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Epidemiologic studies conducted to date have shown evidence of a causal relation between smoking and non-Hodgkin lymphoma (NHL) risk. However, previous studies did not account for passive smoking exposure in the never-smoking reference group. The California Teachers Study collected information about lifetime smoking and household passive smoking exposure in 1995 and about lifetime exposure to passive smoking in 3 settings (household, workplace, and social settings) in 1997–1998. Multivariable-adjusted relative risks and 95% confidence intervals were estimated by fitting Cox proportional hazards models with follow-up through 2007. Compared with never smokers, ever smokers had a 1.11-fold (95% confidence interval (CI): 0.94, 1.30) higher NHL risk that increased to a 1.22-fold (95% CI: 0.95, 1.57) higher risk when women with household passive smoking were excluded from the reference category. Statistically significant dose responses were observed for lifetime cumulative smoking exposure (intensity and pack-years; both P ’s for trend = 0.02) when women with household passive smoking were excluded from the reference category. Among never smokers, NHL risk increased with increasing lifetime exposure to passive smoking (relative risk = 1.51 (95% CI: 1.03, 2.22) for >40 years vs. ≤5 years of passive smoking; P for trend = 0.03), particularly for follicular lymphoma (relative risk = 2.89 (95% CI: 1.23, 6.80); P for trend = 0.01). The present study provides evidence that smoking and passive smoking may influence NHL etiology, particularly for follicular lymphoma.
Most epidemiologic studies conducted to date have not shown evidence of a causal relation between smoking and risk of non-Hodgkin lymphoma (NHL) (1–21). Although results of several studies have suggested increasing risks associated with smoking history (20, 22–29), few studies showed a dose response for smoking intensity (number of cigarettes smoked per day) or pack-years (26, 30–32). Investigators conducting a pooled analysis of case-control studies from the International Lymphoma Epidemiology Consortium (6,594 cases and 8,892 controls) did not find a strong association between smoking and overall NHL risk, but they did note a modest association between smoking and the rate of follicular lymphoma (12). Of the 7 cohort studies conducted to date (1, 7–9, 14, 15, 18, 30), only the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort showed a dose-response association between smoking and NHL risk; this was observed among women but not among men (30). The data on specific subtypes of NHL, particularly follicular lymphoma, were also inconsistent. Importantly, no prior studies on smoking and NHL accounted for exposure to passive smoking among never smokers or evaluated the effects of passive smoking on NHL risk.
It has been well documented that passive smoking, like active smoking, has a dose-response relation with the risk of many types of cancers (33). Both cohort studies and case-control studies have demonstrated this dose-response relation for smoking and lung cancer (34), and other evidence has suggested a link between passive smoking and cancers of the breast, nasopharynx, cervix, and colon (35). If a causal relation between passive smoking and NHL were to exist, one might hypothesize that the inclusion of passive smokers in the reference category of never smokers would cause underestimation of or conceal an existing association between smoking and NHL.
The California Teachers Study (CTS), a prospective cohort study of women that included detailed information on active and passive smoking, provides a unique opportunity to address for the first time these effects on the risk of NHL overall and by subtype in women.
A detailed description of the CTS has been published elsewhere (36). Briefly, this prospective study comprises 133,479 female California public school employees. In 1995, all participants completed a self-administered baseline questionnaire that collected information on disease histories and demographic, anthropometric, reproductive, and lifestyle factors, including smoking behavior and household exposure to passive smoking. Use of human subjects in this study was approved by each participating institution.
Because of the high prevalence of lifetime never smokers among CTS participants, in 1997–1998, we distributed a second self-administered questionnaire that collected more detailed information on exposure to passive smoking, including time period, age of exposure, and setting (household, workplace, and social).
For analyses of smoking behavior and exposure to household passive smoking as reported at baseline, we sequentially excluded women who, at baseline, were not California residents (n = 8,867), had an unknown cancer history (n = 663), limited their participation to breast cancer research (n = 18), had a prior history of a hematologic malignancy (n = 536), or were 85 years of age or older (n = 2,179). The resulting analytic cohort consisted of 121,216 women aged 22–84 years. Of these participants, 90,640 returned the second questionnaire.
The second questionnaire collected information on exposure to passive smoking in household, workplace, and social settings. We sequentially excluded women who reported being current or past smokers at baseline (n = 30,583), did not answer any passive smoking questions (n = 243), developed a hematologic malignancy between the baseline and second questionnaires (n = 55), or moved out of California between the baseline and second questionnaires (n = 823). A total of 58,936 women were eligible for the analyses of the effect of lifetime passive smoking on the risk of NHL.
The CTS cohort is followed annually to collect information on cancer diagnosis, death, and change of address. Follow-up began on the date on which a participant completed her baseline questionnaire (for the analyses of smoking behavior and exposure to household passive smoking) or her second questionnaire (for the analyses of passive smoking in 3 settings) and ended at the earliest of the following event dates: diagnosis of NHL; relocation outside of California; diagnosis of Hodgkin lymphoma, multiple myeloma, or leukemia other than prolymphocytic leukemia or chronic lymphocytic leukemia (CLL); death; or December 31, 2007. The status of California residence was monitored through multiple avenues (36). Information on dates and causes of death was obtained from the California state mortality files, the Social Security Administration Death Master File, and the National Death Index.
Incident diagnoses of NHL (International Classification of Diseases for Oncology, Third Edition (ICD-O-3) (37) morphology codes 9590, 9591, 9670–9675, 9678–9699, 9700–9702, 9705, 9708–9709, 9714, 9716–9719, 9727–9729, 9761, 9764, 9820, 9823, 9827, 9831–9837, 9940, 9948, and 9970) were identified through annual linkages with the population-based California Cancer Registry, which receives information on over 99% of all cancer diagnoses occurring in California residents. Of the 121,216 women in the analytic cohort in whom we studied smoking behavior and household passive smoking exposure as reported at baseline, 629 women developed incident NHL between 1995 and 2007 (diffuse large B-cell lymphoma (DLBCL): ICD-O-3 codes 9678–9680, and 9684, n = 155; follicular lymphoma: ICD-O-3 codes 9690, 9691, 9695, and 9698, n = 122; CLL/small lymphocytic lymphoma (SLL): ICD-O-3 codes 9670 and 9823, n = 125; and other NHL histologic types: n = 227). Of the 58,936 women who were never smokers at baseline and who returned both questionnaires, 249 developed incident NHL between 1997 and 2007 (DLBCL, n = 61; follicular lymphoma, n = 59; CLL/SLL, n = 41; and others, n = 88).
In the baseline questionnaire, each participant was asked if she had smoked at least 100 cigarettes during her lifetime, and if so, at which ages she first and last (if applicable) smoked cigarettes. Smoking intensity was measured based on each participant’s report of the average number of cigarettes smoked per day. Total pack-years of smoking were defined as the number of packs of cigarettes smoked per day times the number of years smoked.
In the baseline questionnaire, we determined household passive smoking exposure based on a participant’s report of ever having lived with a smoker during her childhood or adulthood. Among never smokers, we further grouped participants into 4 categories: no household passive smoking exposure, only childhood household passive smoking exposure, only adulthood household passive smoking exposure, and both childhood and adulthood household passive smoking exposure.
In 1997–1998, the second questionnaire was used to collect detailed information on exposure to passive smoking in the household, the workplace, and social settings during 6 age periods (0–19, 20–29, 30–39, 40–49, 50–59, and ≥60 years of age). A total of 97% of never smokers who reported household passive smoking exposure in the baseline questionnaire also reported household passive smoking exposure in the second questionnaire. For each combination of setting and age period, participants were asked whether they were exposed to tobacco smoke from others. If they answered in the affirmative, they were further asked about the duration and intensity of this exposure. Duration was estimated by asking about the number of years of exposure within specific age periods (<1, 1–3, 4–6, or ≥7 years). Passive smoking intensity for each age period was estimated by a qualitative description: a little smoky, fairly smoky, or very smoky.
As described previously (38), we created variables for duration (years) and intensity (smokiness) of lifetime exposure to passive smoking from all 3 settings combined, as well as from the combination of duration and intensity (intensity-years). We assigned a numerical score of 1, 2, or 3 to represent the intensity of passive smoking (1 = a little smoky, 2 = fairly smoky, and 3 = very smoky). The lifetime intensity for each exposure setting was calculated by averaging the numerical scores across all age periods. An overall lifetime intensity score was obtained by summing the intensity scores from the 3 settings. Because of the limited number of participants who reported no exposure to any setting of passive smoking, all of the cumulative exposure measures were categorized into quartiles based on the distribution among all women, including those with zero values for passive smoking exposure.
To estimate the relative risk of NHL associated with active and passive smoking, we fitted multivariable Cox proportional hazards regression models to compute hazard rate ratios and 95% confidence intervals. Age (in days) at cohort entry or at the time of the second questionnaire, as appropriate, and age (in days) at the end of the individual’s follow-up were used to define the time scale. All models were stratified by age in continuous years at cohort entry or at the time of the second questionnaire, as appropriate, and adjusted for race (non-Hispanic white or other) and level of alcohol consumption 1 year before cohort entry (0 g/day, <15 g/day, ≥15 g/day, or unknown). Additional adjustment for other potential confounders, including area-level socioeconomic status (39), height, body mass index (weight in kilograms divided by height in meters squared), number of full-term pregnancies, history of diabetes mellitus, and long-term physical activity level, had little influence on relative risk estimates (<10%); therefore, none of these variables was included in the final multivariate models.
Sensitivity analyses were conducted after excluding women with any prior cancer history at cohort entry (for analyses based on the baseline questionnaire) or at the time of completing the second questionnaire (for analyses of lifetime passive smoking). Women diagnosed with any other type of cancer during follow-up were also censored at the time of their first incident cancer diagnosis.
We performed tests for trend for ordinal variables by fitting the median value of each category as a continuous variable. Two-sided P values are reported for tests for trend, with P < 0.05 considered statistically significant. The assumption of proportionality of hazards was assessed for each final model by testing the null hypothesis of no correlation between the scaled Schoenfeld residuals and time under study; no violation of the proportional hazards assumption was observed. Analyses were performed using SAS, version 9.2 (SAS Institute, Inc., Cary, North Carolina).
In the present analysis of data from the CTS cohort, the average follow-up was 11 years from baseline (9.4 years from second questionnaire). The mean age at cohort entry was 52.7 years, and the mean age at diagnosis of NHL was 69.1 years (range, 33–94 years). A total of 79,006 (66%) women were lifetime never smokers, 29% were former smokers, and 5% were current smokers at the time that they completed their baseline questionnaire (Table 1). Among women who were never smokers at baseline, 70.9% reported some household passive smoking exposure. Compared with lifetime never smokers, ever smokers (defined as current and former smokers) were more likely to be non-Hispanic white and older and to have had higher levels of alcohol consumption in the year before joining the cohort. Among lifetime never smokers, women with household passive smoking exposure were more likely to be older, to have had higher levels of alcohol consumption, and to have had a higher body mass index at cohort entry (Table 1). A comparison of the basic demographic characteristics and smoking statuses of the cohort members who did and did not respond to the second questionnaire revealed no substantial differences (40).
Table 2 presents the adjusted relative risks of NHL associated with cigarette smoking using different reference categories with or without participants who reported any lifetime (childhood or adulthood) exposure to household passive smoking. Compared with all never smokers, ever smokers had a slight but statistically nonsignificant increase in risk of NHL (relative risk (RR) = 1.11, 95% confidence interval (CI): 0.94, 1.30), which increased to 1.22 (95% CI: 0.95, 1.57) when women with household passive smoking exposure were excluded from the reference category. The increased risk associated with ever smoking was largely driven by former smokers because of the small numbers of current smokers in our study population. Among ever smokers, we observed increases in the relative risks associated with smoking intensity, total smoking years, and smoking pack-years when women with household passive smoking exposure were excluded from the reference category (RRs for the heaviest smoking categories ranged from 1.32 to 1.45 and were all statistically significant) (Table 2). Women who started smoking before the age of 18 years also had a statistically significantly increased risk of NHL (RR = 1.47, 95% CI: 1.07, 2.01) (Table 2). These relative risks were attenuated when women with household passive smoking exposure were included in the reference category (Table 2). We also observed an increased risk of follicular lymphoma in association with almost all of these smoking exposures, although no relative risk estimates were statistically significant (former smokers: RR = 1.36, 95% CI: 0.72, 2.57; current smokers: RR = 1.90, 95% CI: 0.79, 4.60, compared with never smokers without household passive smoking exposure). No consistent associations were observed for DLBCL or CLL/SLL (Appendix Table 1).
In analyses of the effect of household passive smoking exposure on NHL risk, we found that among never smokers, women who reported being exposed to household passive smoking exposure had a slight, albeit statistically nonsignificant, increase in the risk of NHL (RR = 1.15, 95% CI: 0.90, 1.46) compared with those who did not (Table 3). The relative risk was highest in women who were exposed during both childhood and adulthood (RR = 1.23, 95% CI: 0.93, 1.63). In analyses that divided the participants by NHL subtype, we observed a significantly increased risk of follicular lymphoma for women exposed to household passive smoking during both childhood and adulthood (RR = 2.02, 95% CI: 1.06, 3.87) compared with those who were exposed to neither.
To further evaluate the effects of passive smoking on NHL risk, we analyzed data among never smokers who completed the follow-up questions about exposure to passive smoking in 3 settings. Of these never smokers, 86% reported some exposure to passive smoking during their lifetimes. Most (71%) reported exposure to household passive smoking, 50% reported workplace exposure, 37% reported social-setting exposure, and 20% reported exposure in all 3 settings. We observed a statistically significantly increased risk of NHL in women with the highest duration, intensity, and intensity-years of total passive smoking exposure from all 3 settings combined (RRs ranged from 1.49 to 1.75) (Table 4). Although the results were based on a limited number of cases for specific NHL subtypes, our data further suggested an increased risk of follicular lymphoma associated with increasing duration and intensity of passive smoking exposure (both P’s for trend = 0.01). For CLL/SLL, we observed a statistically significantly increased risk for women with the highest-intensity exposure (RR = 3.52, 95% CI: 1.54, 8.06) but not for other measures. No consistent association was observed for DLBCL. The results from the sensitivity analyses are virtually identical to the results presented above (data not shown).
The present large cohort study of female public school professionals contributes to the current literature on the association between smoking and NHL risk in 3 important ways. First, among lifetime never smokers, we observed a statistically significantly increased risk of NHL for those exposed to high levels of passive smoking. Although results were based on small numbers, we also found that follicular lymphoma was associated with long duration, high intensity, and high level of intensity-years of lifetime passive smoking exposure from household, workplace, and social settings combined. Second, the present study demonstrated that the estimated relative risks of NHL associated with smoking were strengthened when women with household passive smoking were excluded from the reference category. Thus, previous studies that did not account for passive smoking in the reference category might have underestimated the adverse effects of smoking on NHL risk. Third, our data further strengthened the evidence regarding the increased risk of follicular lymphoma among ever smokers that was observed in previous studies (4, 5, 8, 12, 13, 15, 24, 25, 30, 32), and particularly in women (4, 13, 15, 16, 24, 30).
The few studies in which a dose-response relation between smoking and increased NHL risk was observed were mainly case-control studies (24, 26, 30–32). However, the recall bias, selection bias, and survival bias inherent to case-control studies generally mitigated their findings. Results of 6 of the 7 cohort studies for which data have been published showed no association between smoking and NHL risk (1, 7–9, 14, 15, 18); only the CPS-II cohort study showed an increased risk of NHL associated with smoking (30). Our CTS data showed that lifetime cumulative exposure to passive smoking was highest among those born from the 1920s through the 1940s (40). Interestingly, participants in the 4 US cohort studies that evaluated the dose-response effects of smoking on NHL risk were born during this period (birth year range, 1917–1946) (9, 15, 18, 30). If the referent category of never smokers in these studies indeed included a large proportion of passive smokers, this misclassification of overall smoking exposure may explain the lack of association detected in many of the cohorts.
In the CPS-II study, we observed a much stronger effect of smoking on NHL risk in women than in men (30). Interestingly, investigators in all cohort studies that presented results separately for women reported an increased risk of follicular lymphoma among smokers (14, 15, 30), whereas the findings of studies presenting results for men and women combined were mixed, showing both increased risk (8) and decreased risk (9, 18) of follicular lymphoma. Results from the Third National Health and Nutrition Examination Survey showed that, between 1988 and 1991, 43.5% of US men and 32.9% of US women who were not tobacco users reported exposure to passive smoking at home or at work. Further, among adults 20 years of age or older, men had significantly higher mean serum cotinine concentrations than did women (41). The passive smoking experience of CPS-II participants is likely therefore more representative of the national data than that in other studies because it collected smoking information in 1992 from men and women aged 50–74 years in 21 states. Thus, it is plausible that both the prevalence and intensity of passive smoking in the reference category of never smokers were higher for men than for women in CPS-II. Consequently, the higher level of misclassification of passive smoking in the reference category of nonsmokers among men would be more likely to bias the results toward the null, potentially accounting for the observed gender difference in the association between smoking and NHL risk.
Although the association between smoking and NHL risk became stronger when household passive smoking was excluded from the reference category, we note that our relative risk estimates for smoking may still have been underestimated because we were unable to exclude women who were exposed to passive smoking outside of the household, such as in the workplace or in social settings. However, based on data from our second questionnaire, we found that only 15% of women had either workplace or social exposure to passive smoking but no household exposure. Therefore, we expect that the misclassification effect of including such women in the reference category for the analyses of active smoking exposure was limited.
Potential mechanisms of importance include those associated with active smoking, such as initiation of lymphomagenesis by carcinogens (34), in addition to altered immune function (34), alterations in T-cell subsets, and a decrease in circulating natural killer cells (42, 43). Carcinogens, including benzene and many others, have been detected in passive smokers (34). Animal studies, such as those in mice, have shown that concentrations of certain cytokines, including interleukin 4 and interleukin 10, are significantly higher in smoke-exposed animals than in nonexposed animals, a finding that could have relevance to the early events in carcinogenesis, in which an inflammatory response often precedes mild hyperplasia (44). Moreover, it has been reported that sidestream smoke, which constitutes approximately 85% of passive smoking, might be more toxic than mainstream smoke (45).
The chromosomal translocation t(14;18) has been hypothesized by some researchers to be a potential biologic mechanism for the association between follicular lymphoma and active smoking. This somatic mutation joins the immunoglobulin heavy chain gene on chromosome 14 with the bcl-2 gene on chromosome 18 and results in overexpression of bcl-2 protein, which inhibits apoptosis (46). Both increasing age and smoking have been associated with t(14;18) translocation (47, 48). Our reported association between passive smoking and follicular lymphoma risk suggests that t(14;18) might also be a relevant mechanism for follicular lymphomas associated with passive smoking and warrants further investigation.
Our study had several strengths. First, our study population was optimal for studying NHL risk associated with passive smoking because 66% of all participants were never smokers. Further, the extensive evaluation of lifetime exposure to passive smoking from household, workplace, and social settings offered a detailed assessment of exposure in a way that no other large-scale cohort study has been able to do. Second, our study’s prospective design circumvented potential problems with the recall bias, selection bias, and survival bias that are common to case-control studies. Finally, the CTS utilized detailed follow-up procedures and had virtually complete ascertainment of cancer outcomes.
The main limitations of our study were the small number of smokers, particularly current smokers, and the small number of NHL cases available for subtype analyses, which resulted in a lack of precision in relative risk estimates. Another limitation was that our results could not be generalized to men, and as a group, CTS participants might not be representative of the general population of women because all CTS participants at some time in their lives have worked as public school professionals (primarily as teachers). Finally, the measures of smoking and passive smoking were derived from self-reports rather than from biologic measures. However, the reliability of respondents in recalling passive smoking history, especially for spousal and parental sources, has been demonstrated to be high (49, 50).
Our results are consistent with previous studies on the association between smoking and increased risk of follicular lymphoma (4, 13, 15, 16, 24, 30). Our data further support an association between passive smoking and NHL (especially follicular lymphoma) risk. Future research to clarify the association between smoking and NHL risk should take into account exposure to passive smoking.
Author affiliations: Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, California (Yani Lu, Sophia S. Wang, Huiyan Ma, Jane Sullivan-Halley, Leslie Bernstein); and Cancer Prevention Institute of California, Fremont, California (Peggy Reynolds, Ellen T. Chang, Christina A. Clarke).
This work was supported by the California Breast Cancer Act of 1993; the National Institutes of Health (grants R01 CA77398 and K05 CA136967 to L. B.); and the California Breast Cancer Research Fund (contract 97-10500). Collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program under contract N01-PC-35136 awarded to the Cancer Prevention Institute of California (formerly the Northern California Cancer Center), contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement U55/CCR921930-02 awarded to the Public Health Institute.
The ideas and opinions expressed herein are those of the authors, and endorsement by the state of California Department of Public Health, the National Cancer Institute, the Centers for Disease Control and Prevention, or their contractors and subcontractors is not intended or should be inferred.
Conflict of interest: none declared.
|Smoking Characteristic||Diffuse Large B-Cell Lymphoma||Follicular Lymphoma||Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma|
|No. of Cases||RR||95% CI||No. of Cases||RR||95% CI||No. of Cases||RR||95% CI|
|Never smoker with no passive exposure||27||1.00||Referentb||14||1.00||Referentb||17||1.00||Referentb|
|Ever smoker||60||1.00||0.62, 1.60||44||1.44||0.77, 2.66||54||1.08||0.62, 1.89|
|Former smoker||52||1.00||0.62, 1.62||36||1.36||0.72, 2.57||51||1.17||0.67, 2.06|
|Current smoker||8||0.99||0.44, 2.20||8||1.90||0.79, 4.60||3||0.46||0.13, 1.58|
|Ever-smoking dose response|
|Smoking intensity, cigarettes/day|
|<10||21||0.78||0.44, 1.41||18||1.34||0.66, 2.74||23||1.05||0.55, 1.99|
|10–19||20||1.08||0.60, 1.96||18||1.90||0.93, 3.89||17||1.10||0.56, 2.19|
|≥20||18||1.36||0.74, 2.51||8||1.16||0.48, 2.79||13||1.17||0.56, 2.45|
|P for trend||0.37||0.62||0.75|
|Total no. of smoking years|
|≤10||11||0.86||0.42, 1.76||12||1.61||0.74, 3.53||9||1.16||0.62, 2.19|
|11–20||13||1.00||0.51, 1.96||5||0.72||0.26, 2.03||15||0.89||0.38, 2.08|
|>20||34||1.13||0.67, 1.91||22||1.51||0.76, 3.02||27||1.12||0.57, 2.20|
|P for trend||0.44||0.20||0.89|
|No. of smoking pack-years|
|≤10||20||0.78||0.43, 1.41||19||1.38||0.68, 2.79||24||0.92||0.41, 2.08|
|11–20||11||1.05||0.51, 2.13||9||1.66||0.71, 3.88||8||1.44||0.71, 2.92|
|>20||26||1.42||0.81, 2.49||11||1.21||0.54, 2.72||18||1.01||0.54, 1.89|
|P for trend||0.05||0.67||0.90|
|Age at smoking initiation, years|
|<18||24||1.65||0.94, 2.90||15||1.84||0.87, 3.85||12||1.02||0.48, 2.16|
|≥18||34||0.82||0.49, 1.38||24||1.15||0.59, 2.27||39||1.11||0.62, 1.99|
|No. of years since quitting smoking among former smokers|
|≤10||5||0.50||0.19, 1.30||7||1.32||0.53, 3.30||7||0.89||0.36, 2.16|
|11–20||16||1.28||0.68, 2.41||10||1.48||0.65, 3.37||9||0.88||0.39, 1.99|
|>20||30||1.16||0.68, 1.98||17||1.33||0.64, 2.74||33||1.44||0.79, 2.62|
Abbreviations: CI, confidence interval; RR, relative risk.