1 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT.
2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
3 Department of Pathology, Yale University School of Medicine, New Haven, CT.
4 Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.
5 Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT.
6 Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
Received for publication June 30, 2003; accepted for publication September 15, 2003.
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ABSTRACT |
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case-control studies; diet; dietary fats; lymphoma, non-Hodgkin; proteins; risk factors; women
Abbreviations: Abbreviations: CI, confidence interval; NHL, non-Hodgkins lymphoma; OR, odds ratio; RR, relative risk.
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INTRODUCTION |
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In spite of the considerable public health significance of the disease, little is known about the etiology of NHL. The established risk factors for NHL are primary, acquired, or iatrogenic immunodeficiencies, but these conditions are extremely rare and have not increased in prevalence during the past decades (3). While the epidemic of acquired immunodeficiency syndrome has contributed to much of the recent increase in young people, it cannot explain the observed long-term increase in incidence among the elderly (4). Therefore, NHL differs from the two other cancers for which incidence rates are increasing rapidly, melanoma and lung cancer, in that the risk factors responsible for its increasing incidence are largely unknown.
Several recent epidemiologic studies have suggested that dietary factors influence NHL risk. For example, four studies have proposed an increased risk of NHL associated with milk intake (59), while others have not (1012). An inverse association was observed for intakes of whole-grain foods (5, 8) and for higher intakes of vegetables (6, 8, 10, 13) and citrus fruits (6, 10). More recent studies have suggested that saturated fat (10, 12) and animal protein intakes (10) may be associated with the risk of NHL. An increased risk of NHL associated with high protein and fat intakes is biologically plausible because diets high in protein and fat may lead to altered immunocompetence, and immune system impairment is the only established risk factor for NHL (14). A reduced risk of NHL associated with vegetable and fruit intake is also biologically plausible because of the antioxidant properties of these foods or their ability to inhibit nitrosation reactions (14).
Although these earlier epidemiologic studies have provided new leads linking diet and nutrient intakes to the risk of NHL, few have systematically examined the relation. One study examined the associations by NHL subtype (6), despite the evidence indicating that NHL subtypes may be etiologically distinct. Considering the uncertainty regarding the role of diet and nutrients on the risk of NHL and the rapid increase in the disease, we conducted a population-based case-control study in Connecticut in 19952001 to evaluate the association of NHL with diet and nutrients, specifically animal proteins, fat, vegetables, and fruits.
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MATERIALS AND METHODS |
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To provide accurate and consistent histologic classification of the cases, pathology slides (or tissue blocks) were obtained for all cases from the pathology departments in which each was diagnosed. The specimens were reviewed by two study pathologists (S. F. and G. T.) experienced in the diagnosis of lymphoma. The NHL cases were classified according to the Working Formulation by grade (low, intermediate, or high), histologic type (diffuse or follicular), and immunologic type (B cell or T cell).
Population-based controls with Connecticut addresses were recruited by using random digit dialing methods for those below age 65 years or Health Care Financing Administration files for those aged 65 years or older. The participation rate for controls identified via random digit dialing was 69 percent, and it was 47 percent for Health Care Financing Administration controls. Cases and controls were frequency matched by age in 5-year intervals by adjusting the number of controls randomly selected in each age stratum every few months.
Interviews
All procedures were performed in accordance with a protocol approved by the Human Investigations Committee at Yale University and the Connecticut Department of Public Health and by the National Cancer Institute Special Studies Institutional Review Board. After approval from the hospitals and from each subjects physician (for cases) was obtained, or following selection through random sampling (for controls), potential participants were approached by letter and then by telephone. Those who agreed were interviewed by trained study personnel at the subjects home or at another convenient location. A standardized, structured questionnaire elicited demographic information and other major known or suspected risk factors that might confound the association between dietary intakes and risk of NHL. A semiquantitative food frequency questionnaire developed by the Fred Hutchinson Cancer Research Center (Seattle, Washington) was completed by each subject, who was asked to characterize her usual diet in the year prior to being interviewed, with the understanding that this information is very highly correlated with diet in the more distant past (16). The food frequency questionnaire collects data on consumption frequency and portion size for approximately 120 foods and beverages and is updated periodically to reflect US food consumption patterns and major market changes. This questionnaire has been validated and was designed to optimize estimation of fat intake (17). After completion, the food frequency questionnaire was sent to the Fred Hutchinson Cancer Research Center for analysis. Average daily nutrient intakes were calculated by using the University of Minnesota Nutrition Coding Center Nutrient Data System database.
Data analysis
Unconditional logistic regression was used to estimate the association between the risk of NHL and intakes of macro- and micronutrients and various food items. For each macro- or micronutrient index, quartiles of consumption were produced by dividing the frequency distribution of the control group at the 25th, 50th, and 75th percentiles. The statistical model used to assess the effect of calorie-providing nutrient intakes was suggested by Willett and Stampfer (18). In this model, calculated macronutrient intakes were adjusted by taking the residual from a linear, least-squares regression model in which total energy intake was the dependent variable and the macronutrient was the independent variable. The analysis of micronutrient and food item intakes was adjusted for total energy intake as a categorical variable (<1,269, 1,2691,595, 1,5961,947, >1,947 kcal). Adjustment by total energy intake as a continuous variable in the model produced similar results.
The following confounding variables were also included in the final model: age (in years as a continuous variable), body mass index (weight (kg)/height (m)2: <22, 2224.5, 24.628, >28), and family history of NHL in first-degree relatives. Adjustments of other variables (such as race (White, Black, other), level of education (high school or less, some college or higher), tobacco smoking (ever/never), alcohol consumption (ever/never)) did not result in material changes for the observed associations and thus were not included in the final model. Odds ratios and 95 percent confidence intervals were calculated by using SAS statistical software (19).
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RESULTS |
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Table 6 presents information on specific food items associated with a significant or borderline significantly (upper 95 percent CI: 1.0) reduced risk of NHL. Among fruits, only citrus (oranges, grapefruit, or tangerines), apples, and pears were associated with a reduced risk of NHL. On the other hand, several vegetables were associated with a significantly reduced risk of NHL, particularly tomatoes, broccoli, squash, cabbage, brussels sprouts, cauliflower, onions, leeks, and mixed lettuce salad with vegetables. Higher intakes of tuna, dark breads, tortillas, popcorn, and mayonnaise were also associated with a significantly reduced risk of NHL.
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DISCUSSION |
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It has been suggested that higher intakes of protein may increase the risk of NHL through effects on the immune system, as reviewed by Chiu et al. (10). Excessive absorption of animal protein could lead to chronic hyperstimulation of the immune system (9) and increased immune unresponsiveness (20, 21). An international correlation study by Cunningham (9) reported a strong positive correlation between per capita animal protein consumption and lymphoma mortality rates (r = 0.70, p < 0.01). Three epidemiologic studies reported a significantly increased risk of NHL associated with milk intake (5, 7, 8). Among the three analytical epidemiologic studies that directly investigated dietary protein intake and risk of NHL, Chiu et al. reported a nonsignificantly increased risk of NHL associated with animal protein intake (OR = 1.5, 95 percent CI: 0.9, 2.4), with no association for vegetable protein intake (OR = 1.0, 95 percent CI: 0.6, 1.5). Two other studies, however, found no association between NHL risk and animal or vegetable protein intake (6, 12).
As recently reviewed by others (10, 14), fat in the diet may also influence immune function either by actions on the cyclooxygenase, lipoxygenase, or cytochrome P-450 pathways or directly on cell function through its effects on cell membrane structure and function. Alteration in dietary fat concentration or level of saturation was found to alter membrane phospholipid fatty acid composition in a variety of cellular and subcellular membranes; such alterations, if in lymphocytes, could lead to impaired immune function (10). Two previous studies examined dietary intakes of specific types of fats and risk of NHL. Similar to our study, one by Chiu et al. (10) reported a significantly increased risk of NHL associated with animal fat intake (relative risk (RR) = 2.0, 95 percent CI: 1.2, 3.3) and saturated fat intake (RR = 1.7, 95 percent CI: 1.1, 2.7) but not polyunsaturated fat intake (RR = 1.1, 95 percent CI: 0.7, 1.8) when the highest tertile of intake was compared with the lowest (no actual intake level was reported). Zhang et al. (12) reported an increased risk of NHL associated with higher intakes of transunsaturated fat (RR = 2.4, 95 percent CI: 1.3, 4.6) and, perhaps, saturated fat (RR = 1.4, 95 percent CI: 0.7, 3.0) when the highest quintile of intake was compared with the lowest (no actual intake level was reported). It is interesting to note that white bread, one of the major sources of transunsaturated fat intake, was associated with an increased risk of NHL in our study. Ward et al. (6) also found that bread and cereal consumption was associated positively with NHL risk. However, the study did not distinguish between types of breads and cereals.
Chiu et al. (10) reported a significant trend for NHL risk and red meat consumption (RR = 1.7, ptrend = 0.04). In that study, analysis of consumption of specific items in the red meat group showed that hamburger was the only food item associated with increased NHL risk. Our study did not show an increased risk of NHL associated with red meat intake, however. An odds ratio of 0.8 (95 percent CI: 0.5, 1.1) was observed for consumption of hamburger when the highest level of intake was compared with the lowest. However, as reviewed by Chiu et al., carcinogens and mutagens such as heterocyclic amines can be generated during the cooking of red meat, and feeding experiments have shown that these compounds can induce immunotoxicity and lymphomas. Further investigation of the relation between red meat intake and risk of NHL is warranted
One of the major findings from our study was an increased risk of NHL associated with higher consumption of eggs and dairy products. Of seven previous analytical epidemiologic studies that investigated the association between dietary intakes and NHL risk, three found a significantly increased risk of NHL associated with milk intake (5, 7, 8) while the remaining four found no significant association (6, 1012). Ross and Bras (22) have reported an increased risk of lymphomas in experimental rats after augmentation of the diet with casein, the major protein found in milk. Milk and other dairy products are important sources of fat and vitamin A. Similar to our study, one by Tavani et al. (5) also reported a statistically significantly increased risk of NHL associated with retinol intake, with an odds ratio of 2.4 (p < 0.05) for the highest tertile of intake compared with the lowest. Middleton et al. (23) also reported an increased risk of Hodgkins disease associated with vitamin A intake, calculated largely on the basis of milk and vegetable consumption. It has been suggested that a bovine leukemia virus, which can cause lymphosarcomas in cattle, can be transmitted through milk to humans (24). However, no study has demonstrated that the virus can actually infect humans (25). The data from three large cohort studies in the United States (the Nurses Health Study, the Health Professionals Follow-up Study, and the Cancer Prevention Study II) do not support a relation between dietary intake of vitamins A (including carotenoids), C, or E (13 ) or use of individual supplements of vitamins A, C, and E or multivitamins and the risk of NHL (26, 27).
In our study, a higher dietary fiber intake was associated with a significantly reduced risk of NHL. Few previous studies have investigated specific fiber intakes and NHL risk. Chiu et al. (10) reported a nonsignificantly reduced risk of NHL associated with dietary fiber intake for moderate intake levels (OR = 0.77, 95 percent CI: 0.48, 1.25) and for high intake (OR = 0.86, 95 percent CI: 0.54, 1.36) when compared with low intake. A recent report of the Nurses Health Study found that intake of dietary fiber from vegetable sources was related to a significantly reduced risk (OR = 0.5, 95 percent CI: 0.3, 0.9) for women in the highest quintile compared with those in the lowest (13). Tavani et al. (5) reported a significantly reduced risk of NHL associated with higher consumption of whole-grain foods (OR = 0.4, p < 0.05), an important source of fiber. An earlier case-control study by Franceschi et al. (8) also reported a reduced risk of NHL associated with whole-grain bread or pasta intake. An odds ratio of 0.53 was reported when the highest intake was compared with the lowest (ptrend < 0.05). To explain the observed inverse association between fiber intakes and NHL risk, Franceschi et al. (8) hypothesized that alimentary fibers may affect the dilution, absorption, and/or breakdown of fat and animal protein in the gut, either directly or indirectly by modifying the gut microflora composition.
Another major finding of our study was that higher intakes of tomatoes, broccoli, squash, cauliflower, onions, and mixed lettuce salad were associated with a significantly reduced risk of NHL. The Nurses Health Study (13) also reported that higher intake of cruciferous vegetables was associated with a decreased risk of NHL (ptrend = 0.02). In that study, a relative risk of 0.6 (95 percent CI: 0.4, 0.9) was observed for a combination intake of cabbage, cauliflower, and brussels sprouts for consumption frequencies greater than or equal to two servings per week compared with less than one serving per week. Ward et al. (6) reported that of various dark green vegetables (including broccoli, green beans, kale/collard and turnip greens), broccoli intake was associated with a decreased risk of NHL.
It is hypothesized that the antioxidant properties of vegetables and fruits or their ability to inhibit nitrosation reactions may protect against NHL. We found a reduced risk of NHL associated with intake of citrus fruit (in the middle categories), apples, and pears in this study. The study by Ward et al. (6) also reported a significantly decreased risk of NHL for men associated with high levels of consumption of citrus fruits, including oranges/grapefruits and orange/grapefruit juices, and the risks decreased with increasing intake (p for trend = 0.003). However, no significant association was found for women in Wards study. A significantly reduced risk of NHL for higher intake of all fruits was reported by Chiu et al. (10). A nonsignificantly reduced risk of NHL for the higher intakes of all fruits was reported by De Stefani et al. (11) (OR = 0.78, 95 percent CI: 0.33, 1.83) and by Tavani et al. (5) (OR = 0.9, p > 0.05). The Nurses Health Study also reported a nonsignificantly reduced risk of NHL associated with fruit intake. In that study, citrus fruit intake was not associated with NHL risk (13).
In his review of nutritional factors and the risk of NHL for a 1992 meeting sponsored by the National Cancer Institute ("The Emerging Epidemic of NHL"), Davis pointed out that "future studies must be designed to investigate specific histologic subtypes of lymphoma or groupings of related types, for it may be that dietary influences are somewhat specific in their action" (28, p. 5494s). Our study results indicate that the risk of NHL associated with various dietary intakes may vary by NHL subtype. However, few other earlier studies have evaluated the association by NHL subtype because of various reasons, such as relatively small sample sizes. NHL represents a heterogenous group of lymphoid malignancies ranging in aggressiveness from very indolent cellular proliferation to highly aggressive and rapidly proliferative processes. It is possible that specific subgroups of the disease may have different etiologic profiles. Epidemiologic studies of other exposures, such as hair dye products, occupational exposures, and viruses, have shown that the risk of NHL associated with these exposures may vary by NHL subtype (2933). Further investigation of the relation between dietary intake and NHL risk by NHL subtype is warranted.
A major advantage of our study is that the food frequency questionnaire we used was specifically developed by the Fred Hutchinson Cancer Research Center to evaluate dietary intakes and womens health. The questionnaire has been validated and was designed to optimize estimation of fat intake, one of the major hypotheses of the study. However, unlike prospective follow-up studies, for which data on dietary intakes are collected long before disease diagnosis, case-control studies rely on retrospective recall by study subjects through a food frequency questionnaire to estimate dietary intakes, which would undoubtedly introduce misclassification of exposure. It is suggested that usual diet in the year prior to being interviewed is highly correlated with diet in the more distant past (16), and, since so little is known about the etiology of NHL, particularly the etiologic role of diet and nutrients in the risk of NHL, the misclassification should be nondifferential, and nondifferential misclassification of exposure would lead to underestimation of the observed association.
Another concern for population-based epidemiologic studies is the relatively low rate of participation by the eligible cases and controls, particularly the older controls. However, it is unlikely that the potential study subjects decision to participate was affected by their dietary intake history. In addition, although our study included more than 600 female cases and 700 sex-matched controls, the statistical power to investigate the relation by NHL subtype was still limited, especially for exposures with low frequencies in the study population. Given that numerous comparisons were made in this study in assessing the association between diet and nutrient intakes and NHL risk, chance could explain some of the observed associations.
In summary, in this population-based case-control study, we found an increased risk of NHL associated with higher consumption of animal protein, saturated fat, retinol, eggs, and dairy products. We also found a significantly reduced risk associated with higher consumption of dietary fiber, tomatoes, broccoli, squash, cabbage, cauliflower, onions, leeks, mixed lettuce salad with carrots and tomatoes, and citrus fruits. Considering how little is known about the etiology of NHL, a disease rapidly increasing worldwide, further investigation of the role of dietary intakes on the risk of NHL, particularly by NHL subtype, is warranted.
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ACKNOWLEDGMENTS |
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Certain data used in this study were obtained from the Connecticut Tumor Registry, located in the Connecticut Department of Public Health. The authors assume full responsibility for the analyses and interpretation of these data.
The authors thank the institutions that allowed access to diagnostic materials and pathology reports, including the following Connecticut hospitals: Charlotte Hungerford Hospital, Danbury Hospital, Greenwich Hospital, Griffin Hospital, Hartford Hospital, Johnson Memorial Hospital, Middlesex Hospital, Lawrence and Memorial Hospital, New Britain General Hospital, Bradley Memorial Hospital, Norwalk Hospital, St. Francis Hospital and Medical Center, St. Marys Hospital, Hospital of St. Raphael, St. Vincents Medical Center, Stamford Hospital, William W. Backus Hospital, Waterbury Hospital, Yale-New Haven Hospital, Manchester Memorial Hospital, Rockville General Hospital, Bridgeport Hospital, Windham Hospital, Sharon Hospital, Milford Hospital, New Milford Hospital, Bristol Hospital, MidState Medical Center, and Day-Kimball Hospital.
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NOTES |
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REFERENCES |
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