents, siblings, and offspring) recorded in the Danish Civil Registration System.
The cohorts of patients with Hodgkin lymphoma (total = 4381 patients) and their relatives (total = 7388 relatives) were followed in the Danish Multiple Sclerosis Registry for a diagnosis of multiple sclerosis from the date that Hodgkin lymphoma was diagnosed or the date of birth (for patient relatives), whichever came later, until the date that Hodgkin lymphoma was diagnosed (in the relatives), death, emigration, disappearance, or December 31, 1997, whichever came first.
Statistical Analyses
The ratio of the observed to the expected number of outcomes (specific cancer types in the cohorts of patients with multiple sclerosis and their relatives, and multiple sclerosis in the cohorts of patients with Hodgkin lymphoma and their relatives), i.e., the standardized incidence ratio, served as measure of relative risk (RR). The expected numbers of outcomes were estimated by multiplying sex, calendar period, and age-specific (5-year age groups) person-years at risk with correspondingly stratified national population-based incidence rates for the investigated types of cancer and multiple sclerosis. We calculated 95% confidence intervals (CIs) for the relative risks from the Wald test by assuming a Poisson distribution of the observed number of outcomes. All statistical tests were two-sided.
The suspected association between Hodgkin lymphoma and multiple sclerosis rests, among other things, on the frequent onset of disease in young adults (i.e., individuals between the ages of 15 and 44 years) which, for Hodgkin lymphoma, is considered to delineate an epidemiologically meaningful disease entity (13). We therefore conducted additional analyses for Hodgkin lymphoma diagnosed in this specific age interval.
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RESULTS |
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A total of 61 hematopoietic and/or lymphatic cancers were observed among the patients with multiple sclerosis, which corresponded well with the expected number (Table 2). Although slightly more cases than expected of Hodgkin lymphoma and leukemia were observed among the patients with multiple sclerosis, statistically significantly increased risks were not observed for any individual subtype of cancer studied (Table 2). Six cases of Hodgkin lymphoma were observed among patients with multiple sclerosis (RR = 1.40, 95% CI = 0.63 to 3.12), two of which occurred in individuals aged 1544 years (RR = 1.59, 95% CI = 0.40 to 6.37) (Table 3).
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The overall risk for Hodgkin lymphoma was increased in the combined group of first-degree relatives of patients with multiple sclerosis, although the increase was not statistically significant (RR = 1.63, 95% CI = 0.85 to 3.13; n = 9) (Table 2). All nine cases of Hodgkin lymphoma occurred in the young-adult age group, for which the increase was statistically significant (RR for young-adult-onset Hodgkin lymphoma = 1.93, 95% CI = 1.01 to 3.71) (Table 3).
Multiple Sclerosis in Families Afflicted by Hodgkin Lymphoma
Two cases of multiple sclerosis were observed in patients with Hodgkin lymphoma compared with 2.86 cases expected (RR = 0.70, 95% CI = 0.17 to 2.80). Both cases occurred in patients diagnosed with young-adult-onset Hodgkin lymphoma (RR = 0.82, 95% CI = 0.20 to 3.27) (Table 3). The risk of multiple sclerosis was increased among the first-degree relatives of patients with Hodgkin lymphoma (RR = 2.25, 95% CI = 1.24 to 4.06; n = 11). Nine of the observed cases of multiple sclerosis occurred in relatives of patients with young-adult-onset Hodgkin lymphoma (RR = 2.76, 95% CI = 1.44 to 5.31) (Table 3).
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DISCUSSION |
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Various mechanisms may explain the observed clustering of the two diseases within families, but we find it unlikely to be a chance phenomenon. Specifically, it is consistent with the proposed hypothesis of a common etiology for the two diseases (1), and the familial clustering of the two conditions was independently observed in analyses of both families afflicted by Hodgkin lymphoma and families afflicted by multiple sclerosis. In comparison, the unremarkable risks of disease observed in patients with multiple sclerosis and patients with Hodgkin lymphoma were based on limited numbers of observations. Furthermore, we cannot rule out that treatment of multiple sclerosis or of Hodgkin lymphoma may have influenced the patients subsequent risk for the other disease.
The accumulation of young-adult-onset Hodgkin lymphoma and multiple sclerosis within families may reflect the effects of shared environmental or constitutional risk factors for the two diseases or, more likely, a combination of such factors. It is particularly interesting that EpsteinBarr virus (EBV) infection may be implicated in the development of both Hodgkin lymphoma and multiple sclerosis. Elevated levels of anti-EBV antibodies precede diagnosis of Hodgkin lymphoma (14) and of multiple sclerosis (15), and infectious mononucleosisrelated EBV infection has been associated with increased risk of both Hodgkin lymphoma (16,17) and multiple sclerosis (18) in young adults.
The clustering of Hodgkin lymphoma and multiple sclerosis is unlikely to be merely a consequence of a shared association with socioeconomic status for Hodgkin lymphoma, multiple sclerosis, and infectious mononucleosis (1,17,19). First, in a large Danish survey of patients with multiple sclerosis, no correlation with socioeconomic status was observed (20). Second, a Canadian investigation showed that adopted (i.e., nonbiologic) relatives of patients with multiple sclerosis, unlike biologic relatives, were not at increased risk of multiple sclerosis, suggesting that shared genetic rather than shared socioeconomic characteristics are more critical to the aggregation of multiple sclerosis in families (21). Third, we recently demonstrated that first-degree relatives of Danish patients with infectious mononucleosis were not at increased risk of developing Hodgkin lymphoma as young adults (22).
Smoking may be associated with an increased risk of Hodgkin lymphoma and multiple sclerosis according to some but not all studies, as summarized previously (23,24). Because of the register-based nature of our investigation, we cannot rule out the possibility that smoking may have confounded our analyses. However, we found no evidence of an increased risk of smoking-related cancers in patients with multiple sclerosis or in their relatives (data not shown). Therefore, we consider such confounding unlikely to account for our observations.
We speculate, rather, that other mechanisms, possibly of an immunologic nature, account for the observed familial aggregation of young-adult-onset Hodgkin lymphoma and multiple sclerosis. Interestingly, both familial Hodgkin lymphoma and multiple sclerosis have been associated with the HLA-DR2 allele (25,26). Moreover, the association between infectious mononucleosis on the one hand and the risk of Hodgkin lymphoma (16,17) and of multiple sclerosis (18) on the other could suggest that a common genetic and/or immunologic predisposition to the two diseases may be mediated through interaction with environmental risk factors such as EBV infection, as was recently proposed for multiple sclerosis (27).
We used unique and compatible population-based Danish registers of multiple sclerosis and cancer as well as the Danish Civil Registration System in this historical cohort analysis. Both disease registers are characterized by high degrees of validity and completeness (11,12); therefore, we are confident that surveillance bias does not account for our observations. Moreover, we found no unusual overall cancer risk among the relatives of patients with multiple sclerosis in supplemental follow-up analyses (data not shown). We did not validate the diagnoses of the observed cases of Hodgkin lymphoma, but we do not believe that diagnostic misclassification could explain our findings. Although previous incidence rates of Hodgkin lymphoma have been inflated by the erroneous classification of non-Hodgkin lymphomas as Hodgkin lymphomas (28), this problem primarily concerned Hodgkin lymphoma in the elderly and was much less pronounced in young adults (28). In addition, a 1991 survey of 489 Danish patients with Hodgkin lymphoma diagnosed from 1971 through 1983 found that only two (0.4%) cases had originally been erroneously classified as Hodgkin lymphomas (29). Identification of first-degree relatives of a patient with multiple sclerosis or Hodgkin lymphoma in the study was dependent on their being alive as of April 1, 1968 (the starting date of the Danish Civil Registration System), or later. Because information on familial relations is not available for persons who died before April 1, 1968, we cannot rule out the possibility that survivor bias may have been introduced into our analyses. However, this bias would most likely lead to conservative risk estimates and therefore is not likely to explain the observed association between Hodgkin lymphoma and multiple sclerosis. Similarly, although information on family structure (parents, siblings, and offspring) in the Danish Civil Registration System can be considered complete only for persons born since the early 1950s, we find this restriction unlikely to have introduced biases that would account for our observations.
In addition to the increased risk of Hodgkin lymphoma, we also observed an increased occurrence of non-Hodgkin lymphoma in first-degree relatives of patients with multiple sclerosis. This observation is consistent with that of a previous Italian casecontrol study, in which a personal or familial history of multiple sclerosis was associated with a 5.0-fold (95% CI = 1.05- to 23.9-fold) increased risk of non-Hodgkin lymphoma (9). The mechanisms underlying this association remain elusive but, given the well-established connection between immune dysfunction, EBV, and the risk of non-Hodgkin lymphoma (30), the association between multiple sclerosis and non-Hodgkin lymphoma may involve an immunologic mechanism similar to that involved in the proposed association between Hodgkin lymphoma and multiple sclerosis.
In conclusion, our study indicates that multiple sclerosis aggregates with young-adult-onset Hodgkin lymphoma and non-Hodgkin lymphoma within families. The mechanisms explaining this phenomenon may involve environmental or constitutional risk factors or most likely both. Our findings should be confirmed in other studies and, if possible, further characterized (e.g., with respect to the EBV status of the observed lymphomas). Regardless, the results of the present investigation support Newells hypothesis (1) of an etiology common to young-adult-onset Hodgkin lymphoma and multiple sclerosis.
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NOTES |
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Manuscript received September 23, 2003; revised March 10, 2004; accepted March 29, 2004.
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