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M. Solans et al.
and particularly diet, with non-Hodgkin lymphoma (NHL). In the 2007 report by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR),3 the Panel decided not to make any judge- ments regarding the causality of associations between specific dietary factors and NHL, but pointed out a sugges- tive inverse association with vegetables, fruit, and alco- holic beverages, and a positive association with meat, total fat, body fatness, and dairy. Recent meta-analyses further support these associations,36,37 but there is still not sufficient evidence to establish a causal role. Similarly, data on the association of diet and CLL are inconclusive and mainly arise from studies on nutrients or single food items. To our knowledge, 9 prospective studies4-12 and 13 case-control studies13-25 have been published on this topic. With the exception of a few studies that found positive associations with consumption of processed meat and poultry,4 total carbohydrate8 or fat (in women)11 intake, and inverse associations with isoflavones consumption,10 gen- erally large prospective studies found no associations between a wide range of dietary factors and CLL. By con- trast, case-control studies have yielded contradictory results for meat,13,14,16,24,25 dairy products,13-17 fish15,18 or veg- etables and fruit14,16,19,22,23,25 intake.
Inconsistencies in previous epidemiological nutritional studies in part reflect the difficulty in disentangling the influence of single food items that, when consumed in combination, may be highly correlated and exert synergis- tic or antagonistic effects on CLL risk. The examination of dietary patterns, which better reflect the complexity of dietary intake, has been used to address such limitations.26 So far, only a few studies have examined associations of dietary patterns and risk of CLL,25,27,28 reporting inconclu- sive findings, mainly due to small sample size. Ollberding et al.28 pointed out that a high adherence to a ‘Meat, Fat and Sweets’ dietary pattern, characterized by a high intake of French fries, red meat, processed meat, pizza, salty snacks, sweets and desserts, was associated with an increased risk of overall NHL (ORQ4 vs. Q1=3.6; 95%CI: 1.9, 6.8) in a Nebraska case-control study. This association was maintained when stratifying according to lymphoma subtypes but sub-analyses did not include CLL cases due to sample size (n=25). By contrast, a large prospective cohort in the US did not find associations with ‘Fat and Meat’ pattern and CLL etiology.27 However, this pattern did not include sweets and deserts, sweetened beverages, or convenience foods, which may be important contribut- ing factors of these associations. Thus, not only differ- ences in the study design and setting, but also in food groups loaded in these data-driven analyses, should be carefully considered when comparing results. In line with our findings, no associations with overall NHL25,27,28 or CLL25,27 were detected for a ‘healthy’ dietary pattern char- acterized by high intake of fruit and vegetables.
We observed opposite trends in relation to a Mediterranean diet pattern and Rai stages, with stronger adherence among cases with higher disease severity (P-het=0.04). We hypothesize that reverse causality could partly explain these results. While Rai 0 patients are usu- ally diagnosed in a routine blood test and present an indo- lent course, Rai I-IV are more prone to be symptomatic (e.g. night sweat, fatigue, weight loss or fever) and to receive active treatment. Thus, those patients with a more severe disease (and probably more concerned about their illness) would be more prone to shift towards a healthier
dietary pattern. However, these results have to be taken with caution since none of the trends showed statistically significant associations.
Chronic lymphocytic leukemia is the most common leukemia in Western countries while its incidence is much lower in Eastern countries, where it accounts for only 1- 3% of NHL in most series.38 While genetic backgrounds may be responsible for some of the differences in the CLL incidence, some studies have suggested that environmen- tal factors also play an important role. A dramatic increase in CLL incidence in Taiwan in recent years was associated with a strong birth-cohort effect, that corresponded to the Westernization of lifestyle in Taiwan since 1960.39 In addi- tion, a higher incidence of CLL has been reported among US-born Asians compared to foreign-born Asians, point- ing out the influence of environmental factors that change with immigration and acculturation to a Westernized lifestyle.40 Our results further support the view that adopt- ing a Western diet could partly explain these incidence patterns.
A Western diet has been associated with obesity pheno- types,41 including a higher waist-to-hip ratio, which has in turn been recently linked to higher OR of CLL, particular- ly in women, in the MCC-Spain study.42 Despite the fact that CLL cases showed a higher waist-to-hip ratio than controls in our study, waist-to-hip ratio and BMI were not included as covariates in the final multiple-adjusted model since they did not change risk estimates. Hence, an inde- pendent effect of the Western dietary pattern may be con- tributing to CLL lymphomagenesis, which seems plausi- ble from a mechanistic point of view. On one hand, it has been well-established that dietary changes, and particular- ly switching from a low-fat, plant polysaccharide-rich diet to a high-fat, high-sugar Western diet, can induce alter- ations in microbiota composition.43 Beyond its role in the biosynthesis of key components (e.g. vitamins, essential amino acids or short chain fatty acid byproducts), several studies using germ-free mice suggest that microbiota also plays a fundamental role on the induction, training, and function of the host immune system.44 Exposure to a Western diet may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses, and this phenomenon is proposed to account for some of the dramatic rise in autoimmune and chronic inflammatory disorders found in high-income countries. On the other hand, a diet high in fat, refined grains, red and processed meats, and sweets has been largely associated with higher levels of inflammatory markers45 and with inflammation-related chronic diseases.46 In particular in CLL, the strong production of inflammatory cytokines and chemokines accompanied by activation of intra-cellular pro-inflammatory pathways, and the presence of somatic mutations that activate pro- inflammatory signaling pathways, suggest that chronic inflammation plays a pathophysiological role in this dis- ease.47 Thus, an inflammation-related mechanism may in part underlie the observed associations with CLL, although no research on the inflammatory potential of diet and CLL risk has yet been conducted.
The dietary patterns used in this study were identified using the control population of a multicentric case-control study on female breast cancer in Spain.30 By contrast, the MCC-Spain study included male participants, who may have different dietary habits. However, this difference does not preclude the application of the original scoring
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haematologica | 2018; 103(11)