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Am J Epidemiol 2002; 156:1011-1020.
Copyright © 2002 by Johns Hopkins Bloomberg School of Public Health

ORIGINAL CONTRIBUTIONS

Cigarette Smoking and Risk of Hodgkin’s Disease: A Population-based Case-Control Study

Nathaniel C. Briggs1, H. Irene Hall2, Edward A. Brann3, Cynthia J. Moriarty1 and Robert S. Levine1

1 Division of Preventive Medicine, Department of Internal Medicine, Meharry Medical College, Nashville, TN.
2 National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA.
3 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA.

Received for publication April 23, 2002; accepted for publication July 19, 2002.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 REFERENCES
 
Previous reports offer limited support for an association between cigarette smoking and Hodgkin’s disease. The authors investigated dose-response effects for smoking in relation to the risk of Hodgkin’s disease using data from the Selected Cancers Study. Cases (n = 343) were men aged 32–60 years identified from eight US population-based cancer registries in 1984–1988. Controls (n = 1,910) were men recruited by random digit telephone dialing and frequency matched to cases by age and registry. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals adjusted for age, registry, race/ethnicity, Jewish upbringing, education, and childhood domicile. Compared with never smokers, current smokers had a significantly increased risk of Hodgkin’s disease (odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.3, 2.9). Risks increased linearly (p < 0.001) with increasing packs per day (OR>=2 = 2.5, 95% CI: 1.6, 4.0), years (OR>=30 = 2.4, 95% CI: 1.5, 3.9), and pack-years (OR>40 = 2.7, 95% CI: 1.8, 4.3) of smoking. These associations were significant for the nodular sclerosis and mixed cellularity subtypes but were much stronger for mixed cellularity. Stratified analyses by age (<=42 years, >42 years) and subtype suggested that the effects of smoking are more closely related to histology than age. In contrast to findings from previous studies, these data suggest that smoking is an important preventable risk factor for Hodgkin’s disease.

case-control studies; Hodgkin disease; risk; smoking

Abbreviations: Abbreviations: CI, confidence interval; OR, odds ratio.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 REFERENCES
 
Hodgkin’s disease has been of great epidemiologic interest because of contrasting histologic and demographic risk factor profiles that correspond to bimodal age-incidence peaks (1). From ages 15–34 years, Hodgkin’s disease is largely nodular sclerosis by subtype and has been associated with measures of increased childhood social class, including childhood residence in a single-family home, small sibship size, and a higher level of education (1). In contrast, from the age of 50 years onward, Hodgkin’s disease is predominantly of the mixed cellularity subtype, and risk has been inversely associated with childhood social class, particularly among men (1).

It is hypothesized that Hodgkin’s disease in these age groups represents two unique diseases resulting from exposure to infectious agents during childhood (1). However, only a single agent, the Epstein-Barr virus, has been implicated in pathogenesis, and molecular epidemiologic support for this association is limited to a minority of cases in both age groups (2). Therefore, new etiologic paradigms are needed, especially from the standpoint of prevention.

Cigarette smoking is one potentially important preventable risk factor for Hodgkin’s disease. Findings from more than 10 studies (3–13) provide modest support for an association (table 1). However, results have been inconclusive because of limitations of analyses, including no assessment of dose-response effects, no investigation of differences in risk among current and former smokers, lack of adjustment for potential confounders, and small sample sizes.


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  		TABLE 1. Previous studies reporting associations for smoking and Hodgkin’s disease
 
In one study reporting no association (11), smoking was not defined and no data were shown. In five other studies, four case-control (4, 6, 7, 12) and one prospective (13), only summary measures of Hodgkin’s disease risk were reported for ever smokers. Odds ratios in the case-control studies were all close to unity, although the prospective study found a nonsignificantly increased relative risk of 2.7. Data from two prospective studies (5, 9) and two population-based case-control studies (3, 8) that examined associations in greater depth provide somewhat more support. In three studies comparing current and former smokers (3, 5, 9), current smokers had greater Hodgkin’s disease risks. In four studies investigating dose-response relations for the number of cigarettes smoked per day (3, 5, 8, 9), the risk of Hodgkin’s disease increased with greater intensity. In one case-control study (10), dose-response effects were assessed for pack-years of smoking, but a small sample size precluded meaningful interpretation of results.

We have attempted to address the limitations of previous studies by investigating the relation between cigarette smoking and Hodgkin’s disease risk among men aged 32–60 years using data from the Selected Cancers Study (14, 15).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 REFERENCES
 
Study population
The Selected Cancers Study (14, 15) was a large population-based case-control study designed to investigate associations between Agent Orange exposure during US military service in Vietnam and subsequent risk of Hodgkin’s disease, non-Hodgkin’s lymphoma, and several other cancers. The study population comprised men born between 1929 and 1953 to define a birth cohort of military service age (15–39 years in 1968) during the Vietnam conflict (15). This analysis focuses on the risk of Hodgkin’s disease in relation to cigarette smoking.

Cases and controls
Eligible cases were men presumptively diagnosed with a lymphoma (Hodgkin’s disease, non-Hodgkin’s lymphoma, or "lymphoma not otherwise specified") between 1984 and 1988. Cases were identified from eight US cancer registries, five covering metropolitan areas (Atlanta, Georgia; Miami, Florida; Detroit, Michigan; Seattle, Washington; and San Francisco, California) and three covering US states (Connecticut, Iowa, and Kansas); all registries except those in Miami and Kansas were part of the Surveillance, Epidemiology, and End Results Program. A rapid case-reporting scheme was used to obtain interviews as soon as possible after diagnosis.

Of 2,354 presumptive lymphoma cases identified, 2,073 (88 percent) participated (table 1). For 97 percent of participants, microscopic slides or tissue blocks were available for confirmation of the original diagnosis. After an independent and blinded rereview of tissue specimens by three hematopathologists, a consensus diagnosis was reached for 343 Hodgkin’s disease cases, 1,511 non-Hodgkin’s lymphoma cases, and 14 unclassifiable lymphomas. Confirmed Hodgkin’s disease cases were classified by histologic subtype using the International Classification of Diseases for Oncology (16).

Controls were identified by random digit telephone dialing and frequency matched to presumptive lymphoma cases by 5-year date-of-birth intervals (1929–1933, 1934–1938, 1939–1943, 1944–1948, 1949–1953) and within geographic strata corresponding to cancer registries. Of 15,768 households contacted for screening to select potential controls, 14,328 (91 percent) provided eligibility information, 4,381 of 4,822 (91 percent) households with eligible men provided a name and address, 2,299 men were randomly selected for interview, and 1,910 (83 percent) men completed interviews.

This analysis was limited to 308 Hodgkin’s disease cases and 1,796 controls with no history of acquired immunodeficiency syndrome, who were directly interviewed, and for whom interviews were judged by the interviewer to be of at least fair quality.

Data collection
Information on demographic factors, medical history, occupation, and lifestyle exposures, including cigarette smoking, was collected by trained interviewers who administered structured questionnaires by telephone. Interviews took an average of 50 minutes to complete. Study participants were classified as smokers or nonsmokers on the basis of the question, "Did you ever smoke at least of a pack of cigarettes weekly for at least one year?" Smokers were queried about current and past smoking habits, including average intensity (packs per day of cigarettes smoked), duration (cumulative number of years of smoking), onset age, and, for former smokers, number of years since quitting. We used pack-years of smoking, the product of intensity and duration, to estimate the lifetime total number of cigarettes smoked. Men who reported smoking 2 years or less before the interview date were considered current smokers.

Statistical analysis
Conditional logistic regression (17) was performed using the PHREG procedure in SAS statistical software (18) to calculate odds ratios and 95 percent confidence intervals that accounted for the matching factors of 5-year birth date interval and cancer registry. To adjust for residual confounding, we included the birth year within each 5-year interval as a covariate. All models also contained categorical variables to adjust for potential confounding related to race/ethnicity (White, Black, Hispanic, other), education (high school or less vs. more than high school), residence at age 8 years (single-family home, multiunit dwelling), and Jewish upbringing.

Separate models were used to examine associations for smoking in relation to overall risk of Hodgkin’s disease and risks for the two major histologic subtypes, nodular sclerosis and mixed cellularity. The measures used to assess linear dose-response effects for current smokers were duration (<=19, 20–29, >=30 years), intensity (<1, 1, >1–<2, >=2 packs per day), and pack-years (<=20, 21–40, >40) of smoking. Odds ratios and linear trend for onset age of smoking among current smokers were assessed across four age categories (<15 years, 15–16 years, 17–18 years, >=19 years), using the oldest age category as the reference group. The effects for elapsed time since cessation of smoking were assessed across three time intervals (current smokers and former smokers <= 9 and >=10 years before interview), using current smokers as the reference category. In analyses for onset age of smoking and time since cessation of smoking, we added pack-years to the base model as a continuous covariate to adjust for confounding. Tests for linear trend were performed by treating levels of categorical variables as an ordinal variable in conditional logistic regression models; p values were based on the Wald test.

Hodgkin’s disease in adults has been described as two disease entities characterized by unique age-dependent etiologic factors, which correspond to the age ranges of peak incidence (approximately 15–34 years and >50 years) and which have overlapping distributions in the intermodal age range (19). Because most Hodgkin’s disease cases in the Selected Cancers Study were aged 35–50 years, the two-disease model was investigated for smoking across the intermodal age range. We conjectured that, if smoking were a risk factor conforming to the two-disease model, the association should be strong at one end of the intermodal age range and weak at the other, whereas, in the alternative, the association should be uniform across the age range. To evaluate the model, we calculated odds ratios among current smokers after stratification by age (<=42 years vs. >42 years) based on the mean age of cases (43.4 years), which was less than 1 year from the midpoint (42.5 years) for the conventional intermodal age range in the general population. Because age may be a surrogate for histology subtype-specific risk factors more directly related to pathogenesis (20), age-specific effects were also calculated for subtypes.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 REFERENCES
 
Of 308 cases of Hodgkin’s disease, 65 percent (n = 199) were diagnosed as nodular sclerosis, 24 percent (n = 74) as mixed cellularity, 8 percent (n = 26) as lymphocyte predominance, and 3 percent (n = 9) as unclassified (table 2).


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  		TABLE 2. Selection of Hodgkin’s disease cases and controls, Selected Cancers Study, United States, 1984–1988
 
In table 3, exposure frequencies and proportions among cases and controls are shown for demographic characteristics and selected medical conditions. Hodgkin’s disease cases were slightly younger than controls (mean, 3 years), because controls were frequency matched on age to the group of all men with a presumptive lymphoma diagnosis, which included a comparatively older subgroup of men with non-Hodgkin’s lymphoma. Overall, 88 percent of the Hodgkin’s disease cases were White men, compared with 83 percent of the controls. Among cases, the proportion of White men with nodular sclerosis was slightly increased. Compared with controls, a lower proportion of men with Hodgkin’s disease had advanced education, and higher proportions resided in a multiunit dwelling during childhood and were raised Jewish.


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  		TABLE 3. Demographic and medical history characteristics of Hodgkin’s disease cases and controls, Selected Cancers Study, United States, 1984–1988
 
The distribution of cases and controls by smoking status and the adjusted risks of Hodgkin’s disease in relation to smoking status are shown in table 4. Compared with never smokers, ever smokers had an increased Hodgkin’s disease risk of borderline significance. However, stratification revealed that current smokers had a significant increase in Hodgkin’s disease risk, whereas former smokers had a nonsignificantly decreased risk. For current smokers, highly significant linear associations (p < 0.001) were evident for increasing intensity, duration, and pack-years of smoking. These associations were significant for both the nodular sclerosis and mixed cellularity subtypes, but the effects were consistently stronger for mixed cellularity.


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  		TABLE 4. Adjusted odds ratios for risk of Hodgkin’s disease among men aged 32–60 years who were smokers, Selected Cancers Study, United States, 1984–1988
 
The overall risks of Hodgkin’s disease were significantly increased among current smokers aged 42 years or less and more than 42 years, and these risks were of similar magnitude (table 5). Stratification by histologic subtype revealed that, in both age groups, only the risks for mixed cellularity were significantly increased, although they approached significance for nodular sclerosis.


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  		TABLE 5. Adjusted odds ratios for risk of Hodgkin’s disease among men aged 42 years or less and over 42 years who were current smokers, Selected Cancers Study, United States, 1984–1988
 
Compared with current smokers, former smokers with increasing time since smoking cessation had significant linear decreases in the risk of Hodgkin’s disease overall and by subtype (table 6). No significant associations were evident for onset age of smoking.


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  		TABLE 6. Time since quitting among former smokers and onset age of smoking among current smokers in relation to risk of Hodgkin’s disease, Selected Cancers Study, United States, 1984–1988
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 REFERENCES
 
Our data suggest that cigarette smoking is an important risk factor for Hodgkin’s disease. Stratification by age showed risks of similar magnitude for younger and older men. However, stratification by histologic subtype revealed associations that were stronger for mixed cellularity than for nodular sclerosis.

Most previous studies (3–13) have found little support for smoking as a Hodgkin’s disease risk factor (table 1), but associations may have been missed because of the limited depth of the analyses. In addition to lack of stratification by histologic subtype, other major limitations have included failure to stratify by history of current versus past smoking and little or no assessment of dose-response relations. The strongest evidence comes from those studies that investigated dose-response effects or assessed risks for current smokers (3, 5, 8, 9).

In a prospective study of Swedish male construction workers, Adami et al. (5) found a nonsignificantly increased relative risk of 1.3. However, there was a significant interaction with age. Stratification revealed that current smokers of 14 or more cigarettes per day who were under age 60 years had a significantly increased relative risk of 1.5, whereas older men had a nonsignificantly decreased risk. Data from a prospective study of American male college graduates (9) showed a nonsignificantly increased relative risk of 1.4 for all smokers, but smokers of 10 or more cigarettes per day had a relative risk of 2.8 that approached significance. A population-based case-control study of Australian men and women (8) revealed an odds ratio of 1.1 for a combined group of all former smokers and current smokers of less than 1 pack per day. In contrast, current smokers of 1 or more packs per day had an odds ratio of 2.1, and a test for trend was significant. In a population-based case-control study of Italian men and women (3), a decreased Hodgkin’s disease risk was observed among ever smokers (odds ratio (OR) = 0.7, 95 percent confidence interval (CI): 0.5, 1.0), but current smokers had an increased risk (OR = 1.2, 95 percent CI: 0.9, 1.6). Smoking for more than 36 years was associated with a significantly increased risk of Hodgkin’s disease (OR = 1.7, 95 percent CI: 1.1, 2.7). This association was strongest for men (OR = 1.9, 95 percent CI: 1.1, 3.4).

Differences in the composition of study populations by age, gender, and birth cohort may have contributed to inconsistent findings for smoking and Hodgkin’s disease. Given the strong association that we observed between smoking duration and Hodgkin’s disease risk and the similar findings by Stagnaro et al. (3), a long latency period may precede symptomatic disease. Hence, previous studies that included pediatric and young adult cases may have lacked sufficient power to detect an association. At the other end of the age spectrum, the observation by Adami et al. (5) that increased risk of Hodgkin’s disease was limited to current smokers aged 60 years or less suggests that inclusion of older cases may also contribute to inconsistent findings. Perhaps the 32- to 60-year age range of our study population targeted those at highest risk for smoking-associated Hodgkin’s disease. Gender-specific differences, especially across the intermodal age range, may account for some inconsistent study findings. A secondary Hodgkin’s disease incidence peak is evident among middle-aged men that is absent for women (1). This has been attributed to gender-specific hormonal and immunologic changes that protect women against Hodgkin’s disease during their reproductive years (21, 22), but findings are inconsistent (23). Because "antiestrogenic" effects have been reported for women who smoke (24), some of this inconsistency may reflect uncontrolled confounding, or effect modification, related to smoking. The possibility is supported by findings of Stagnaro et al. (3) that the association between smoking duration and risk of Hodgkin’s disease was stronger for men than women. Finally, the Selected Cancers Study may have had considerable power to detect an increased risk of Hodgkin’s disease among smokers, because participants comprised men aged 15–39 years in 1968, a cohort with a high prevalence of smokers. Whereas 29.5 percent of US men aged 25–34 years smoked in 1995, 60.7 percent were smokers in 1965 (25).

The prevailing paradigm for epidemiologic research on Hodgkin’s disease distinguishes two disease entities based on age-dependent etiologic factors uniquely corresponding to either of two age ranges of peak incidence (approximately 15–34 years and >50 years), with overlapping distributions in the intermodal age range (1). However, our findings show little support for smoking as a risk factor that conforms to the two-disease model as stratification by age revealed increased risks of Hodgkin’s disease that were of similar magnitude for younger and older men. In contrast, stratification by histologic subtype (nodular sclerosis, mixed cellularity) showed associations to be consistently stronger for mixed cellularity. This suggests that age-related risk factors may be surrogates for histology subtype-specific risk factors that are more directly related to pathogenesis. The two-disease model based on age was first described by MacMahon in 1957 (26) and 1966 (27). However, it is noteworthy that MacMahon, in an article coauthored by Cole and Aisenberg, later added the caveat that "for the present the separation of Hodgkin’s disease into two components must be made on the basis of age, but it is to be hoped that a more fundamental criterion will soon be available. Histological appearance seems the most promising" (20, p. 1375). Because the distribution of Hodgkin’s disease by subtype corresponds closely to age incidence peaks, age could be confounding associations for histologic subtype. Nevertheless, because diagnostic correlation between cancer registries and expert review panels is of questionable reliability for Hodgkin’s disease subtypes (28) and because expert rereview of pathology specimens in large population-based studies is seldom economically feasible, a two-disease model based on age may be the most practical framework for epidemiologic research.

The finding that Hodgkin’s disease risk among current smokers increased linearly with increasing duration of smoking and decreased linearly with time since smoking cessation among former smokers suggests that smoking affects promotion of carcinogenesis. The mechanisms by which this might occur are unclear, but indirect and direct effects are possible. Nonspecific immunologic abnormalities associated with smoking, including impaired humoral and cellular responses to immune challenges, altered levels of T-lymphocyte subtypes, and depressed activity of natural killer cells (24), might predispose to carcinogenesis indirectly. Direct carcinogenic effects could be mediated by various chemicals implicated as risk factors for Hodgkin’s disease that are constituents of tobacco and cigarette smoke (29), including benzene (30), formaldehyde (31), and chromium (32).

Immunophenotypic and immunogenetic data support biologic plausibility for a mechanism that involves inhibition of CD95-mediated apoptosis or programmed cell death. The CD95 receptor is expressed in Hodgkin’s disease (33). Smoking has been reported to downregulate CD95 expression in peripheral blood cells of chronic smokers (34). Hence, a similar antiapoptotic mechanism could exist for Hodgkin’s disease. Smoking can also inhibit CD95-mediated apoptosis by increasing levels of the lymphomagenic antiapoptosis protein Bcl-2 (35, 36), expressed in many cases of Hodgkin’s disease (37, 38). Interestingly, the Epstein-Barr virus latent membrane protein LMP1 can also inhibit CD95-mediated apoptosis, although the mechanism does not appear to involve Bcl-2 (39). Therefore, smoking and Epstein-Barr virus infection could have additive or synergistic effects on the risk of Hodgkin’s disease. This possibility is underscored by a report of synergism between cigarette smoking and Epstein-Barr virus infection in relation to the risk of nasopharyngeal carcinoma (40), which shares identical LMP1-mediated pathophysiologic mechanisms with Hodgkin’s disease (41).

Advantages of this study include the use of population-based cancer registries to identify a large number of Hodgkin’s disease cases, random digit telephone dialing to identify population-based controls, and administration of a structured questionnaire that covered smoking history in sufficient detail to allow for a comprehensive assessment of dose-response relations. In addition, pathology specimens were obtained for nearly all presumptive cases and confirmed by consensus after an independent and blinded rereview by three hematopathologists. Confirmed Hodgkin’s disease cases were further classified into histologic subtypes.

Several study limitations also need to be considered. First, selection bias may have arisen through recruiting cases and controls for study participation. However, this possibility was reduced by using population-based cancer registries to identify cases and random digit dialing to randomly select controls from corresponding geographic regions. The validity of random digit dialing to generate population-based samples has been well documented for the time when the Selected Cancers Study was conducted (42, 43). In addition, participation rates for both cases and controls were high. Second, our findings could have been influenced by confounders. To address potential confounding, we adjusted for age, cancer registry, race/ethnicity, Jewish upbringing, education, and residence in childhood. Nevertheless, residual confounding may have occurred in relation to exposure characteristics, such as the use of filtered or nonfiltered cigarettes, use of mentholated or nonmentholated cigarettes, and whether cigarette smoke was or was not inhaled, that could not be addressed because of lack of information. Differences in Epstein-Barr virus DNA status among smokers and nonsmokers could be another source of residual confounding, and it will be important in the future to investigate associations for smoking and Hodgkin’s disease stratified by Epstein-Barr virus-positive and Epstein-Barr virus-negative cases. Third, our findings may have been due to chance, although this seems unlikely given the magnitude, consistency, and significance of the results. Fourth, our assessment of dose-response relations for intensity, duration, and pack-years of smoking may have been subject to measurement error because we did not specifically ask study participants about variation in the intensity of smoking over time or possible gaps in continuous smoking.

In conclusion, our data suggest that smoking is an important preventable risk factor for Hodgkin’s disease. Among current smokers, the risk of Hodgkin’s disease increased linearly with increasing intensity, duration, and pack-years of smoking, whereas, among former smokers, the risk decreased linearly with increasing time since cessation of smoking.


   ACKNOWLEDGMENTS
 
The authors thank Drs. Ruth F. Jarrett and Wei Zheng for their helpful suggestions and the US Centers for Disease Control and Prevention and the Selected Cancers Cooperative Study Group for collecting the original data.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
REFERENCES
 


   NOTES
 
Reprint requests to Dr. Nathaniel C. Briggs, Division of Preventive Medicine, Department of Internal Medicine, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Boulevard-Box 52A, Nashville, TN 37208-3599 (e-mail: nbriggs{at}mmc.edu). Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 REFERENCES
 

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