In this large, population-based prospective cohort study of older adults, enlarged body size, as measured by body mass index, height, and weight, was associated with elevated risk of NHL, with height being a risk factor only in men. Smoking was not related to NHL overall but was inversely associated with follicular lymphoma, and alcohol consumption was unrelated to NHL risk.
Our study adds to existing evidence suggesting that increased body mass index is modestly associated with elevated NHL risk (9
). Our observation of increased risk of NHL with greater height also agrees with prior reports (13
). Anthropometry-related risk of NHL is not consistent in the literature, however. Several prior studies have shown no association of body mass index (19
) or height (12
) with NHL, and to our knowledge only 1 other study has shown increased risk of NHL associated with higher weight (18
). Results of our sex-specific analyses of body mass index and NHL risk were consistent with those of prior studies, showing slightly higher risk among men than among women (17
), although our male-specific height finding contradicts the strong height-related risk detected in a large all-female cohort (18
). Our nonsignificant findings for lifetime weight change were similar to those reported previously (14
). Results of our analyses by NHL subtype were consistent with those of prior studies, with somewhat higher risks for diffuse large B-cell lymphoma and plasma cell neoplasms as compared with CLL/SLL and follicular lymphoma (12
Several plausible mechanisms exist through which enlarged body size might increase NHL risk. Greater height may be an indicator of childhood nutrition patterns that could indirectly affect NHL risk—for example, by altering the likelihood of childhood infection (37
). Alternatively, elevated body mass index and weight may be markers for certain dietary patterns, insulin resistance, inflammation, and lower levels of physical activity that may influence cancer risk (38
). Future studies of anthropometric factors and NHL would benefit from assessing these parameters in conjunction with weight and height.
Our observation that smoking was unrelated to the risk of NHL overall is consistent with prior case-control (7
) and cohort (24
) studies. The inverse association we noted between smoking and follicular lymphoma was unexpected, however. Case-control (7
) and some cohort (24
) studies have shown smoking to be associated with an increased risk of follicular lymphoma, although at least 1 cohort study showed no association between smoking and follicular lymphoma (26
) and 1 found an inverse association (28
) similar to our observation in the PLCO Trial. Our failure to detect a dose-response with intensity, duration, or cumulative lifetime exposure to cigarette smoking suggests confounding rather than a true protective association. However, the inverse association we observed between smoking and follicular lymphoma persisted after we accounted for alcohol, body mass index, and dietary factors that might lower the risk of NHL or its subtypes. Other sources of confounding that we were unable to control for may include immunity-modulating comorbid conditions, such as atopy, that have been shown to be protective against follicular lymphoma (39
). Although it is likely that the inverse association between follicular lymphoma and smoking was due to chance or unmeasured confounding, the subtype specificity and the consistency with another study of older US adults (28
) suggests that additional research in prospective studies is warranted.
We did not observe any significant association between total alcohol consumption and risk of NHL overall in the PLCO cohort, nor did we observe any association between beverage type and NHL risk, even after controlling for smoking status and dietary factors. Because of the unusually large number of nondrinkers in the PLCO cohort, we were able to separate nondrinkers (<1 drink/month) from light drinkers (<1 drink/week). Under the hypothesis that alcohol is inversely associated with NHL risk, we expected to observe increased risk among nondrinkers as compared with light drinkers and progressively decreasing risk as consumption increased. Although our risk estimates were generally less than 1 for participants who consumed the highest amounts of alcohol, we did not observe any significant associations for NHL overall, and the inverse association we observed for diffuse large B-cell lymphoma was based on few cases. Our overall null results cannot rule out the hypothesis that the inverse association observed in case-control studies (8
) is part of a prodrome in which patients reduce or eliminate alcohol consumption prior to diagnosis. However, several other large cohorts with similar levels of alcohol consumption have shown an inverse association between alcohol and NHL risk (28
). In addition, high levels of alcohol consumption (≥300 g/week) were associated with significantly decreased risk of NHL in a Japanese cohort (31
). However, similar to our observation in the PLCO Trial, risk among nondrinkers in the Japanese cohort was not elevated relative to light drinkers. Decreased risk of NHL associated with alcohol consumption is supported by evidence that alcohol modulates the immune system (40
) and retards the growth of malignant lymphoid cells via inhibition of the mammalian target of rapamycin (mTOR) (41
). In light of such evidence, in future studies of alcohol use and NHL risk, investigators should combine data on drinking behavior with biologic measures of exposure that may affect alcohol-related NHL risk.
The strengths of our study include its prospective design; the availability of a large number of histologically confirmed incident cases, which enabled us to analyze risks by NHL subtype; data on anthropometric factors at different ages; our ability to examine nondrinkers versus light drinkers; the length of follow-up; the consistency of anthropometric and smoking exposures in the PLCO cohort over time; and the similarity of NHL risk patterns in the PLCO cohort with the broader population of white, non-Hispanic US adults. However, our failure to observe a dominant effect of body mass index, height, or weight may have been due to underestimation of body size in self-reports, which could have attenuated risk estimates (42
). Our findings of decreased risk of follicular lymphoma among smokers and no association between NHL and alcohol consumption may have resulted from residual confounding. In addition, we performed many statistical tests, and thus some findings could have been due to chance; and we did not have data on some potential confounders such as physical activity.
In summary, anthropometric factors were modestly associated with increased risk of NHL in the PLCO cohort and were slightly stronger predictors of risk in men than in women; no clear association was observed between smoking and NHL; and alcohol consumption appeared unrelated to NHL. Our data support previous studies suggesting that body mass index is associated with NHL risk. Future studies of anthropometric factors and NHL that incorporate measurement of biomarkers are essential to help elucidate potential causal mechanisms. The protective effect of smoking on follicular lymphoma has been observed previously but may have been due to residual confounding, so additional prospective studies are warranted to clarify the association between smoking and follicular lymphoma. Finally, although our findings for alcohol consumption argue against a biologic association with NHL risk, future laboratory research into the action of alcohol on the immune system may identify genetic or other biologic risk factors that could be measured in epidemiologic investigations of alcohol use and NHL risk.