REPORTS

Risk of Hodgkin's Disease and Other Cancers After Infectious Mononucleosis

Henrik Hjalgrim, Johan Askling, Per Sørensen, Mette Madsen, Nils Rosdahl, Hans H. Storm, Stephen Hamilton-Dutoit, Lise Stener Eriksen, Morten Frisch, Anders Ekbom, Mads Melbye

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).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Infectious mononucleosis, which is caused by the Epstein-Barr virus, has been associated with an increased risk for Hodgkin's disease. Little is known, however, about how infectious mononucleosis affects long-term risk of Hodgkin's disease, how this risk varies with age at infectious mononucleosis diagnosis, or how the risk for Hodgkin's disease varies in different age groups. In addition, the general cancer profile among patients who have had infectious mononucleosis has been sparsely studied. Methods: Population-based cohorts of infectious mononucleosis patients in Denmark and Sweden were followed for cancer occurrence. The ratio of observed-to-expected numbers of cancers (standardized incidence ratio [SIR]) served as a measure of the relative risk for cancer. SIRs of Hodgkin's disease in different subsets of patients were compared with the use of Poisson regression analysis. All statistical tests including the trend tests were two-sided. Results: A total of 1381 cancers were observed during 689 619 person-years of follow-up among 38 562 infectious mononucleosis patients (SIR = 1.03; 95% confidence interval [CI] = 0.98–1.09). Apart from Hodgkin's disease (SIR = 2.55; 95% CI = 1.87–3.40; n = 46), only skin cancers (SIR = 1.27; 95% CI = 1.13–1.43; n = 291) occurred in statistically significant excess. In contrast, the SIR for lung cancer was reduced (SIR = 0.71; 95% CI = 0.58–0.86; n = 102). The SIR for Hodgkin's disease remained elevated for up to two decades after the occurrence of infectious mononucleosis but decreased with time since diagnosis of infectious mononucleosis (P for trend <.001). The SIR for Hodgkin's disease tended to increase with age at diagnosis of infectious mononucleosis (P for trend = .05). Following infectious mononucleosis, the SIR for Hodgkin's disease at ages 15–34 years was 3.49 (95% CI = 2.46–4.81; n = 37), which was statistically significantly higher than the SIR for any other age group (P for difference = .001). Conclusion: The increased risk of Hodgkin's disease after the occurrence of infectious mononucleosis appears to be a specific phenomenon.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Despite distinct epidemiologic characteristics, the causes of Hodgkin's disease remain unknown. In young adults, epidemiologic findings (1,2) suggest that Hodgkin's disease may arise as a pathologic host response to a common but delayed infection. Infection with Epstein-Barr virus (EBV) manifesting as infectious mononucleosis is one such delayed infection that has been associated with an increased risk of Hodgkin's disease in cohort studies (38) and less consistently in case–control studies (916).

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.


    SUBJECTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Two population-based cohorts of infectious mononucleosis patients were established in Denmark and Sweden. In Denmark, Statens Serum Institut, Copenhagen, served as the national reference laboratory for serologic diagnosis of EBV infections during the cohort enrollment period from 1940 through 1978. The diagnostic method used throughout this period was a modification of the Paul-Bunnell test for heterophile antibodies (20). The Danish cohort, which has been described elsewhere (6,21), is made up of individuals with positive serology (i.e., Paul-Bunnell reaction positive at titers of 1/32 or higher) during the enrollment period. For each individual, information on name, date of birth, and date of positive serologic test was recorded. By linking the cohort on date of birth and name with the Danish Civil Registration System, we determined the 10-digit personal identification number unique to every Danish citizen for all subjects alive on April 1, 1968, or born later, as well as the vital status for these individuals by the end of 1995. Of 22 017 records sought in the Civil Registration System, personal identification numbers were established for 17 052 (77.4%). Using the personal identification number, we linked this infectious mononucleosis cohort to the Danish Cancer Registry (22) to obtain information on cancers occurring in the cohort.

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 used—hence, 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 1Go), 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, 1978–1982, 1983–1987, 1988–1992, and 1993–1995), 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, 15–34 years, 35–44 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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Table 1. Selected characteristics of the cohorts of patients studied with infectious mononucleosis: number of persons at risk for cancer and number of person-years of follow-up
 

    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The characteristics of the cohorts are presented in Table 1Go. A total of 1381 cancers were observed versus 1342.40 expected (SIR = 1.03; 95% CI = 0.98–1.09) (Table 2Go). Except for an excess of cancers in the first year after infectious mononucleosis diagnosis, the total number of cancers observed corresponded well with the number expected in all follow-up periods (Table 3Go).


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Table 2. Observed and expected numbers of cancers by anatomic sites after diagnosis of infectious mononucleosis and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs)
 

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Table 3. Observed (Obs) and expected (Exp) numbers of cancers in a cohort of patients after diagnosis of infectious mononucleosis with standardized incidence ratios (SIRs) and 95% confidence intervals (CIs)
 
With few exceptions, no excess risk was found for specific cancer types, either overall or in any time interval (Table 2Go). Both malignant melanoma and nonmelanoma skin cancers were observed in slight but statistically significant excess of the expected, whereas the risk of lung cancer was statistically significantly reduced (Table 2Go). The risk of the combined group of cancers of the hematopoietic and lymphatic tissues was increased (Table 2Go). This increase was primarily accounted for by an excess occurrence of Hodgkin's disease (Table 2Go), whereas the SIR for hematopoietic and lymphatic cancers other than Hodgkin's disease did not deviate significantly from unity overall or in any follow-up period beyond the first year after diagnosis of infectious mononucleosis (Table 3Go).

Overall, 46 cases of Hodgkin's disease were observed versus only 18.04 expected (SIR = 2.55; 95% CI = 1.87–3.40) (Table 2Go). 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 = 0.83–2.95; 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 = 0.61–2.21; 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 3Go), 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 3Go). The SIR for development of Hodgkin's disease at different ages also varied (SIR for <15 years = 3.32 [95% CI = 0.04–18.46; n = 1]; SIR for 15–34 years = 3.49 [95% CI = 2.46–4.81; n = 37]; SIR for 35–44 years = 1.11 [95% CI = 0.30–2.85; n = 4]; and SIR for >=45 years = 1.13 [95% CI = 0.30–2.88; n = 4]). When we compared the SIR for Hodgkin's disease in age group 15–34 years with the SIR for Hodgkin's disease in all other age groups combined by Poisson regression analysis, the SIR for age group 15–34 years was statistically significantly higher (SIR ratio = 3.66; 95% CI =1.57–8.55) 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 = 0.46–2.57). 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).


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To our knowledge, this is the largest study ever reported on cancer among patients with infectious mononucleosis. Our study shows that, except for an increased risk of Hodgkin's disease, skin cancers were the only other types of cancer that occurred in excess of the expected among infectious mononucleosis patients. The relative risk of Hodgkin's disease remained increased for up to 20 years after the diagnosis of infectious mononucleosis. Earlier cohort studies reporting on the risk of Hodgkin's disease after infectious mononucleosis (38,31) included considerably smaller cohorts for shorter follow-up periods. This shorter follow-up is reflected in that two thirds of the total of 41 Hodgkin's disease cases reported in all previous cohort studies combined were observed within 5 years of diagnosis of infectious mononucleosis. Similarly, the association between the occurrence of infectious mononucleosis and the risk of Hodgkin's disease derived from case–control studies rests mainly on self-reported history of infectious mononucleosis, often by a limited number of patients (916). Consequently, factors such as low statistical power, diagnostic misclassification, surveillance, and recall biases may have influenced previous studies.

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 case–control 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.


    NOTES
 
Supported by funding from the Danish Cancer Society (KB 97-100-07) and the Danish National Research Foundation.

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).


    REFERENCES
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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Manuscript received December 1, 1999; revised June 29, 2000; accepted July 20, 2000.


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