Affiliations of authors: H. Hjalgrim, P. Sørensen, M. Frisch, M. Melbye, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; J. Askling, A. Ekbom, Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden; M. Madsen, L. S. Eriksen, The Danish Institute for Clinical Epidemiology, Copenhagen; N. Rosdahl, Medical Office of Health, City of Copenhagen; H. H. Storm, Institute of Cancer Epidemiology, The Danish Cancer Society, Copenhagen; S. Hamilton-Dutoit, Institute of Pathology, Aarhus University Hospital, Denmark.
Correspondence to: Henrik Hjalgrim, M.D., Department of Epidemiology Research, Statens Serum Institut, 5 Artillerivej, 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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The association between the occurrence of infectious mononucleosis and the risk of Hodgkin's disease remains, however, poorly characterized. Little information on the long-term risk of Hodgkin's disease after infectious mononucleosis or its variation with age is available from previous studies. Moreover, only a few investigations (35,15) have reported on the risk of cancers other than Hodgkin's disease among patients with infectious mononucleosis. Such data on the general cancer risk in infectious mononucleosis patients are, however, pertinent to the interpretation of the association between infectious mononucleosis and the risk of Hodgkin's disease and, consequently, to the understanding of the role of EBV in Hodgkin's disease in young adults (1719).
To further characterize the association between the occurrence of infectious mononucleosis and the risk of Hodgkin's disease, we assessed the risk of cancer in general and the risk of Hodgkin's disease in particular in a cohort study of 38 562 patients diagnosed with infectious mononucleosis.
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SUBJECTS AND METHODS |
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In Sweden, individual information on inpatient care has been registered county-wise in the Inpatient Register since 1964 (23). The Swedish cohort comprised all individuals registered with a diagnosis of infectious mononucleosis [International Classification of Diseases, Injuries, and Causes of Death (ICD) 7th revision = 093 (24), ICD 8th revision = 075 (25), and ICD 9th revision = 075 (26)] in the Register during the period 1964 through 1994. By use of the national registration number, a 10-digit number unique to each Swedish citizen, the cohort was linked to the Cause of Death Register as well as to the Register of Population and Population Changes to ascertain vital status as of the end of 1995 and to the Swedish Cancer Registry (27) to obtain information on cancer among the infectious mononucleosis patients.
The standardized incidence ratio (SIR), i.e., the ratio of observed-to-expected numbers of cancers, served as a measure of the relative risk for cancer.
In Denmark, follow-up for each individual began from April 1, 1968, or the month following the diagnosis of infectious mononucleosis, whichever came later, until the date of death, date of emigration, or December 31, 1995, whichever came first. In Sweden, follow-up started the month after infectious mononucleosis diagnosis and ended on the date of diagnosis of cancer, emigration, death, or December 31, 1995, whichever came first. Swedish infectious mononucleosis patients with cancer developing before infectious mononucleosis (n = 59) were excluded.
We estimated the expected number of cancers by multiplying age-, sex-, and period-specific strata of person-years of follow-up by corresponding age-, sex-, and period-specific cancer incidence rates in the general population. In Denmark the population-based cancer incidence rates include multiple primary cancers, whereas in Sweden the rates for first primary cancers were usedhence, the difference in definitions of end of follow-up.
Because of differences between the two cohorts with respect to age at and calendar period of infectious mononucleosis diagnosis and follow-up (Table 1), we first evaluated country-specific, age-specific, and follow-up period-specific SIRs. Because no systematic variation in SIRs was apparent between the countries, the observed and expected numbers of cancers in the two cohorts were combined to yield single estimates of the relative risk. We estimated SIR for cancer overall and by anatomic sites, calculating 95% confidence intervals (CIs) for the SIRs assuming a Poisson distribution of the observed cases (28). SIRs for Hodgkin's disease in different subsets of patients, as defined by nationality, sex, calendar period of follow-up (before 1978, 19781982, 19831987, 19881992, and 19931995), age at diagnosis of infectious mononucleosis, and time since diagnosis of infectious mononucleosis were compared by Poisson regression analyses (29). Finally, the significance of attained age, i.e., age treated as a continuously increasing variable, was assessed by comparing SIRs for Hodgkin's disease in four different age strata (<15 years, 1534 years, 3544 years, and
45 years) defined by reported age-dependent variation in the prevalence of EBV gene products in tumor tissues (18,19,30). All Poisson regression analyses were adjusted for sex, country, age at diagnosis of infectious mononucleosis, and time since diagnosis of infectious mononucleosis. Tests for differences between the groups including tests for linear trends were done by likelihood ratio tests. Because the three time-dependent variables (i.e., age at diagnosis of infectious mononucleosis, time since diagnosis of infectious mononucleosis, and attained age) are collinear and, therefore, difficult to assess simultaneously, two analyses of the significance of attained age were made: Besides attained age, age at infectious mononucleosis diagnosis and time since infectious mononucleosis diagnosis were included alternatively in the statistical model. All statistical tests were two-sided.
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RESULTS |
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Overall, 46 cases of Hodgkin's disease were observed versus only 18.04 expected (SIR = 2.55; 95% CI = 1.873.40) (Table 2). Poisson regression analyses showed no statistically significant differences in SIR for Hodgkin's disease between the Swedish and Danish cohorts (SIR ratio = 1.56; 95% CI = 0.832.95; adjusted for sex, age at diagnosis of infectious mononucleosis, and time since diagnosis of infectious mononucleosis), between men and women (SIR ratio = 1.16; 95% CI = 0.612.21; adjusted for country, age at diagnosis of infectious mononucleosis, and time since diagnosis of infectious mononucleosis), or between different calendar periods of follow-up (P homogeneity = .18). The SIR for Hodgkin's disease remained increased in all follow-up periods up to two decades after diagnosis of infectious mononucleosis (Table 3
), but it decreased with time since diagnosis of infectious mononucleosis (P linear trend <.001). The SIR for Hodgkin's disease tended to increase with age at infectious mononucleosis diagnosis (P linear trend = .05) (Table 3
). The SIR for development of Hodgkin's disease at different ages also varied (SIR for <15 years = 3.32 [95% CI = 0.0418.46; n = 1]; SIR for 1534 years = 3.49 [95% CI = 2.464.81; n = 37]; SIR for 3544 years = 1.11 [95% CI = 0.302.85; n = 4]; and SIR for
45 years = 1.13 [95% CI = 0.302.88; n = 4]). When we compared the SIR for Hodgkin's disease in age group 1534 years with the SIR for Hodgkin's disease in all other age groups combined by Poisson regression analysis, the SIR for age group 1534 years was statistically significantly higher (SIR ratio = 3.66; 95% CI =1.578.55) when adjusting for sex, country, and age at diagnosis of infectious mononucleosis (P for difference = .001). However, when the variable time since diagnosis of infectious mononucleosis was substituted for the variable age at diagnosis of infectious mononucleosis in the same statistical model, no difference in the SIR for development of Hodgkin's disease was apparent between the age groups (SIR ratio =1.09; 95% CI = 0.462.57). Neither the association with time since diagnosis of infectious mononucleosis nor the risk patterns observed for age at diagnosis of infectious mononucleosis and for attained age differed significantly between the two cohorts; moreover, the risk estimates did not change materially by excluding the first year of follow-up from the analyses (data not shown).
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DISCUSSION |
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Recall bias is not a problem in our study, since we relied on information from population-based registers. During the first year of follow-up, but not thereafter, the overall risk of cancer and the risk of hematopoietic and lymphatic cancers, in particular, were statistically significantly increased among infectious mononucleosis patients. Diagnostic misclassification is the most likely explanation for this time pattern. While this source of error may also apply to the risk of Hodgkin's disease shortly after the occurrence of infectious mononucleosis, it would not explain the increased risk up to two decades after infectious mononucleosis diagnosis.
Except for the moderately increased risk of skin cancers, the risk of cancers other than Hodgkin's disease was not increased among infectious mononucleosis patients. Indeed, the risk of lung cancer was reduced in such patients. In general, however, the study did not support previous suggestions of a decreased cancer occurrence among infectious mononucleosis patients (15,31). Our observations are consistent with the association between high socioeconomic status and risk of infectious mononucleosis (32). Furthermore, according to our data, the increased risk of Hodgkin's disease following the diagnosis of infectious mononucleosis appears to be a rather specific phenomenon.
Most of the observed cases of Hodgkin's disease occurred among young adults, and the SIR for Hodgkin's disease in this age group was higher than that in other age groups. Although it is difficult to confirm or refute an independent effect of attained age, our results suggest that the higher SIR among young adults could also reflect the age composition of infectious mononucleosis patients and the high risk of Hodgkin's disease shortly after infectious mononucleosis diagnosis. For Hodgkin's disease in young adults, the association with high socioeconomic status is a critical argument for the late infection hypothesis that has been described for Hodgkin's disease (12). Several of our findings make EBV a strong candidate as the hypothesized infectious agent. Apart from the generally increased risk of Hodgkin's disease among infectious mononucleosis patients, the suggestive findings include the correlation between age at infectious mononucleosis occurrence and Hodgkin's disease risk and the inverse association with time since infectious mononucleosis diagnosis. EBV has also been incriminated in Hodgkin's disease pathogenesis by the demonstration of viral gene products in tumor tissue (33,34). The prevalence of EBV in Hodgkin's disease, however, varies with the histologic subtype of Hodgkin's disease and is lower in young adults than in children and older persons (18,19,30). Unfortunately, data on EBV status and histologic subtype for the observed cases of Hodgkin's disease were not available in our study. Although it has been proposed that EBV may be lost during Hodgkin's disease development (hit-and-run hypothesis) (17,35), it is noteworthy that EBV has been demonstrated in only nine of 32 cases of Hodgkin's disease occurring after infectious mononucleosis in previous studies (16,17,36). Also, it is interesting that, while aberrant patterns of antibodies against EBV may precede diagnosis of Hodgkin's disease by years (37), there seems to be no clear association between such antibody patterns and the presence of EBV-genome products in the Reed-Sternberg cells in tumors of patients with Hodgkin's disease (38,39). Our finding of a more than threefold increased risk of all Hodgkin's disease subtypes combined among young adults may reflect a particularly high relative risk for EBV-related Hodgkin's disease subtypes, as was also suggested by a recent casecontrol study (16). Alternatively, exposures other than late infection with EBV may play a role in Hodgkin's disease development in young adults. If so, such exposures, whether infectious or not, must share epidemiologic features with infectious mononucleosis.
The strengths of our study lie in its population-based setting, the size of the cohort followed, the long follow-up period, the unbiased ascertainment of both exposure and outcomes through high-quality registers, and our ability to compare findings in two independent and different cohorts. The Danish cohort was made up of patients tested at a national laboratory and, thus, mostly nonhospitalized patients (6,21); in contrast, the Swedish cohort comprised hospitalized patients with infectious mononucleosis. In Denmark, only serologic evidence of acute infectious mononucleosis infection was available, whereas enrollment in the Swedish cohort rested on combinations of serologic and clinical evidence of infectious mononucleosis. However, despite the presumed variation in the severity of infectious mononucleosis and possibly also in the accuracy of infectious mononucleosis diagnosis between the two cohorts, estimates of Hodgkin's disease risk were rather similar in the two cohorts. Of the original Danish cohort of infectious mononucleosis patients, only 77% were available for follow-up. Still, with regard to the risk of Hodgkin's disease, substantial bias due to incomplete identification of the cohort is unlikely, since the overall cancer risk in the cohort was close to unity. The consistent risk patterns seen in the two countries also render major selection bias unlikely.
The cohorts were linked to the Danish and Swedish cancer registries to identify cases of cancer following infectious mononucleosis diagnosis. Both registries have a reputation of high registration quality and completeness (22,27), and we are confident that virtually all cancers occurring during the follow-up period have been identified. Misclassification of non-Hodgkin's lymphoma as Hodgkin's disease has occurred more frequently in earlier years than in more recent years (4042). If non-Hodgkin's lymphoma were more likely to be misclassified in patients with antedating infectious mononucleosis than in other patients, this situation would have led to an overestimation of the observed risk of Hodgkin's disease. The risk of Hodgkin's disease after infectious mononucleosis occurrence did not, however, vary significantly between calendar periods in our investigation; moreover, the risk of non-Hodgkin's lymphoma was not increased after the occurrence of infectious mononucleosis. Consequently, it seems unlikely that histopathologic misclassification would account for the observed increased risk of Hodgkin's disease.
In conclusion, our study shows that patients with infectious mononucleosis are at increased risk of Hodgkin's disease for up to two decades after the diagnosis of infectious mononucleosis. The excess of Hodgkin's disease is remarkable, inasmuch as no other cancers, except skin cancers, occurred in excess among these patients. Rather, the risk of lung cancer was significantly reduced. These findings are compatible with the previously established association between high socioeconomic status and infectious mononucleosis. Our finding of a threefold increased risk of Hodgkin's disease in young adults, a group in whom Hodgkin's diseases are generally dominated by EBV-negative subtypes (18,19,30), is interesting. The increased risk of Hodgkin's disease in this age group in cohorts we studied may reflect a particularly high relative risk for EBV-positive subtypes of Hodgkin's disease, an hypothesis that needs to be explored further.
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NOTES |
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We thank Professor Per Kragh Andersen and Klaus Rostgaard for valuable statistical advice.
The study was approved by The Scientific Ethics Committee for the Copenhagen and Frederiksberg Municipalities (KF-11-116/99) and the Danish Data Surveillance Authority (1997-1200-272).
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Manuscript received December 1, 1999; revised June 29, 2000; accepted July 20, 2000.
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