Leukemia & Lymphoma, December 2006; 47(12): 2477 – 2487

REVIEW

The role of dietary factors in the epidemiology

of non-Hodgkin’s lymphoma
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AMANDA J. CROSS & UNHEE LIM

Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute,
Rockville, MD, USA

(Received 19 July 2006; accepted 24 July 2006)

Abstract
The incidence of non-Hodgkin’s lymphoma (NHL) has risen dramatically over recent decades and, despite some known risk
factors, such as compromised immunity, the etiology of NHL and the reasons for most of this increase are unknown. Dietary
components may be a common and critical source of immunologic antigens and promoters, which needs to be incorporated
more in the etiologic research of NHL. To date, epidemiologic evidence suggests that obesity and fat intake, in particular
For personal use only.

saturated or animal fat, may increase the risk of NHL; whereas whole-grains, vegetables and moderate consumption of
alcohol may be inversely associated with NHL risk. Much of the current evidence is obtained from case-control studies,
which are subject to dietary recall bias; therefore, this area of research requires further study within prospective cohorts with
detailed dietary information and with a large number of cases to examine disease sub-type heterogeneity.

Keywords: Diet, non-Hodgkin’s lymphoma, cancer, epidemiology, review

Abbreviations: BMI, body mass index; CI, confidence interval; DiMeIQx, 2-amino-3,4,8-trimethylimidazo[4,5-
f]quinoxaline; FFQ, food frequency questionnaire; HCAs, heterocyclic amines; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-
f]quinoxaline; MTHFR, (5,10-)methylenetetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase
reductase; NHL, non-Hodgkin’s lymphoma; OR, odds ratio; PAHs, polycyclic aromatic hydrocarbons; PhIP, 2-amino-1-
methyl-6-phenylimidazo[4,5-b]pyridine; RR, relative risk; SHMT1, cytoplasmic serine hydroxymethyltransferase; TYMS,
thymidylate synthase

NHL is more common in Caucasians than other

Introduction
Non-Hodgkin’s lymphoma (NHL) is a heteroge-
neous group of malignancies that originate from
lymphocytes [1]. The incidence of this malignancy
has doubled in developed countries over the past
three decades; for example, the age-adjusted inci-
dence of NHL in the US has risen from 11.1 to 19.8
cases per 100 000 men and women from 1975 – 2003
[2]. According to the current consensus to combine
solid and circulating phases of lymphoid cancer [3],
NHL and lymphoid leukemia together now rank the
sixth most common cancer in men and fifth most
common in women, with *58 870 new cases and 18
840 deaths expected in the year 2006 [4]. Although
ethnicities, the increase in incidence is seen across all
races, particularly in individuals over the age of 60
years [5]. Established risk factors for NHL include a
compromised immune status, as is the case for
individuals with autoimmune disease, primary or
acquired immunodeficiency syndromes or for indi-
viduals who have undergone solid organ transplant
with immunosuppressive therapy [6]. Furthermore,
NHL has been positively associated with some
infectious agents, occupational and environmental
toxins and family history [7,8]. These reported risk
factors, especially the rise in human immunodefi-
ciency virus infection, as well as improved detection
and reporting in the recent decades partly explain the

Correspondence: Amanda J. Cross, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS,
Rockville, MD 20852, USA. E-mail: crossa@mail.nih.gov

ISSN 1042-8194 print/ISSN 1029-2403 online Ó 2006 Informa UK Ltd.

DOI: 10.1080/10428190600932927
 2478 A. J. Cross & U. Lim
increase in NHL incidence; however, the majority of
cases remain largely unaccounted for by the estab-
lished risk factors [1,9].
It has been hypothesized that a Westernized
lifestyle may account for elevated rates of many
malignancies, including NHL. In particular, the
Western diet has changed substantially over the past
decades to include more processed and refined
foods. Laboratory research has demonstrated that
diet serves as an important source of both mutagenic
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and chemopreventive agents and an increasing
number of epidemiologic studies are being con-
ducted to test the diet-related hypotheses on NHL.
Methodological issues of nutritional
epidemiology
In order to critically evaluate the epidemiologic
evidence on diet and NHL risk, it is essential to
consider the methodological issues regarding study
design and dietary assessment. Observational epide-
miologic studies of diet fall into the categories of
ecologic, case-control or cohort studies [10]. Ecolo-
gic studies that examine the correlation between
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dietary patterns and corresponding cancer rates at
the population level are invaluable for generating
hypotheses, but insufficient to provide a conclusion
because the association at the aggregate level may be
different from that among individuals. Case-control
studies recruit cases after diagnosis and compare
their recalled past diet with controls; these studies are
subject to biases from the disease affecting dietary
habits or differential recall of past diet between cases
and controls. In addition, the recruited controls may
not represent the source population of the cases,
particularly for case-control studies with low re-
sponse rates or hospital-based design. Biases asso-
ciated with case-control studies are virtually
eliminated in prospective cohort studies, where
participants free of cancer are asked to provide
information on dietary habits and then followed up
for a number of years for subsequent cancer
developments. It is considered that the prospective
cohort study provides the most reliable data in
observational nutritional epidemiology.
Epidemiologic studies generally utilize self-
administered semi-quantitative food frequency ques-
tionnaires (FFQ) for dietary assessment. Study
participants are asked to choose the average fre-
quency and typical serving size for a list of food items
consumed during a reference time, sometimes with
added questions on types (e.g. fat content of milk) or
cooking methods (e.g. meat module developed by
Sinha et al. [11]). FFQ-based dietary assessments are
often calibrated against alternative methods thought
to be more accurate, such as the 24-h recall, which
involves an in-person interview of dietary intake over
the previous 24 h, or a diet record, which is an open-
ended food diary kept at the time of consumption.
Calibration studies have demonstrated that FFQs
perform well in ranking people in the relative order of
nutrients consumed, which is its main use in etiologic
studies, but contain substantial random measure-
ment error that may attenuate the true underlying
association [12 – 15].
In the following review, we have examined the
observational epidemiologic studies to date with a
focus on diet and incident NHL development rather
than survival or mortality because the role of diet in
the two phases may be different and many other
factors such as treatment may affect the latter.
Energy intake and obesity
Many Westernized countries have rising rates of
obesity, which is thought to be a contributory factor
for many diseases, including cancer. Obesity has
been investigated as a risk factor for NHL, but the
findings have been contrasting. Some case-control
[16,17] and cohort [18 – 20] studies have found no
association between obesity and NHL; whereas a
recent large case-control study of over 1000 NHL
cases reported a significant 1.6- and a 1.4-fold
increased risk for men and women, respectively, for
a body mass index (BMI) of 30 kg m72 or above,
compared to those with a BMI between 18.5 –
25 kg m72 [21], confirming previous findings from
case-control studies [22 – 24]. With regard to NHL
sub-types, two case-control studies found the positive
association for BMI and NHL risk to be similar in
diffuse and follicular sub-types of NHL [21,23],
whereas a case-control study of over 1300 cases
finding no association overall for BMI and NHL
found a positive association for the diffuse sub-
type of NHL (OR ¼ 1.73; 95% CI, 1.15 – 2.59 for a
BMI435 vs 525 kg m72) [25].
As is the case for some other cancers, the obesity-
NHL association appears stronger for mortality than
incidence: a BMI over 35 kg m72 was associated with
a 1.5-fold (p trend 5 0.001) elevated risk of mortality
in men and a 2-fold (p trend 5 0.001) elevated risk in
women [26]. In addition to the association between
BMI and NHL, individuals in the highest quartile of
reported total caloric intake have been associated with
an increased risk of NHL [21,27].
Studies in animals and humans have indicated that
obesity can lead to impaired immune function,
characterized by a decreased number of T- and
B-cells and a reduced response to mitogens, which
can be restored if calories are restricted [28,29].
One recent population-based case-control study
found that genetic polymorphisms in leptin, an

adipocyte-derived hormone that regulates energy
balance and immune responses, and its receptor
were associated with an obese phenotype and an
increased risk of NHL [23]. Obesity may also affect
the metabolism of endogenous hormones, which
could distort the normal balance between cell
proliferation, differentiation and apoptosis [30].
Carbohydrates, glycemic load and desserts
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Two prospective studies [19,31] and most popula-
tion-based case-control studies [27,32,33] of total
carbohydrates or the main food sources of carbohy-
drates (bread, pasta, cereals) were null; although a
positive association was indicated for high consump-
tion of white bread or pasta/rice [34 – 36]. Dessert
consumption has been linked to a higher NHL risk
[19,27], but sugar intake has not [36] . In a follow-up
study, women who frequently consumed cakes
(relative risk (RR) for 2 servings/week vs 51
serving/month ¼ 2.0; 95% confidence interval (CI),
1.2 – 3.4) or pies (RR for 1 serving/week ¼ 1.6; 95%
CI, 1.0 – 2.6) were associated with an elevated risk
for NHL [19]. Similarly, people consuming 9
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dessert foods weekly showed a moderately higher
risk, particularly for the diffuse sub-type of NHL
[27]. Consumption of low-fat desserts (such as
frozen yogurt and sherbet), on the other hand,
was associated with a moderately lower risk (OR for
43/month vs 51/month ¼ 0.7; 95% CI, 0.5 – 0.9
[34]). Data are scarce regarding glycemic index/load
for the potential carcinogenic effect of carbohydrate-
containing foods through post-prandial hyperinsuli-
nemia and stimulation of tumor growth; although
one study found a positive association, especially
among women below age 60 [36].
Fat
The most common dietary components to be
investigated with regard to NHL are fat and protein.
The interest in these two macronutrients is based
upon their ability to induce chronic hyperstimulation
of the immune system [37 – 41]. Fat may influence
immune function either by actions on the cycloox-
ygenase, lipoxygenase or cytochrome P-450 pathways
or directly on cell function through its effects on cell
membrane composition [42]. Improvements in the
immune status can be achieved by reducing total fat
intake to 25% of total energy intake [43].
There have been several epidemiologic studies
assessing the role of fat and fat sub-types and the risk
of NHL. Both case-control and cohort studies suggest
that there is a significant positive association between
total fat intake and risk of NHL [19,27,31,34,44,45],
with risks ranging from 1.3 – 1.8-fold for those in the
Diet and NHL 2479
highest quantile of intake. Investigations of fat sub-
types have shown that saturated fat appears to be
contributing to the positive association, with risks
ranging from 1.3 – 1.9-fold [19,27,31,34]. The posi-
tive association for total fat and saturated fat intake
was the highest in the diffuse sub-type of NHL
[27,34]. In particular, animal fat was associated with
an increased risk of NHL in two cohorts of US
women (RR ¼ 1.4; p trend ¼ 0.06 [19] and RR ¼ 1.9;
p trend ¼ 0.01 [31]), whereas there was no clear
association with vegetable fat [19,31].
Some studies have also reported findings for
monounsaturated and polyunsaturated fat (PUFA)
intake. An increase in n-6 PUFAs suppresses the
immune status in several animal models [46], but
this has not been reproduced in humans fed PUFAs
[43]. The epidemiologic evidence does not find any
association for PUFAs and NHL, but suggests a
positive association for monounsaturated fat in three
[19,27,31] of four studies. More recently, interest has
arisen in trans-unsaturated fat and the one study
reporting trans-unsaturated fat intake was of 199
NHL cases from the Nurses’ Health Study cohort,
which found a 2.2-fold significant increased risk
(p trend ¼ 0.002) of NHL in the highest quintile of
intake [19].
Specific fat sources that have been investigated
include margarine, for which there was no associa-
tion [16,19], but the three studies reporting findings
for butter all reported significant 1.6 – 1.7-fold
increased risks of NHL in the highest quantile of
intake [16,34,44]. Of two studies reporting data for
oil intake, one hospital-based case-control study
found a 1.9-fold elevated risk [16], but a larger
case-control study found no association [44].
Protein
Consuming consistently large amounts of dietary
protein may lead to prolonged antigenic stimulation
and increased immune tolerance [47,48]. Rats fed
high protein diets are at increased risk of lymphoma
independent of total caloric intake [38].
Epidemiologic studies of total dietary protein have
been inconsistent, with two cohort studies finding no
association in the highest vs lowest quantile of intake
[19,31]; whereas two US case-control studies found
opposing results, comparing the highest to the lowest
quartile, one study found an inverse association
(OR ¼ 0.38; 95% CI, 0.20 – 0.75; p ¼ 0.01) [45],
whilst the other found a positive association
(OR ¼ 1.4; 95% CI, 1.0 – 1.9), although the trend
for the latter was not significant [34]. Splitting total
protein intake into animal and vegetable sources
showed that animal protein was associated with a
suggestion of an increased risk in some [31,34,49],
 2480 A. J. Cross & U. Lim
but not all studies [19,27,33,45]; whereas vegetable
protein was not associated with risk in any of the
studies [31,33,34,45] and was actually associated
with a significant inverse association in one US
cohort study [19]. With regard to sub-types of NHL,
the elevated risk associated with animal protein
consumption was particularly prominent for diffuse
and B-cell lymphoma, with significant 2-fold risks in
the highest quartile of consumption [34].
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Meat
The overall evidence for the intake of total meat has
been inconsistent; with increased risks reported in
both a cohort [31] and a large case-control study of
over 1500 NHL cases [27], but no association in
three case-control studies, all of *400 cases
[33,44,45]. There are several potential mechanisms
linking meat to the carcinogenic process, which
include meat type, cooking methods and doneness
levels, as well as meat processing procedures; there-
fore, studies of sub-groups of meat are important.
Several studies of NHL have reported risks specifi-
cally for red meat, although there are inconsistencies.
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Some case-control and cohort studies finding no
association for red meat and NHL [16,27,32 –
34,36,45,50], whilst two female cohort studies found
significantly increased risks of *2-fold in the highest
vs lowest quantile [19,31] and one case-control study
found a significant 2.5-fold increased risk in men in
the highest tertile of consumption [51].
As is the case for cancers at other sites, white meat
does not appear to be associated with NHL risk
[27,32,36,45], this includes sub-groups such as
chicken with or without skin [19,31] and fish as
assessed in both case-control studies, with case
numbers ranging from 190 – 1642 [16,27,32 –
34,36,44,45,49,52,53] and cohort studies [19,31],
with case numbers of 104 and 199, respectively.
The cooking method and doneness level of meat
has generated interest with regard to carcinogenesis
because high temperature cooking methods, such as
barbecuing and pan-frying, and prolonged cooking of
meat can lead to the formation of mutagenic
compounds known as heterocyclic amines (HCAs)
and polycyclic aromatic hydrocarbons (PAHs). Ani-
mal feeding experiments have shown that HCAs and
PAHs can induce lymphomas in mice [54 – 57].
Supporting this notion, hamburgers, which tend to
contain comparatively high levels of HCAs and
PAHs due to the technique they are usually cooked
by, have been associated with an elevated risk of
NHL [31]. Furthermore, a case-control study from
Sweden found a significant 1.5-fold elevated risk in
the highest quartile of pan-fried red meat for both
men and women [32], although another case-control
study [45] and a cohort study found no association
[19]. No study has found a significant association for
barbecued red meat and NHL [32,45,51], although
there was a suggestion of an elevated risk in one
cohort study (RR for consuming barbecued red meat
at least once per week, compared to less than once
per month ¼ 1.5; 95% CI, 0.9 – 2.4) [19]. With
regard to NHL sub-types, the risk associated with
fried meat was prominent for T-cell and diffuse large
B-cell lymphoma and grilled meat increased the risk
for diffuse large B-cell lymphoma [32].
HCA and PAH levels are also high in meat cooked
well-done, although no study able to address this
question [19,31,32,45] found a positive association;
in fact two cohort studies found an inverse associa-
tion with well-done meat, with significant risks of 0.5
and 0.7, respectively [19,31]. A supporting hypoth-
esis for an inverse association for well-done meat
could be the presence of transmissible agents, such as
oncogenic viruses or other contaminants in meats
consumed rare, which are destroyed by prolonged
cooking in well-done meats.
One recent study has specifically assessed
intake of three individual HCAs: 2-amino-3,4,8-
trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), 2-
amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)
and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyri-
dine (PhIP), as well as benzo[a]pyrene (a carcino-
genic PAH) and total mutagenic potential, which is a
combined measure of all mutagens in the meat. This
case-control study found no positive associations for
any of these meat-mutagen variables [45].
Processed meat can be a source of N-nitroso
compounds (NOCs), formed as a result of the
processing procedure and the addition of nitrate or
nitrite to preserve the meat. NOCs are also able to
induce tumors in animal models at a variety of sites,
including lymphomas [58 – 60]. Of the nine epide-
miologic studies that have looked at processed meat
intake and risk of NHL [16,19,27,31,33,36,44,
45,51], only two found a significant association, with
risks in the highest tertile of 1.5-fold from a large
Canadian case-control study [27] and 1.4-fold risk in
an Italian case-control study [44]. Furthermore, one
case-control study consisting of 160 cases from
Uruguay investigated salted meat and found a
significant 5-fold elevated risk for NHL in men in
the highest tertile of intake, although no association
in women [51]. Studies of specific processed meats
have not revealed associations for either bacon or
hotdog consumption [19,31].
Nitrate
In addition to certain vegetables, contaminated
drinking water can be a substantial source of nitrate.

Nitrate from drinking water is estimated to be a
major source of nitrate intake when levels exceed
the maximum contaminant level of 45 mg L71
[61]. Nitrate accumulates in ground water from
fertilizers, as well as from animal and human waste
and, once ingested, this nitrate may further
contribute to endogenous formation of NOCs
[62]. Nitrate from drinking water has been
positively associated with NHL risk in one US
case-control study [63]; although two other US
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studies did not find a positive association [64,65].
The most recent study failed to find an association
between drinking water nitrate and NHL; although
there was an inverse association for dietary nitrate
(OR for the highest compared with the lowest
quartile ¼ 0.54; 95% CI, 0.34 – 0.86) [66]. Despite
being a major source of dietary nitrate, vegetables
also contain vitamin C, for example, which is
known to inhibit N-nitrosation reactions, which
may explain an inverse association.
The contribution of nitrate to endogenous NOC
formation is thought to arise as a result of its
reduction to nitrite, which can in turn be converted
to nitrosating species. One recent population-
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based case-control study reported an elevated risk
of NHL for those in the highest, vs lowest, quartile of
dietary nitrite intake (OR ¼ 3.1; 95% CI, 1.7 – 5.5)
[66].
Dairy
Overall, there is a suggestion of a positive association
between dairy products and risk of NHL [32,33],
particularly for diffuse large B-cell lymphoma [32];
although some studies only found associations with
specific dairy products. Milk is a source of fat and
protein, which are both thought to be risk factors for
NHL, as well as calcium, riboflavin and vitamin A,
which may be protective [67]. Ross and Bras [38]
reported an increased risk of lymphomas in experi-
mental rats after feeding a diet with casein, the major
protein found in milk. It has also been suggested that
a bovine leukemia virus, which can cause lympho-
sarcomas in cattle, can be transmitted through milk
to humans [68].
After 11.5 years of follow-up, a Norwegian cohort
of 15 914 men and women found those who drank
two or more glasses of milk a day, compared to 51
glass a day, were at a 3.4-fold increased risk of NHL
(95% CI, 1.4 – 8.2), although milk consumption was
also associated with meat, egg, coffee and alcohol
consumption [69]. Two Italian and one US case-
control study have also supported a positive associa-
tion between milk consumption and risk for NHL, all
reporting significant risks of 1.6 or higher [16,34,44].
Consideration must also be given to several studies
Diet and NHL 2481
finding no association between milk consumption
and NHL [19,27,31,33,36,49,51].
In general, the consumption of cheese has not
been associated with NHL risk, with the majority of
studies reporting null findings [16,33,36,44],
although two case-control studies have reported a
significant risk in the highest quantile of intake in
women only [27,36]. The evidence for a role of eggs
is contrasting, with significant associations reported
in both a positive [27,34] and an inverse direc-
tion [36], with others reporting no association
[16,19,32,33,44].
Residues in animal products
A diet high in animal products, such as meat and
dairy, could be a marker for other carcinogens in the
diet, such as lipophilic pesticide residues and dioxins,
that may increase NHL risk [70], although pesticide
residues in food are lower than occupational ex-
posure [71]. Foods high in animal fat are the primary
source of exposure to dioxins in non-occupationally
exposed individuals [72]; a survey in New York state
supermarkets found the highest levels of dioxins in
ground beef [72]. Chiu et al. [31] found no
association for milk and dairy, yet they found an
association for beef.
Fruits and vegetables
Thus far we have considered dietary components
potentially able to elevate the risk of NHL; other
components may be beneficial and exert some degree
of protection. Fruit and vegetable intake have been
examined as protective factors for a number of tumor
sites, including NHL. Two prospective [31,73], six
population-based [27,32 – 34,51,74] and six other
case-control [16,36,44,49,75,76] studies have eval-
uated the association of vegetable intake and NHL
risk. The majority of studies indicated a protective
effect of all vegetables combined [32,36,73,74] (RR
for 3 servings vs 51 per day ¼ 0.65; 95% CI,
0.37 – 1.13; p ¼ 0.04 [73]), green leafy vegetables
[32,33,74], cruciferous vegetables [32,34,73,74],
yellow/orange vegetables [27,34,44,49] or tomatoes
separately [34] and allium vegetables [34]. Weaker
evidence from prospective data [31,73] and incon-
sistencies within studies, such as gender differences
[32] and across studies [16,51,76] need to be
resolved before a conclusion can be made. One
reason for the inconsistency may be potentially dele-
terious components in vegetable-containing mixed
dishes. Out of all studies investigating fruit intake
and NHL [16,27,31 – 34,46,44,49,51,73 – 76], five
studies [16,31,32,36,76] demonstrated that diets
high in fruits may lower NHL risk (e.g. RR for high
 2482 A. J. Cross & U. Lim
vs low tertiles ¼ 0.64; 95% CI, 0.40 – 1.05; p ¼ 0.07
[31]), with some additional evidence for a protective
effect of citrus fruits in men [33]. Fruits and vege-
tables contain numerous antioxidants, folate and
fiber that may explain the cancer-preventive effect.
Antioxidants and vitamin supplements
Antioxidants such as vitamins A, C and E may
protect immune cells from DNA-damaging effects of
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free radicals [46,77]. Lower intake of antioxidants
has been linked to compromised immune responses
[46,77] and low serum levels of antioxidants have
been associated with childhood leukemia and lym-
phoma [78]. Currently, there is no strong epidemio-
logic evidence to support an inverse association for
dietary or supplemental intake of vitamins A
[34,73,74], C [31,34,35,74] or E [31,73,74] or
carotenoids [31,34,73,74], especially among pro-
spective data with adjustments for potential con-
founders. However, there are some supportive data
for an inverse association for carotenes [33,35,44]
(OR for high vs low tertiles ¼ 0.6; 95% CI, 0.4 – 1.0
[35]) and vitamin C in men [33] and a suggestive
For personal use only.
deleterious association for retinol [34,35,44] (OR for
extreme quartiles ¼ 1.4; 95% CI, 1.0 – 2.1 [34]).
Prospective data on female nurses showed a positive
association between the use of individual supple-
ments of vitamins A, C or E with NHL risk; however,
the associations were confounded by multivitamins
and became non-significant after adjustments [79].
In addition, the same vitamins showed no association
among male health professionals with incident NHL
[79] and with NHL mortality in both women and
men [80]. Epidemiologic data concerning other
antioxidant nutrients, including selenium and zinc
(OR for extreme quartiles ¼ 0.58; 95% CI, 0.36, 0.91
for both dietary and total intake [74]) or a composite
indicator of dietary antioxidant intake are limited.
Long-term use of multivitamin supplements was
associated with a lower risk of NHL in men only
(OR ¼ 0.5; 95% CI, 0.3 – 0.9) in a population-based
case-control study [33], but with a higher NHL
incidence among women only (RR for 10þ years of
use vs never use ¼ 1.48; 95% CI, 1.01 – 2.16) in a
prospective study [79]. Since there is no biological
basis to suspect a differential effect of multivitamin
supplements in women vs men and because null
associations were detected for mortality in a compa-
nion study [80], the authors considered a possible
chance-finding.
Folate and other one-carbon nutrients
Polymorphisms in one-carbon metabolism genes
such as MTHFR ((5,10-)methylenetetrahydrofolate
reductase), MTR (methionine synthase), MTRR
(methionine synthase reductase), SHMT1 (cytoplas-
mic serine hydroxymethyltransferase) and TYMS
(thymidylate synthase) have been associated with
NHL [81 – 84], indicating an etiologic role of one-
carbon metabolism. One-carbon metabolism is
mediated by a number of nutrients, most notably
folate and also vitamins B2, B6 and B12 and
methionine [85] and contributes to normal DNA
methylation and synthesis/repair [86]. While limited
epidemiologic data are available on specific one-
carbon nutrients in relation to NHL risk, folate is
speculated to be a constituent for the protective effect
associated with fruits and vegetables or grains and
cereals that are the major food sources of natural or
synthetic folate, respectively [87]. The Nurses’
Health Study revealed a borderline protective asso-
ciation of vegetable intake, but did not show any
association of dietary or supplemental folate [73]. A
population-based multi-center case-control study in
the US yielded supportive evidence of the one-
carbon hypothesis: food-derived vitamin B6 (OR for
highest vs lowest quartile ¼ 0.57; 95% CI, 0.34 –
0.95) and methionine (OR ¼ 0.49; 95% CI, 0.31 –
0.76) were associated with lower risk of NHL and
food-derived folate was inversely associated with the
diffuse sub-type of NHL (OR ¼ 0.47; 95% CI, 0.23 –
0.94 [85]). However, a hospital-based case-control
study in Italy did not confirm such associations [35]
and a Finnish cohort of male smokers indicated a
protective effect of vitamin B12 [88]: population-
specific genetic and nutritional status related to one-
carbon metabolism may in part account for the
inconsistency.
Whole grains and fiber
Studies have tended to find a risk-lowering effect of
whole grains [16,34,44,89,90], although there have
been some null findings [27,32,74]. Whole grains,
compared with refined grains, contain more fiber,
vitamins and minerals, which individually or in
combination may promote health. The recom-
mended dietary allowances for total dietary fiber,
supplied from fruits and vegetables as well as whole
grains, are 30 – 38 g per day for men and 21 – 25 g
per day for women, only about half of which is
consumed by Americans on average [91]. The Iowa
Women’s Health Study cohort did not find any
association between high fiber and NHL [31] and
the 40% lower risk associated with 25 g vs 510 g
fiber in the Nurses’ Health study was substantially
confounded by saturated and trans-unsaturated fat
intake [73]. On the other hand, a case-control study
of US women reported a protective association of
total, water-soluble (from oats, legumes and fruits)

and water-insoluble (from whole grains and vegeta-
bles) fiber, especially for B-cell lymphoma [34]. The
specific physiologic role of fiber remains ill-defined
other than acting through a lower glycemic impact of
high-fiber foods and their promotion of a negative
energy-balance.
Alcohol
A pooled analysis of nine case-control studies from
Leuk Lymphoma Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 10/27/14
the US, UK, Sweden and Italy in the International
Lymphoma Epidemiology Consortium (Inter-
Lymph) reported that, compared with those who
did not drink alcohol, ever drinking (OR ¼ 0.83; 95%
CI, 0.76 – 0.89) or current drinking (OR ¼ 0.73; 95%
CI, 0.64 – 0.84) were associated with a lower risk
among *6500 cases and 8700 controls; however,
there was no dose-response relation (up to 28 or
more drinks per week vs none) or a stronger trend
with longer duration [92]. Another recent multi-
center case-control study of six European countries
(Epilymph) with *2500 cases and 1700 controls
reported a null finding overall, but an inverse
association among men (OR ¼ 0.76; 95% CI,
For personal use only.
0.62 – 0.93) and in non-Mediterranean countries
(OR ¼ 0.73; 95% CI, 0.61 – 0.86 [93]). A prospective
study among older women in Iowa [94] and several
case-control studies [85,95 – 97] have demonstrated
a similar inverse association, with some showing a
dose-response among moderate drinkers [96]. Retro-
spective studies, however, have shown null results
[16,22,51,98 – 103] or a positive association in a
follow-up of men [104] or in male beer drinkers [51].
It has been suggested that different drinking culture,
such as binge drinking vs drinking as a part of a meal,
may explain the inconsistency among the studies
from different countries [93].
The proposed carcinogenic effect of alcohol, even
at moderate levels, on a number of cancers through
the mutagenic effect of acetaldehyde [105] and/or the
inhibitory effect on one-carbon metabolism [106]
appears irrelevant to lymphoma etiology. Similarly,
the inverse alcohol-NHL association is not likely to
have been confounded by cigarette smoking, which is
not a strong risk factor for NHL [93,107]. The
potential beneficial effect of alcohol remains unclear
[108]; although moderate alcohol consumption (up
to one drink for women and two for men daily) has
shown advantageous host cellular and humoral
immune responses [109]. On the other hand, social
and behavioral factors correlated with recent moder-
ate drinking among mature adults might have driven
the association [110 – 112], although similar findings
with different beverage types (beer, wine or liquor)
across NHL sub-types and before and after statistical
adjustments for socio-economic factors do not
Diet and NHL 2483
provide a strong indication of such confounding
results [92].
Coffee and tea
There is no consistent or compelling evidence to
suggest either protective or deleterious effect of
methylxanthine-containing beverages, such as coffee
and tea or their decaffeinated counterparts. Combined
consumption of coffee and tea has been positively
associated with NHL risk, but the association was
attenuated when adjusted for other dietary risk factors
[16]. An Italian case-control study [113], a Japanese
study on coffee and both green and black tea [49] and a
population-based case-control study in Sweden [32]
found no significant associations; whereas US studies
associated coffee intake with a lower risk among men
[33] or for diffuse sub-type only [32].
Conclusions
The most consistent epidemiologic evidence for
dietary factors associated with an elevated NHL risk
is for obesity and fat intake, particularly animal fat
and saturated fat, which could also explain associa-
tions with red meat; red meat may be a marker for
saturated and/or animal fat intake or conversely the
fats may be a marker of red meat intake. In contrast,
studies consistently suggest a lower NHL risk as-
sociated with higher consumption of whole grains
and vegetables and a moderate amount of alcohol.
The evidence is suggestive but insufficient for other
food groups and nutrients, including desserts, dairy,
fruits, antioxidants and one-carbon nutrients.
Our review of the epidemiologic literature on diet
and NHL reveals a number of future directions.
Overall, more studies are required to resolve incon-
sistent findings, especially where significant findings
are limited to retrospective studies. Prospective co-
horts would deliver risk estimates less biased by
differential recalls by patients or any recent dietary
changes due to disease. Some evidence indicates that
there may be etiologic heterogeneity among the
lymphoma sub-types, but most studies have been ill-
equipped in sample size to compare sub-types
properly, which indicates the need for pooling and
consortium efforts. As confounding by other risk
factors is a common problem of all observational
studies, a thorough ascertainment of data on potential
confounders and adjustments are imperative to assess
the true diet-NHL associations. Furthermore, biomar-
ker studies may provide more direct evidence for
certain nutrients and the examination of nutrient
interactions with relevant genetic polymorphisms
may shed light on the potentially complex involvement
of nutrition in lymphoma etiology.
 2484 A. J. Cross & U. Lim
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