In this large, prospective cohort study of California women, we found little evidence that alcohol consumption during various time periods in adulthood is associated with risk of overall B-cell NHL or multiple myeloma, although we may have lacked sufficient statistical power to detect associations. We detected a weak inverse association of moderate baseline alcohol intake with risk of DLBCL, but the association was not consistent across different types of alcoholic beverages, nor did risk decline with increasing total alcohol intake, suggesting that the observed association was not due to an effect of alcohol itself. Conversely, we found positive associations of alcohol intake at all assessed time points with risk of CLL/SLL, although most of these associations lacked evidence of a dose-response trend. Thus, the observed associations with risk of DLBCL and CLL/SLL may have been due to chance or confounding. Alternatively, these associations may reflect true biologic heterogeneity between NHL subtypes and could perhaps point to an effect of alcohol on B-cell differentiation.
Most notably, we observed positive associations between former intake of alcohol in the year before baseline and risk of overall B-cell NHL, follicular lymphoma, and possibly CLL/SLL. This result was not explained by the wide array of confounders examined and may point to an etiologic role of other factors, such as illness or efforts to improve general health, that lead to cessation of alcohol use. The persistence of the positive association with former drinking after we excluded diagnoses made within 3 years of baseline indicates that such factors are unlikely to be alcohol pain/intolerance or other preclinical symptoms of lymphoma or that such symptoms occur more than 3 years before diagnosis. This general premise is consistent with our observation that recent moderate alcohol consumption (within the past 5 years) was suggestively associated with decreased risk of overall B-cell NHL, indicating that current alcohol consumption may be a surrogate for better current health.
The limited evidence of an inverse association with DLBCL risk in our study accords with the inverse association detected in an InterLymph pooled analysis of 9 NHL case-control studies (7
) and several other studies (10
) and in 4 of 6 prospective cohort studies of NHL (16
). A number of biologically plausible mechanisms could underlie such a protective effect. Whereas heavy alcohol intake has been shown to have immunosuppressive effects that result in increased susceptibility to infections and impaired host response to injury (1
), light or moderate alcohol consumption can have a beneficial attenuating effect on proinflammatory cytokines and chemokines (35
) that may otherwise promote lymphomagenesis (37
). Alcohol can also increase insulin sensitivity (38
), which may in turn decrease NHL risk (39
). Antioxidants such as resveratrol in wine and flavonoids in beer may have additional anticarcinogenic effects (40
), and alcoholics have been found to have better DNA repair capacity than nonalcoholics (42
However, our overall finding of no association of alcohol consumption with risk of B-cell NHL or multiple myeloma is more consistent with the results of previous case-control studies (9
) and 2 prospective cohort studies (20
) that similarly detected no association. Some of the heterogeneity among previous studies may be due in part to the substantial potential for recall and selection biases in retrospective case-control studies. Given that alcohol consumption has variable connotations of social and cultural desirability (48
) and is well known to affect health, cases may report alcohol intake differently from controls, resulting in recall bias. In addition, early symptoms or the diagnosis itself may cause patients to stop drinking alcohol, leading to a false inverse association between alcohol consumption and disease risk at the time of the study interview. Finally, if alcohol consumption is associated not with NHL or multiple myeloma risk but with more severe or fatal disease, then case-control studies, in which deceased patients are usually excluded and those with debilitating disease often do not participate, may again detect a spurious inverse association with alcohol consumption. Therefore, prospective cohort studies generally have higher validity for assessing the etiologic role of alcohol intake.
Nonetheless, in both retrospective and prospective studies, it is important to collect information on not only current alcohol intake but also past alcohol intake to distinguish among current, former, and never drinkers. Given that poor health is a major reason for reducing or ceasing alcohol consumption (30
), former drinkers may have higher disease risk than never drinkers or current drinkers. Therefore, regardless of study design, combining former drinkers with never drinkers may produce a spurious inverse association with current drinking, whereas combining former drinkers with current drinkers may generate a false-positive association or obscure a true inverse association. Indeed, in our study, when we combined never drinkers with former drinkers as the reference group, the association with current alcohol intake was decreased, whereas combining former drinkers with current drinkers inflated the association with ever drinking. Nearly all previous studies of alcohol and risk of lymphoid malignancies combined former drinkers with either never drinkers or current drinkers, and many investigators were unclear about whether “alcohol consumption” referred to current (excluding former) drinking or ever (including former) drinking. A few studies included in the InterLymph analysis (7
) classified former drinkers as a separate group and found no association between former (versus never) drinking and risk of NHL or its histologic subtypes. However, none of the previous 5 prospective cohort studies of alcohol and risk of lymphoid malignancies analyzed former alcohol intake separately.
Another potential source of misclassification in previous studies of alcohol and risk of lymphoid malignancies is a failure to distinguish between never drinkers and occasional drinkers, who can differ markedly in behaviors, health status, and—particularly if abstinence is due to religious or cultural reasons—genetic traits (30
). Especially in European studies, true abstainers have often been combined with infrequent drinkers (e.g., <1 drink monthly or weekly) for comparison with frequent drinkers (10
). Such variability in the definition of the reference group for relative risk estimates may explain some of the inconsistency in results among previous studies.
In the California Teachers Study, we prospectively collected information on recent and past alcohol consumption, and our questionnaire distinguished between women who consumed low quantities of alcohol and those who did not drink at all, enabling us to classify women according to both past alcohol intake and true abstinence. This information was necessary to reveal that risks of overall B-cell NHL and follicular lymphoma differed between former drinkers and never drinkers.
However, our study had some limitations. First, we did not assess alcohol intake continuously throughout the participant's lifetime and therefore could not construct a detailed history of alcohol consumption. Second, our analyses were constrained by the limited number of incident cases, which prevented us from examining numerous categories of alcohol intake, drinking patterns over time, or associations with less common lymphoma subtypes. Notably, 2 of the previous prospective cohort studies that observed an inverse association with alcohol consumption had substantially more incident cases than we did (17
), giving them considerably more statistical power to detect a true association. Thus, the absence of an association with risk of overall B-cell NHL, some NHL subtypes, and multiple myeloma in our study may have been due to insufficient statistical power. Third, we did not assess reasons for cessation of alcohol consumption and therefore could not compare women who quit drinking because of ill health with those who quit for other reasons. Finally, we could not examine the effects of changes in alcohol consumption (including cessation or resumption of drinking) after baseline, which may have influenced subsequent risk of B-cell NHL or multiple myeloma.
Despite these limitations, ours is the first prospective cohort study of lymphoid malignancies to examine alcohol intake before baseline and to distinguish current drinkers from former drinkers at baseline. Our results are strengthened by detailed covariate data and complete and valid follow-up for incident cancer among California residents. In summary, we found that alcohol consumption is not associated with risk of overall B-cell NHL or multiple myeloma and that former drinkers may have higher risks of follicular lymphoma and CLL/SLL, for reasons that may be related to illness, lifestyle changes, or other factors that prompt people to stop drinking prior to diagnosis. Moreover, the relation of alcohol consumption with B-cell NHL risk may vary by histologic subtype. Future studies of the role of alcohol in the development of lymphoid malignancies or any other health outcomes should account for former drinking and changing drinking patterns over time. Only with consistent attention to these distinctions can future investigators determine whether alcohol truly protects against lymphomagenesis or whether other factors explain the inverse associations detected in past studies.