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Cancer Research 67, 2382, March 1, 2007. doi: 10.1158/0008-5472.CAN-06-3566
© 2007 American Association for Cancer Research
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Epidemiology and Prevention

Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma

Henrik Hjalgrim1, Karin Ekström Smedby3, Klaus Rostgaard1, Daniel Molin5, Stephen Hamilton-Dutoit7, Ellen T. Chang3,8, Elisabeth Ralfkiaer2, Christer Sundström6, Hans-Olov Adami3, Bengt Glimelius4,5 and Mads Melbye1

1 Department of Epidemiology Research, Statens Serum Institut and 2 Institute of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 3 Institute of Medical Epidemiology and Biostatistics and 4 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; 5 Departments of Oncology, Radiology, and Clinical Immunology and 6 Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; 7 Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark; and 8 Northern California Cancer Center, Fremont, and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California

Requests for reprints: Henrik Hjalgrim, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. Phone: 45-3268-3961; Fax: 45-3268-3165; E-mail: hhj{at}ssi.dk.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18–44 years) and older (45–74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89–5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86–2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19–7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8–4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (ORIM EBV+ HL versus EBV– HL, 2.68; 95% CI, 1.40–5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies. [Cancer Res 2007;67(5):2382–8]


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In 1957 and 1966, two seminal papers hypothesized that Hodgkin lymphoma (HL) in younger and older adult patients differed with respect to natural history, and in particular, that HL in younger adults was of an infectious etiology (1, 2). From reported associations of the lymphoma in this age group with small sibship size, low birth order, and other correlates of childhood socioeconomic affluence, it has been inferred that the postponement of common childhood infections may be accompanied by elevated HL risk in young adulthood (3–10). Consistent with this, an increased risk of HL after infectious mononucleosis (IM), the characteristic clinical manifestation of primary Epstein-Barr virus (EBV) infection delayed to adolescence, has been reported in several studies (4, 5, 11–18). EBV has also been linked with HL by other lines of evidence. Serologically, HL patients seem to have elevated anti-EBV antibody titers both before (19) and at (20) HL diagnosis, and more compellingly, clonal EBV genome products can be shown in the neoplastic Hodgkin-Reed-Sternberg (HRS) cells in the lymphoma (21).

EBV is, however, not uniformly present in all HL cases. Paradoxically, it is particularly infrequently encountered in HL in young adults (22), the age group for which the IM association is the strongest (4, 5, 11–16, 18, 23, 24). This apparent inconsistency has led to speculation concerning the role of EBV in HL pathogenesis. Firstly, the association between IM and HL has generally been stronger in cohort than in case-control studies (25), raising concern of uncontrolled confounding in the former (26). Thus, the childhood environment characteristics associated with risk of HL in young adults could also entail an increased risk of IM. Secondly, EBV could be an etiologically innocent passenger in the virus-positive tumor subset (27). Thirdly, EBV may be involved in the pathogenesis of all HL, but in a proportion of cases, the virus could be lost from the neoplastic cells during progression, rendering them EBV negative at diagnosis, the so-called hit-and-run theory of pathogenesis (28). Finally, it is possible that tumor EBV status defines etiologically distinct diseases, i.e., EBV-positive and EBV-negative HL (29, 30).

To advance our understanding of the connection between IM and HL, we studied the association in a large population–based case-control study in Denmark and Sweden, taking into consideration both tumor EBV status and measures of childhood socioeconomic environment.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study subjects. The investigation was part of the Scandinavian Lymphoma Etiology (SCALE) study, a large Danish-Swedish case-control study of risk factors for HL and non-HLs (31, 32). Briefly, the HL study base encompassed the entire Danish population aged 18 to 74 years in the period June 1, 2000, to August 30, 2002, and the corresponding Swedish population in the period from October 1, 1999, to April 15, 2002. Participants recruited in a Danish regional pilot phase starting November 1, 1999, were also included, as were prevalent cases of HL diagnosed since January 1, 1999, in either country. The source population was further restricted to persons with sufficient knowledge of the Danish/Swedish language, and with no history of organ transplantation, HIV infection, or of other hematopoietic malignancies.

All patients diagnosed with histologically verified HL according to the WHO classification (33, 34) during the study period were eligible for inclusion into the study. The patients were identified through a rapid case ascertainment system set up for the purposes of the study in the two countries. A network of contact physicians was established with all departments where malignant lymphomas are diagnosed and treated (internal medicine, hematology, oncology, and clinical pathology), involving a total of 39 departments in Denmark and 118 in Sweden. Continuous collaboration with the national pathology registry in Denmark and the six regional cancer registries in Sweden ensured complete reporting through the network. The estimated coverage of the Danish Pathology Register and the Swedish cancer registries is close to 100% (31).

Controls were randomly sampled from the entire Danish and Swedish populations using continuously updated computerized population registers. A subset of controls was sampled every 6 months during the study period and frequency-matched within each country on the expected age (10-year strata) and sex distribution of the combined group of HL and non-HL patients.

Among eligible subjects, the participation rates were 91% in patients and 71% in controls. The study was approved by regional scientific ethics committees and data protection agencies in both countries, and informed consent was obtained from each participant before interview.

Exposure information. Information on relevant exposures was obtained through standardized telephone interviews, identical between the two countries and conducted by trained interviewers. The interviewers could not be blinded to the case-control status of the participants, but were unaware of the hypotheses under study (31). Among other things, recorded information included suspected childhood socioeconomic risk factors for HL reported in the literature such as family characteristics (parental age at participant's birth, sibship size, and birth order), parental and personal education (grouped ≤9, 10–12, and ≥13 years), type of housing in childhood (i.e., before age 7 years), number of persons per room in childhood household, and history of preschool attendance and of IM.

Classification of cases. Tumor biopsies from participating patients were retrieved from Danish and Swedish pathology departments for diagnostic validation and EBV analysis. Patients whose specimen could not be retrieved were classified according to the original histopathologic description leading to the inclusion into the study. Because nodular lymphocytic predominant HL is believed to constitute a unique HL subgroup (34), such cases were omitted from the present analyses.

The retrieved tumor biopsies were analyzed for the presence of EBV in the neoplastic HRS cells by immunohistochemical staining for EBV latent membrane antigen (LMP)-1 and/or in situ hybridization for EBV-encoded small RNAs (EBER). Antibodies used for EBV analyses were from DAKO (Glostrup, Denmark). In Denmark, paraffin sections were stained using standard EnVision (DAKO) immunohistochemistry, and EBV LMP-1 was detected in HRS cells with antibody cocktail CS 1-4. Antigen was retrieved by microwave superheating in TEG buffer (10 mmol/L Tris, 0·5 mmol/L EGTA; pH, 9). EBERs were detected by in situ hybridization using single-stranded digoxenin-labeled riboprobes or equivalent commercial EBER probes (35). In Sweden, LMP-1 stainings and EBER in situ hybridization were done with a Ventana Benchmark (LMP-1) and a Ventana Benchmark XT (EBER) machine. The same primary antibody for LMP-1 as in Denmark was used and visualized with a Ventana kit (Ventana, Tucson, AZ), and a Ventana kit was used for EBER-ISH. Two slightly different approaches for EBV classification were pursued in Denmark and Sweden. In Denmark, all cases were tested by both described methods and were classified as EBV positive when both tests were positive. In Sweden, the majority of cases were first tested for LMP-1, and all cases with negative or ambiguous test results were then analyzed for EBER. A total of 126 Swedish cases were only tested for EBER. Swedish cases were classified as EBV positive upon a positive test for either EBER or LMP-1.

Statistical analyses. We used logistic regression in all analyses. Results are presented as odds ratios (OR) with 95% confidence intervals (95% CI). All analyses were adjusted for the matching strata (the combination of country, sex, and age group in 10-year intervals). Statistical significance was tested using likelihood ratio tests. All tests were two sided.

The potential effects of the investigated risk factors were a priori assumed to follow a monotonic dose-response pattern, and accordingly, equidistant categories (1, 2, 3, etc.) were created based on the questionnaire information and fitted as trends. The only exception from this was the type of childhood housing, for which tests for risk homogeneity between multiple family units, single family units, and farms were made. We used a forward inclusion strategy to identify variables to be included as potential confounders in the statistical analyses. Specifically, in a series of age-stratified analyses [18–44 years (younger adults); ≥45 years (older adults)] of HL risk overall, the effect of each of the selected exposures (both alone and country-specific) was evaluated in turn, the statistically most significant (if any) was included in the statistical model, and the procedure was repeated. Because we assumed that the effect of each of the other risk factors would be mediated through IM, it was included in all models. By this approach, IM history and a country-specific measure of maternal education were the only exposures included in all analyses.

Besides analysis for HL overall, analyses were carried out stratified by tumor EBV status and by age, i.e., younger and older adults. The significance of IM history was assessed both as ever versus never and by time since IM (never IM, 1–4, 5–9, 10–14, 15–19, ≥20 years). To reduce the impact of putative diagnostic misclassification, IM less than a year before HL diagnosis (one EBV-negative case) or interview (one control) was disregarded. To further evaluate the EBV specificity of the suspected risk factors, we also did a case-series analysis, in which patients with EBV-positive HL were compared with patients with EBV-negative HL in the analyses of each risk factor. Like the case-control comparison, these analyses were adjusted for matching factors, history of IM, and country-specific measures of maternal education.

The robustness of our results for mononucleosis history was tested in supplementary analyses, including additional adjustment for all other investigated measures of childhood socioeconomic environment, both individually and combined. Moreover, in a competing risk analysis approach using combinations of histology (nodular sclerosis/mixed cellularity) and tumor EBV status as outcomes, we evaluated whether histologic subtype provided a better means of discriminating among the effects of childhood social environment risk factors than mere tumor EBV status.

Finally, we also modeled the association with IM as a continuous function of time since exposure under similar assumptions as in ref. 36. Thus, we assumed that for each individual in the study, the incidence rate of the outcome, I(t), was of the form RR x ß(t) + h(t), where ß(t) is the individual background incidence rate, based on the observed prevalence of tumor EBV positivity and otherwise calculated as in ref. 36; h(t) is the component of the incidence rate directly attributable to IM and only present in persons having had IM; and t is the time from IM to lymphoma diagnosis (for cases) or interview (for controls). We assumed h(t) was shaped as a gamma density, i.e., bell shaped and positively skewed. Thus, h(t) = exp({phi}+{nu}log(t) – t{nu}/{theta}) where {nu} is a shape variable, and {phi} and {theta} determine the bell shape's height and width, respectively, on the time scale. The sampling design implies that log ORs in the analysis model correspond to log rate ratios in the sampling model. Thus, we entered log(I(t)) as an offset in a model only containing the matching variables, calculating the likelihood over a grid of parameter values. The grid was made successively finer in the vicinity of the maximum likelihood estimate. Inspection of the maximum likelihood profile for each parameter clearly indicated a unimodal likelihood function. The median incubation time was estimated as the median of the gamma distribution with the same parameter values as those used for h(t). This is a valid approximation if the disease (here HL) is assumed to be rare.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
As shown in Table 1 , a total of 586 patients with classic HL and 3,187 controls were included in the analyses. Tumor cell EBV status was established for 499 (85%) of the participating patients (Table 1). EBV was more often shown in tumors in male than in female patients (P < 0·001) and was more prevalent with increasing age. In addition, the virus was shown more often in tumors of the mixed cellularity than of the nodular sclerosis subtype (P < 0·001). The proportion of Danish versus Swedish HL cases who were EBV positive did not differ significantly (P = 0.33).


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  		Table 1. Characteristics of HL patients and controls, and lymphomas in the Scandinavian case-control study

 
History of IM was associated with an increased HL risk overall. The risk increase was essentially restricted to EBV-positive HL in the younger adults, and conversely, no increased risk was seen for EBV-negative HL (Table 2 ). The relative risk of EBV-positive HL was more elevated in men (adjusted OR, 4.10; 95% CI, 2.11–7.94) than in women (adjusted OR, 2.10; 95% CI, 0.82–5.38), but this difference was not statistically significant (Phomogeneity = 0.25). The relative risk of EBV-positive HL varied by time since IM in all ages combined and among younger adults (Phomogeneity < 0.01 and <0.03, respectively; Table 3 ; Fig. 1 ). Assuming causality, the temporal variation in risk of EBV-positive HL after IM suggested a median incubation time of 2.9 years (95% CI 1.8–4.9 years). In the case-series analysis, younger adults with EBV-positive HL statistically significantly more often recalled the history of IM than patients with EBV-negative HL (Table 2).


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  		Table 2. ORs with 95% CIs for the association of selected factors with risk of HL overall and EBV-negative and EBV-positive tumor in younger and older adults and for all ages combined

 

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  		Table 3. ORs with 95% CIs for the association of between IM and HL overall and for EBV-positive and EBV-negative tumors in young adults and for all ages combined

 

Figure 1
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  		Figure 1. Temporal variation in relative risk of HL overall and by EBV status by time since IM as predicted by statistical modeling based on the age, gender, and country-specific distribution of IM among population controls in the SCALE study.

 
Neither paternal and subject education, number of persons in childhood home, nor preschool attendance was associated with risk of HL, irrespective of age and tumor EBV status (Table 2). Similarly, risk of HL did not vary significantly between the different types of childhood housing in the younger or the older adults, irrespective of tumor cell EBV status (data not shown). In Sweden, higher maternal education was associated with an increased risk of HL in younger adults, whereas there was no evidence of such an association in Denmark (Table 2). The number of siblings was inversely associated with the risk of EBV-positive HL in younger adults, whereas it did not affect the risk of EBV-negative HL (Table 2). In the older adults, the number of older siblings was associated with the risk of EBV-positive HL, whereas it was of no consequence to EBV-negative HL risk.

The results of the mononucleosis analyses with additional adjustment for all other investigated childhood socioeconomic environment risk factors, individual or combined, were not materially different from those presented. In particular, IM history remained exclusively and statistically significantly associated with EBV-positive HL in younger adults (data not shown). In the competing risk analyses, histologic subtype–specific associations were observed for no risk factor after allowing for tumor EBV status–specific associations. In contrast, EBV status–specific associations remained after allowing for histologic type–specific associations (data not shown). This suggests that histologic type is irrelevant as a means of discriminating among the effects of childhood social risk factors once EBV-specific HL outcomes are accounted for.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present investigation of 586 patients and 3,187 healthy controls, self-reported IM history was associated with an increased HL risk, consistent with the majority of previous studies (4, 5, 11–18, 23, 24). Importantly, the increased risk was confined to EBV-positive HL and varied by time since IM, whereby it was effectively restricted to the young adult age group. Moreover, the IM association persisted even after adjustment for risk factors previously associated with HL in young adulthood. In contrast, there was little evidence of an increased risk of EBV-negative HL after IM.

Recent investigations of the IM-HL association have yielded conflicting results. In two American studies, one of which included only women (26), IM was associated with risk of neither EBV-positive nor EBV-negative HL (26, 37). However, an increased risk of both EBV-positive and EBV-negative HL (24) or with EBV-positive HL only (in the age group 16–24 years; ref. 23) was observed after IM in two British investigations. Analogously, IM conferred an increased risk only of EBV-positive HL in a Danish-Swedish cohort study of IM patients (36).

The conflicting results can be due to methodologic differences and/or bias. Current understanding proposes IM risk to be associated with correlates of high socioeconomic status (38), as could also be observed among controls in both countries in the present study (data not shown). Because the likelihood of participation as a control in case-control studies is typically biased toward higher socioeconomic status (24, 37), this could potentially obscure an association between IM and HL. However, although a remarkably high proportion (18%) of younger controls reported IM history in one of the two negative case-control studies (26), a simple comparison of control participation rates in studies observing a positive (refs. 23, 24; and the present investigation) or no IM association (26, 37) suggests that differences in control selection alone do not explain the discrepancy between studies. The observed specificity of the IM association in the present study was further supported by a case-case comparison because IM history was more frequently reported by younger adult patients with EBV-positive HL than those with EBV-negative HL. Again, the literature is ambiguous, with the recollection of IM history seemingly differing between EBV-positive and EBV-negative HL in some (24, 39) but not all studies (40, 41). In addition, patients' participation in case-control studies may vary by gender, socioeconomic status, and prognosis (42, 43), each of which, in turn, may be associated with tumor EBV status. In our study, tumor cell EBV status in young adults was not convincingly associated with parental or subject education. Although reports have suggested that tumor EBV status may carry prognostic significance in both younger (favorable) and older (unfavorable) adult patients (42, 43), the high case participation rate in the present study renders selection bias among cases unlikely to explain our findings.

The association between IM and EBV-positive HL in the present analysis was not explained by confounding from family structure or childhood socioeconomic environmental characteristics previously associated with HL risk (3–10). Indeed, we found little evidence that any of these factors per se was associated with HL risk with a few exceptions. Thus, the number of siblings was inversely associated with risk of EBV-positive HL in younger adults. The association with EBV-positive rather than EBV-negative HL is noteworthy because nodular sclerosis HL, which is typically EBV negative (22), is considered to be the subtype most influenced by childhood socioeconomic affluence (10). Still, assuming that the risk of primary EBV infection in childhood correlates with the number of siblings (44), our finding is consistent with the observed increased HL risk after primary EBV infection (i.e., IM) after childhood. Among older adults, the number of older siblings tended to carry an increased risk of EBV-positive HL. Although not implied so by the analyses of parental education, the opposite effects of sibship characteristics on the risk of EBV-positive HL in the younger and older adults are consistent with previous suggestions of the elderly HL subgroup being associated with poor socioeconomic status in childhood (37).

A direct comparison of the present and previous findings regarding childhood environment (3–10) may not be straightforward. For instance, the incidence of young adult HL has increased over the past decades in both Scandinavia (45) and the United States (46). Because the increase seems to have occurred primarily for the nodular sclerosis subtype of HL, as mentioned predominantly EBV negative, the composition of HL patients subjected to epidemiologic studies may have changed accordingly with respect to EBV status. Therefore, to the extent that risk factor profiles differ between EBV-positive and EBV-negative HL, as observed in the present study, this change in tumor cell EBV status composition would influence associations between childhood social characteristics and the risk of HL overall toward the null, in line with the present findings. In addition, like others (26, 37), we speculate that secular phenomena may have abrogated the previously observed correlation between the investigated characteristics and childhood infectious disease pressure. As in the United States (26, 37), the proportion of Scandinavian children attending day-care facilities has increased over the past decades. It is therefore interesting that Chang et al. (37) recently reported preschool attendance for more than 1 year to be associated with a decreased HL risk. We found no evidence that preschool attendance was associated with a decreased HL risk in younger adults overall, but it deserves mentioning that our results were suggestive of different effects for EBV-positive and EBV-negative HL in young adults, preschool attendance possibly reducing the risk of the latter.

Overall, our finding of a positive association between IM and the risk of only EBV-positive HL is not readily compatible with a hit-and-run pathogenesis (28). Although the idea that EBV is merely an etiologically innocent passenger in the neoplastic cells cannot easily be dismissed, it remains more likely that the observed association indeed reflects causality, i.e., that EBV-positive and EBV-negative HL differ etiologically (29, 30). Consistent with the speculation that tumor EBV status distinguishes between etiologic entities, we found no evidence of histologic subtype–specific risk factors in our analyses. Other supportive evidence includes established demographic determinants of HL EBV status (22), tumor EBV-dependent variation in EBV antibody patterns (40), recent molecular biological studies providing plausible biological mechanisms for the association between EBV and HL (47, 48), and emerging data that HL heritability patterns differ by EBV status (49).

The risk of EBV-positive HL varied with time since IM, and attributable cases tended to occur at a median of 2.9 years after IM, consistent with a previous report (36). Interestingly, the temporal risk variation in HL risk after IM suggests that the predilection for the younger adult age group may simply result from the combination of age at and time since IM rather than from other mechanisms particular to HL in younger adults (18). It is therefore tempting to speculate that a similar association may exist between primary EBV infection and HL risk at any age, e.g., in childhood, which could explain the predominance of EBV-positive HL in this age group (22). On the other hand, EBV-positive HL in the elderly hardly reflects primary infection, but may be related to the loss of control of latent EBV infection for yet unidentified causes (30).

The advantages of our investigation include its population-based setting with a rapid case ascertainment, histopathologic review of >90% of the cases in connection with EBV analysis, grouping of HL cases according to the WHO classification, and a high participation rate among both cases and controls. Conducted simultaneously in two ethnically similar populations, all observations could also be validated by the comparison of population-specific findings.

To summarize, the present investigation provided further evidence of an association between IM and EBV-positive HL. The association was not explained by the confounding of characteristics of childhood socioeconomic environment, displayed temporal variation, and accordingly manifested in the younger adult age group. Our analyses suggested that risk of EBV-positive HL in young adulthood was inversely associated with the number of younger siblings, consistent with late primary EBV infection being causally involved in HL development. With the exception of higher maternal education among Swedes, none of the investigated factors were associated with risk of EBV-negative HL. These findings are therefore compatible with the hypothesis that EBV-positive and EBV-negative HL differ with respect to etiology.


   Acknowledgments
 
Grant support: NIH (5 ROI CA 69269), Nordic Cancer Union (16-02-D), and Plan Danmark. The funding sources were not otherwise involved in the study.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank all of the doctors and nurses in Denmark and Sweden who participated in our rapid case ascertainment system.

Received 9/27/06. Revised 12/20/06. Accepted 1/ 2/07.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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