© 2006 European Society for Medical Oncology
Linoleic acid, vitamin D and other nutrient intakes in the risk of non-Hodgkin lymphoma: an Italian case-control study
1 Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano, Italy; 2 Servizio di Epidemiologia, Istituto Tumori ‘Fondazione Pascale’, Naples; 3 Unità di Igiene e Epidemiologia, Università di Udine, Udine; 4 Struttura Operativa Semplice di Immunologia Clinica e Virologia Dipartimento di Medicina di Laboratorio, Ospedale ‘S. Maria degli Angeli’, Pordenone; 5 Divisione di Oncologia Medica A, Centro di Riferimento Oncologico, Aviano; 6 Istituto di Ricerche Farmacologiche ‘Mario Negri’; 7 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Italy; 8 International Agency for Research on Cancer, Lyon, France
* Correspondence to: Dr J. Polesel, Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Via Pedemontana Occ. 12, I-33081 Aviano (PN), Italy. Fax: +39-0434–659222; E-mail: epidemiology{at}cro.it
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Abstract |
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Background: Dietary habits have been suggested as a factor related to the increase of non-Hodgkin lymphoma (NHL) incidence in western populations, but the role of individual nutrients is still unclear.
Patients and methods: A hospital-based case-control study was conducted in Italy, 1999–2002. Cases: 190 incident, histologically-confirmed NHL cases aged 18–84 years. Controls: 484 subjects admitted to hospital for acute, non-neoplastic diseases unrelated to diet. Dietary habits were assessed by a validated food-frequency questionnaire; nutrient intakes were computed using the Italian food composition database. Odds ratios (ORs) and corresponding 95% confidence intervals (CI) for tertiles of intake of nutrient were computed using the energy-adjusted residual models.
Results: Inverse association emerged for polyunsaturated fatty acids (OR=0.6; 95% CI: 0.4–0.9), linoleic acid (OR=0.6; 95% CI: 0.4–0.9), and vitamin D (OR=0.6; 95% CI: 0.4–0.9). The protective effect for linoleic acid (OR=0.3; 95% CI: 0.2–0.7) and vitamin D (OR=0.4; 95% CI: 0.2–0.9) was stronger in women; no differences emerged according to age. Linoleic acid was inversely related to follicular and diffuse large B-cell lymphoma; the protective effect of vitamin D emerged most clearly for follicular subtypes.
Conclusions: Our study suggests that a diet rich in polyunsaturated fatty acids and vitamin D is associated with a reduced risk of NHL.
Key words: linoleic acid, macronutrient, micronutrient, non-Hodgkin lymphoma, vitamin D
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introduction |
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Incidence and mortality rates of non-Hodgkin lymphoma (NHL) have been increasing in western populations over the last three decades [1
, 2]. However, the factors that could have contributed to these upward trends are still unclear, including selected aspects of the diet.
Increased risks of NHL have been related to animal proteins [3, 4] and total fat intake [5, 6], but fat from fish showed a protective effect [7]. Moreover, the association between fat and NHL risk seemed to be mainly due to saturated and monounsaturated fat [5, 6, 8], whereas polyunsaturated fat showed a protective effect [4].
Most studies on micronutrients and NHL risk are inconclusive. Carotenoid intake has been inversely related to NHL risk in two studies [9, 10], and high intake of ß-carotene has reported a significant protective effect in one study [11]. Unlike vitamin intake from food sources [4, 5, 10], vitamin supplementation has been related to an increased risk of NHL [12].
The present study provides additional information on the relationship between NHL risk and macronutrients and on the possible role of several micronutrients (i.e., fatty acids, minerals, vitamins, and carotenoids) in lymphomagenesis.
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materials and methods |
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Between January 1999 and July 2002, we conducted a case-control study on NHL and hepatocellular carcinoma (HCC) in the province of Pordenone, northern Italy, and in Naples, southern Italy [13
]. Cases were patients between 18 and 84 years old with incident, histologically confirmed NHL. They were admitted to the National Cancer Institute, Aviano, the ‘Santa Maria degli Angeli’ General Hospital, Pordenone, the ‘Pascale’ National Cancer Institute, and four General Hospitals, Naples. Cases were classified according to the International Classification of Disease for Oncology [14], and NHL subtypes were classified using the Revised European-American Lymphoma/World Heath Organization classification [15]. Out of 240 identified NHL, two patients refused to participate, seven were excluded because of previous or concomitant cancer, and six patients did not provide blood samples. Thirty-five additional cases, without comprehensive information on dietary habits, were excluded, thus leaving 190 cases, human immunodeficiency virus (HIV)-negative (median age: 58 years), with available questionnaires and blood samples. The majority of cases (n = 93, 49%) were diffuse large B-cell lymphoma (DLBCL), whereas 31 cases (16%) were follicular NHL, 14 (7%) were T-cell NHL, 46 (24%) were of miscellaneous subtypes, and six (3%) were of unknown histological subtypes.
Controls were patients between 18 and 84 years old, admitted for a wide spectrum of acute conditions to the same hospitals where NHL cases had been interviewed. Specifically excluded from the control group were patients admitted for malignant diseases, conditions related to alcohol and tobacco consumption, hepatitis, any chronic diseases that might have changed lifestyle habits, haematologic, allergic, and autoimmune diseases. Totally, 554 controls were contacted and 550 accepted to participate. Blood samples were available for 504 controls; 20 patients were further excluded because of incomplete dietary questionnaire, thus leaving 484 controls (median age: 63 years). Of these, 27% were admitted to the hospital for trauma; 24% for non-traumatic orthopaedic diseases, 22% for acute surgical conditions, 15% for eye diseases, and 12% for a variety of other illnesses.
All study participants signed an informed consent, according to the recommendations of the Ethical Committee of the Aviano National Cancer Institute. Each case and each control provided a 15 ml sample of blood the day the interview took place. Sera were screened for antibodies against HCV using a third-generation MEIA (AxSYM HCV, version 3.0; Abbott, Wiesbaden, Germany). Positive samples were tested for HCV antibodies using a third-generation LIA (Innogenetics, Ghent, Belgium), and for serum HCV RNA using Amplicor version 2.0 (Roche, Peasanton, CA).
Trained interviewers administered a structured questionnaire to cases and controls during their hospital stay. The questionnaire included information on socio-demographic indicators, tobacco smoking, alcohol drinking, dietary habits, behaviors, and exposures that entailed risk of HCV transmission.
A validated food frequency-questionnaire (FFQ) was employed to assess the usual diet during the 2 years before diagnosis or hospital admission for the controls. Briefly, the FFQ included 63 foods, food groups or recipes divided into seven sections: (i) milk, hot beverages and sweeteners; (ii) bread, cereals and first courses; (iii) second courses (e.g. meat and other main dishes); (iv) side dishes (i.e. vegetables); (v) fruits; (vi) sweets, desserts and soft drinks; (vii) alcoholic beverages. For vegetables and fruit subject to seasonal variation, consumption in season, and the corresponding duration, were elicited. Serving size was defined in ‘natural’ units (e.g. 1 teaspoon of sugar, 1 egg) or as an average in the Italian diet. In the present study, vitamin supplementation was less than 4% among cases (n = 8) and 2% among controls (n = 9), so that it was not considered in the analysis. The reproducibility and validity of the FFQ were satisfactory [16, 17]. Daily intake of energy, macro- and micronutrients were computed using the Italian food composition database [18].
Odds ratios (OR), and their corresponding 95% confidence intervals (CI), for increasing levels of nutrient intakes compared to the lowest one, were computed using unconditional multiple logistic regression models [19]. The models included terms for 5-year age categories, study center, education (<7, 7–11 or 
12 years), seropositivity for HCV, and total energy intake (energy from alcohol included). Adjustment for energy was made using the residual model [20]; nutrients were entered in the model as tertiles of intake based on the distribution of cases and controls combined. The test for trend was based on the likelihood-ratio test between the models with and without a linear term for each nutrient's tertile [19].
In order to rule out chance associations due to multiple testing, associations between nutrients and NHL risk were taken into consideration when significance was found for the OR of the highest tertile versus the lowest, the P-value for trend, and the OR for the continuous term.
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results |
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Table 1 shows the distribution of NHL cases and controls according to gender, age, center and other selected variables. Cases tended to be younger than controls, as the control group had to be used also for HCC cases, which were older than NHL patients. A positive HCV-test was associated with an increased risk of NHL (OR=2.7, 95% CI: 1.6–4.5). No significant difference emerged between NHL cases and controls in respect to education level and total energy intake.
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Table 2 gives the mean daily intake among controls of selected macronutrients, fatty acids, cholesterol, and fibre. The ORs of NHL according to tertile of intake, and for an increment of intake equal to 1 standard deviation (SD) among controls are reported. Total proteins, total fat, total carbohydrates, sugars, starch, saturated fatty acids, and monounsaturated fatty acids were not significantly related to NHL risk. Likewise, when different sources of protein and fat (namely, animal and vegetal source) were considered, no association emerged. High polyunsaturated fatty acids (PUFAs) intake was significantly associated with a decreased risk of NHL (OR=0.6 in the highest versus the lowest tertile of intake; 95% CI: 0.4–0.9; P for trend <0.01). Among specific PUFAs, linoleic acid (OR=0.6; 95% CI: 0.4–1.0, P for trend <0.05), but not linolenic acid, was inversely related to NHL risk. The intake of cholesterol and fibre did not show significant associations with NHL risk.
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None of the examined minerals were associated with NHL risk (Table 3). Among vitamins, vitamin D intake was associated with reduced risk of NHL (OR=0.6; 95% CI: 0.4–0.9; P for trend <0.05). The intake of thiamin, carotene, ß-carotene, and vitamin E were inversely related to NHL risk, but results did not reach statistical significance.
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The relation between linoleic acid and vitamin D and NHL risk was further investigated in separate strata of gender, age, drinking and smoking habits, and according to histological subtypes (Table 4). The protective effect of linoleic acid and vitamin D was stronger in women than in men; whereas, no differences emerged among separate strata of age, though significance was reached only below age 60 years. Likewise, there was no significant modifying effect of drinking and smoking habits. Among different histological subtypes, linoleic acid was inversely related to both follicular and DLBCL, whereas a protective effect of vitamin D emerged especially for follicular subtypes.
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discussion |
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The present study provides convincing evidence on a protective effect of PUFAs, in particular of linoleic acid, on NHL risk. A few studies investigated the relation between PUFAs and NHL risks, and the results were controversial. A case-control study [4
] conducted among Connecticut women reported a reduced risk for an intake of PUFA greater than 20 g/day, especially for diffuse histological subtype (OR=0.5) and intermediate/high grade NHL (OR=0.5). This is consistent with results from our study, where B-cell intermediate/high grade lymphoma accounted for the majority of cases (n = 104, 55%). On the other hand, Purdue and colleagues [6] did not find any effect for a daily intake greater than 11.3 g/day (OR=1.1) and an increased risk was reported for high intake of n-6 polyunsaturated fat and 
-3 fatty acids [8]. An inhibitory effect in vitro of PUFAs on the growth of several tumor cell lines was suggested [21]; in particular, n-3 PUFAs may up-regulate anticancer defence such as natural killer cell cytotoxicity and humoral and T cell responses [21, 22].
To our knowledge, no previous study reported a protective effect of vitamin D on NHL risk. An inverse association between fish, a food rich in vitamin D, and the risk of NHL and other lympho-hematopoietic cancers was reported in four previous studies [4, 7, 23, 24]. Interestingly, the possibility that high levels of vitamin D may protect against NHL is indirectly supported by two recent studies [25, 26], which showed a moderate protective effect of sun exposure on NHL risk. Sun exposure is the major determinant of circulating vitamin D levels in most world populations by means of UV-mediated synthesis of vitamin D. Experimental studies showed that 1,25-dihydroxyvitamin D3(1,25-D3), the active form of vitamin D, has an anti-proliferative and pro-differentiation effect on cells that possess vitamin D receptors in follicular lymphoma cell lines [27]. Moreover, 1,25-D3 has been suggested to interact with Th1 and Th2 cells [28], thus influencing the immune system response to tumor, intra- and extra-cellular pathogens such as viruses, bacteria, and parasites.
The role played by carotenoids on NHL risk is still unclear. An inverse association was reported by a case-control study in Italy [11], but null results were reported in both case-control [4, 9] and prospective studies [5, 10]. Conversely, Ward et al. [9] reported a five-fold increased risk for high intake of carotene among subjects whose relatives were affected by lymphatic or hematopoietic cancers. Decreased risks were reported for high intake of high-carotene-containing foods such as citrus fruits, apricots, carrots, and pumpkins [9, 24, 29].
The present results do not support previous findings from North American studies [3–6] of an increased NHL risk for high intake of protein and fat from animal ones. Differences in diet could partly explain the lack of any association in our study. The Mediterranean diet is rich in carbohydrates, fruits, and vegetables; conversely, consumption of meat and protein from animal sources is higher in North America than in Italy [3].
The study also provides suggestive evidence that carbohydrates, in particular starches, are associated to NHL risk. This may be related to the implications of starches on the insulin-like growth factor (IGF) system [30], but the results of the present study are not significant, and hence inconclusive.
A potential limitation of the present study is the use of hospital controls, which may differ from the general population in relation to their dietary habits. However, in the comparison group, we included subjects admitted for a wide spectrum of acute, non-neoplastic, non-immunological diseases, unrelated to chronic conditions (e.g., diabetes mellitus, cardiovascular diseases, etc.), which could have modified dietary habits. As in most case-control studies, potential recall bias is a possibility. Moreover, cases may recall their diet differently than healthy controls, overestimating the consumption of foods considered unhealthy in an attempt to explain the cause of their disease. The comparability of recall between cases and controls was improved by interviewing all subjects in a hospital setting. Moreover, the lack of differences in intake of total energy and in the majority of nutrients provides reassurance against recall bias, lending support to the possibility that the associations we found (notably with linoleic acids and vitamin D) might be real. An important strength of this study is given by the availability of a detailed and validated FFQ [16, 17] and of the Italian Food Composition Database [18], which allowed the computation of daily intake of a broad range of macro- and micronutrients.
In conclusion, the findings of the present study suggest a possible protective effect of a diet rich in polyunsaturated fatty acids and vitamin D (chiefly contained in fish), in particular for women of all ages, and for people aged below 60 years.
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Acknowledgements |
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This work was supported by grants from AIRC (Italian Association for Cancer Research), the Italian League against Cancer, ‘Compagnia di San Paolo’ Contract No. 11582/23719, and Ministry of Health FSN 2002 Contract No. 122.
The authors wish to thank Drs A. Pinto and V. Canzonieri for the collaboration to the study, Mrs O. Volpato for study coordination, Drs G. Laconca, M. Grimaldi, and O. Manganelli for their help in data collection. We are also deeply thankful to Drs R. Mele, A. Grandi, L. Forner, P. Ascierto, R. Magri, and R. Di Lauro for providing hospital control patients.
Received for publication September 28, 2005. Accepted for publication December 12, 2005.
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