Leukemia & Lymphoma

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Consumption of fruits, vegetables, and risk of

hematological malignancies: a systematic review
and meta-analysis of prospective studies

Theodoros N. Sergentanis, Theodora Psaltopoulou, Ioannis Ntanasis-

Stathopoulos, Athanasios Liaskas, Ioannis-Georgios Tzanninis & Meletios-
Athanasios Dimopoulos

To cite this article: Theodoros N. Sergentanis, Theodora Psaltopoulou, Ioannis Ntanasis-

Stathopoulos, Athanasios Liaskas, Ioannis-Georgios Tzanninis & Meletios-Athanasios Dimopoulos
(2018) Consumption of fruits, vegetables, and risk of hematological malignancies: a systematic
review and meta-analysis of prospective studies, Leukemia & Lymphoma, 59:2, 434-447, DOI:
10.1080/10428194.2017.1339873

To link to this article: https://doi.org/10.1080/10428194.2017.1339873

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LEUKEMIA & LYMPHOMA, 2018
VOL. 59, NO. 2, 434–447
https://doi.org/10.1080/10428194.2017.1339873

ORIGINAL ARTICLE: RESEARCH

Consumption of fruits, vegetables, and risk of hematological malignancies: a

systematic review and meta-analysis of prospective studies
Theodoros N. Sergentanisa, Theodora Psaltopouloua, Ioannis Ntanasis-Stathopoulosb, Athanasios Liaskasa,
Ioannis-Georgios Tzanninisa and Meletios-Athanasios Dimopoulosb
a
Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens,
Athens, Greece; bDepartment of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of
Athens, Athens, Greece

ABSTRACT ARTICLE HISTORY

We examined the association between fruit/vegetable consumption and the risk of hemato- Received 11 January 2017
logical malignancies in cohort studies (end of search: August 31, 2016). Total fruit consumption Revised 28 May 2017
was not associated with the risk of non-Hodgkin lymphoma (NHL) (RR ¼ 1.03, 95% CI: 0.92–1.16, Accepted 4 June 2017
I2 ¼ 12.1%, n ¼ 7), acute myeloid leukemia (RR ¼ 1.23, 95% CI: 0.94–1.61, I2 ¼ 0%, n ¼ 3), multiple
KEYWORDS
myeloma (MM; RR ¼ 1.05, 95% CI: 0.72–1.55, I2 ¼ 60.0%, n ¼ 4), and Hodgkin lymphoma. Vegetables; fruits;
However, citrus fruit consumption was associated with reduced NHL risk (RR ¼ 0.85, 95% CI: hematological cancer; meta-
0.73–1.00, p ¼ .044, I2 ¼ 0%, n ¼ 6). Vegetable intake was marginally associated with reduced NHL analysis
risk (RR ¼ 0.89, 95% CI: 0.79–1.00, p ¼ .056, I2 ¼ 16.2%, n ¼ 7), but not with acute myeloid leuke-
mia, multiple myeloma, and Hodgkin lymphoma risk. Nevertheless, NHL risk was inversely associ-
ated with cruciferous vegetable consumption (RR ¼ 0.84, 95% CI: 0.71–1.00, p ¼ .047, I2 ¼ 0%,
n ¼ 3). Notably, combined fruit/vegetable consumption was associated with decreased NHL risk
(RR ¼ 0.79, 95% CI: 0.65–0.96, I2 ¼ 11.2%, n ¼ 3). This meta-analysis reveals possible protective
effects; however, confounding and reporting bias could have affected the results.

Introduction necessitates the identification of risk factors [7].

Hematological malignancies are a diverse group of
malignant diseases that add significantly to the global
health burden of cancer both in terms of incidence
and mortality [1]. Most patients are diagnosed with
non-Hodgkin lymphoma (NHL), but most cancer
deaths are attributable to leukemias [1,2]. Among the
neoplasms originating from the hematopoietic and
lymphoid tissues there are several differences regard-
ing clinical course, pathogenesis, genetic, and molecu-
lar characteristics, as well as the therapeutic approach
[3–5].
It has been estimated that hematopoietic and
lymphoid cancers will account for approximately 10%
of newly diagnosed cancer cases and 10% of cancer
mortality in the USA in 2016 [2], whereas it has been
predicted that these demographics are going to
increase in the near future due to the aging of the
general population [6]. In that context, attention
should be paid in disease prevention, which
Exposure to radiation, several viral infections, as well
as body fatness and obesity are some reported risk
factors [8–10]. Interestingly, alcohol consumption has
been inversely associated with the risk for lymphomas
and multiple myeloma (MM) [8,11,12], while it does
not increase the risk for leukemias [13].
In the 2007 Report by the World Cancer Research
Fund/American Institute for Cancer Research (WCRF/
AICR), no convincing data regarding the association
between fruit and/or vegetable consumption and the
risk of any type of cancer were reported [14]. There
was only probable or even suggestive evidence of a
protective effect regarding carcinomas of the upper
respiratory and gastrointestinal tracts, lung, colon and
rectum, prostate, pancreas, and endometrium [14]. As
far as hematological malignancies are concerned, no
conclusive associations were reported, since most of
the data were restricted on NHL patients only and
some of them had contradictory results [14].
Furthermore, a more recent report by the European

CONTACT Theodora Psaltopoulou tpsaltop@med.uoa.gr Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National
and Kapodistrian University of Athens, 75, M. Asias Str., Athens 11527, Greece
Supplemental data for this article can be accessed here.
ß 2017 Informa UK Limited, trading as Taylor & Francis Group

Prospective Investigation into Cancer and Nutrition
(EPIC) reported no significant associations [15]; how-
ever, a meta-analysis of observational studies (case-
control and cohort studies) has suggested a significant
reduction in the risk of NHL with vegetable intake,
alone, or combined with fruits [16].
In that context, it seems that the association of
vegetable and fruit consumption with the risk of
hematological malignancies seems worth meta-analyz-
ing. In view of the fact that case-control studies suffer
from inherent biases [17], we conducted a systematic
review and meta-analysis of prospective studies pro-
viding relevant data on the risk of leukemias, NHL,
Hodgkin lymphoma (HL) and MM in order to clarify
their epidemiological characteristics in relation to
vegetable and fruit intake.
Materials and methods
Search strategy and eligibility of studies
This meta-analysis was performed in accordance with
the Meta-analysis Of Observational Studies in
Epidemiology (MOOSE) guidelines [18]. Eligible publi-
cations written in English were retrieved in PubMed
using the following search algorithm: ((fruit OR fruits)
OR (vegetable OR vegetables)) AND ((leukemia OR leu-
kemias OR leukemic OR leukemia OR leukemias OR
leukemic) OR (Lymphoma OR lymphomas OR Hodgkin
OR Hodgkin’s OR non-Hodgkin OR non-Hodgkin’s) OR
(myeloma OR ‘plasma cell’ OR ‘plasma cells’ OR plas-
macytoma OR myelomatosis OR ‘Kahler's disease’ OR
‘Kahler disease’)) AND (prospective OR prospectively
OR follow-up OR ‘followed up’ OR cohort OR cohorts
OR longitudinal). The end of search date was set on
31 August 2016. Only studies written in English,
French, German, and Spanish were examined.
Reference lists were systematically screened for rele-
vant articles in a ‘snowball’ procedure, so as to maxi-
mize the amount of synthesized information.
Eligible articles included cohort studies examining
the association between fruit or vegetable consump-
tion and risk of hematological cancer in adult popula-
tion; randomized controlled trials were not
anticipated on the field given the nature of the topic.
Case series and case reports, in vitro and animal stud-
ies were not included in this meta-analysis; the sys-
tematic review included only prospective cohorts.
Only the larger study was included in case of over-
lapping study populations. Two independently work-
ing reviewers (INS and IGT) performed the selection
of studies and any disagreements were resolved by
team consensus.
FRUITS, VEGETABLES, AND HEMATOLOGICAL CANCER 435
Data extraction and effect estimates
The extraction of data comprised the following: general
information (first author’s name, study year, journal,
title, geographical, and clinical setting), study character-
istics [study design, time period, number of participants
(number of exposed, unexposed and incident cases in
each exposure group), follow-up period, ascertainment
(information sources) regarding nutritional exposure,
ascertainment of outcome] and characteristics of partici-
pants [inclusion and exclusion criteria, race and ethni-
city, age of participants (range, mean), percentage of
males]. Separate data extraction was performed by sub-
types of disease, if applicable. More specifically, regard-
ing leukemia, separate extraction included acute
lymphoblastic leukemia (ALL; precursor B-ALL, precursor
T-ALL, Burkitt’s leukemia, and acute biphenotypic leuke-
mia), chronic lymphocytic leukemia (CLL), acute myelog-
enous leukemia (AML), and chronic myelogenous
leukemia (CML). Regarding NHL, whenever possible,
separate data abstraction was performed for diffuse
large B-cell lymphoma (DLBCL), follicular cell lymphoma
(FCL), small lymphocytic lymphoma/chronic lymphocytic
leukemia (SLL/CLL); and T-cell non-Hodgkin lymphoma
(T-NHL). As far as HL is concerned, whenever possible,
separate data extraction was conducted for mixed cellu-
larity (MC) and nodular sclerosis (NS) subtypes; more-
over, data about the rare Lymphocytic predominance
and Lymphocyte depleted subtypes were also extracted.
Separate extraction for Epstein–Barr virus (EBV) positive
and negative HL was performed. Notably, separate data
abstraction was performed by exposure strata.
Moreover, the data extraction included maximally
adjusted hazard ratios (HRs), and relative risks (RRs)
with their 95% confidence intervals (CIs), adjustment
factors at the multivariate analyses, available raw data
for re-calculation (data checking) or de novo estima-
tion of missing measures. As appropriate, data extrac-
tion was independently performed by two reviewers
(INS, IGT) and final decision was reached by team
consensus.
Statistical analysis
Statistical synthesis of studies was performed in case of
three or more eligible study arms; in case of two stud-
ies, their results are reported narratively in the text.
Similarly to our previously published meta-analyses, the
highest vs. lowest levels of exposure were compared
[19–21]. Random-effects (DerSimonian–Laird) models
were appropriately used to calculate pooled effect esti-
mates. Between-study heterogeneity was assessed
through Cochran Q statistic and by estimating I2.
436 T. N. SERGENTANIS ET AL.
Detailed forest plots are provided for the graphical pres-
entation of results. All analyses were performed using
STATA/SE version 13 (Stata Corp, College Station, TX).
Risk of bias
In order to examine the components of selection bias,
performance bias, detection bias and attrition bias,
jointly envisaged in the notion of ‘study quality’, the
nine-item Newcastle–Ottawa Quality scale, a widely
used tool for the quality assessment of observational/
non-randomized studies, was implemented [22]. It has
to be noted that the cutoff value of the item assessing
whether the follow-up period was enough for out-
comes to occur, was a priori set at 5 years. As far as
the completeness (adequacy) of follow-up is con-
cerned, the corresponding cutoff value was set at 85%
response rate. Two independently working reviewers
(INS and IGT) rated the quality of studies and disagree-
ments were resolved by team consensus.
Results
Selection of studies
Figure 1 presents the successive steps of the selection
of eligible studies. Overall, 51 abstracts were identified
Figure 1. Flow chart presenting the successive steps during the selection of studies.
by the search algorithm and screened. Forty studies
were excluded as irrelevant, three studies as reviews
and their reference lists were screened for potential
eligible articles [15,16,23], while one study was
excluded due to its case-control design [24]. One
potentially eligible study was excluded due to lan-
guage (Japanese) [25]. The study by Chiu et al. [26]
was excluded due to overlap with Thompson et al.
[27], which was an updated report of Iowa Women’s
Health Study. Another study [28] was excluded
because it investigated dietary patterns, not fruit
intake. Four studies were additionally included from
the ‘snowball’ procedure [8,29–31].
Taken as whole, 10 articles were deemed eligible
regarding the association of vegetable and fruit
intake with the risk of hematological malignancies
[8,27,29–36]. Seven of them were conducted in the
USA [8,27,29,31,33,35,36], two in Europe [32,34], and
one in Japan [30]. The cohort size ranged between
35,159 and 491,163; four studies were based only on
females [27,29,31,36]. Food frequency questionnaires
that were used included a variable number of items,
ranging between 35 and 127. All studies presented
adjusted effect estimates, but the adjustment factors
that were entered in the multivariate analyses
varied.

The study by Chang et al. [29] was included in the
analysis of total NHL, given that 90% of total NHL are
B-NHL. The characteristics of the included cohort stud-
ies are presented in Table 1.
Fruits
Fruit consumption and risk of NHL
The synthesis of the five eligible cohort studies (seven
study arms) reporting on overall fruit intake and NHL
risk [8,27,29,34,36] yielded a null association regarding
the comparison between the highest vs. lowest con-
sumption category (pooled RR ¼ 1.03, 95% CI:
0.92–1.16) (Figure 2, Table 2).
Four eligible studies corresponding to six study
arms were deemed eligible regarding citrus fruit con-
sumption and risk of NHL [27,30,34,36]. Their synthesis
pointed to a significantly protective association regard-
ing the comparison between the highest vs. the low-
est consumption category (pooled RR ¼ 0.85, 95% CI:
0.73–1.00, p ¼ .044) (Figure 3, Table 2).
In addition, we conducted analyses concerning the
DLBCL, FL, and CLL/SLL subtypes of NHL. The literature
search revealed three eligible studies concerning the
DLBCL and the FL subtypes [27,29,34]. Pooling of these
studies resulted in null associations between fruit con-
sumption and the risk of these neoplasms (pooled
RR ¼ 0.96, 95% CI: 0.72–1.28, and pooled RR ¼ 0.93,
95% CI: 0.59–1.46, respectively) (Supplemental Figures
1 and 2, Table 2). Regarding CLL/SLL, five studies were
deemed eligible [29,31,32,34,35]; their results pointed
to a non-significant association between the risk of
this subtype and fruit intake (pooled RR ¼ 1.03, 95%
CI: 0.85–1.23) (Supplemental Figure 3, Table 2).
Fruit consumption and risk of leukemias
Three eligible studies [31–33] regarding the association
between AML and fruit consumption were identified;
the synthesis of these studies pointed to a null associ-
ation (pooled RR ¼ 1.23, 95% CI: 0.94–1.61)
(Supplemental Figure 4, Table 2).
Concerning myeloid leukemia overall, the synthesis
of three study arms [8,32] did not reveal any statistic-
ally significant association (pooled RR ¼ 1.15, 95% CI:
0.90–1.47) (Supplemental Figure 5, Table 2).
Two eligible studies reported on total leukemia and
fruit consumption [31,32]; neither showed a significant
association (HR ¼ 1.13, 95% CI: 0.88–1.45 and
RR ¼ 0.77, 95% CI: 0.49–1.20 for leukemia, respectively,
and RR ¼ 0.63, 95% CI: 0.31–1.31 for CML). Regarding
the ALL subtype of leukemia, no eligible studies were
FRUITS, VEGETABLES, AND HEMATOLOGICAL CANCER 437
identified regarding its association with fruit
consumption.
Fruit consumption and risk of MM
No significant association was observed in the meta-
analysis examining the risk of MM and consumption of
fruits (pooled RR ¼ 1.05, 95% CI: 0.72–1.55)
(Supplemental Figure 6, Table 2) [8,29,34]. Similarly, no
associations were reported regarding subggroups of
fruit consumption and MM [30].
Fruit consumption and risk of HL
A null association was also reported by the eligible
studies concerning HL (HR ¼ 0.87, 95% CI: 0.31–2.42 by
Rohrman et al. [34] and RR ¼ 0.82, 95% CI: 0.41–1.65
by Chang et al. [29]).
Vegetables
Vegetable consumption and risk of NHL
The synthesis of the five eligible cohort studies provid-
ing data on total vegetable consumption and NHL risk
[8,27,29,34,36] resulted in a marginally protective asso-
ciation (pooled RR ¼ 0.89, 95% CI: 0.79–1.00, p ¼ .056)
(Figure 4, Table 2).
Pooling of the three eligible studies referring to cru-
ciferous vegetable consumption and NHL risk
[27,29,36] resulted in a significant protective associ-
ation (pooled RR ¼ 0.84, 95% CI: 0.71–1.00, p ¼ .047)
(Figure 5, Table 2). On the other hand, the meta-ana-
lysis of studies reporting leafy vegetable consumption
and NHL risk [27,34,36] resulted in a null association
(pooled RR ¼ 0.94, 95% CI: 0.64–1.37) (Supplemental
Figure 7, Table 2).
Further analyses were conducted concerning the
DLBCL, FL, and CLL/SLL subtypes of NHL. Pooling of
the eligible studies [27,29,34] resulted in a non-signifi-
cant association between vegetable intake and the risk
of DLBCL (pooled RR ¼ 0.90, 95% CI: 0.60–1.36)
(Supplemental Figure 8, Table 2) and FL (pooled
RR ¼ 0.78, 95% CI: 0.53–1.15) (Supplemental Figure 9,
Table 2). Accordingly, in the case of CLL/SLL, the syn-
thesis of the five eligible studies [29,31,32,34,35]
showed no association between the consumption of
vegetables and this NHL subtype (pooled RR ¼ 1.00,
95% CI: 0.84–1.18) (Supplemental Figure 10, Table 2).
Vegetable consumption and risk of leukemias
The synthesis of three studies on AML [31–33] pointed
to a null association between vegetable consumption
Table 1. Characteristics of eligible cohort studies.
Incidence Follow-up Mean Age Categorization of fruit/
Study (Author, cases (years, median Study age range Definition and of hemato- Dietary assessment vegetable intake in the
year) Cohort size in Cohort or mean) period Country, Region Males (%) (years) (years) logical cancer cases in cohort method study Adjusting factors
438

Chang et al. 110,215 female 536 NR 1995–2007 USA (California) 0 NR 20–84 B-cell NHL (ICD-O-3 morph- FFQ, 103 items Quartiles of fruit intake: Age, calendar year, total
(2011) teachers and ology codes 9590, 9591, < ¼0.6 ref. daily energy intake,
administrators 9670–9699, 9727, 9728, (0.7–0.9)  (1.0–1.5) - race/birthplace, and
in the CTS 9761, 9764, 9820, 9823, > ¼2.0 medium alcohol consumption.
cohort 9832, 9833, 9835, 9836, servings
9940, and 9970, excluding
T- and NK-cell types;
N ¼ 536, including 145
women with DLBCL, codes
9678–9680, 9684, 115
with FL, codes 9690–9698,
and 117 with CLL/SLL,
codes 9670, 9823, MM
T. N. SERGENTANIS ET AL.

(codes 9731–9734;
N ¼ 104), or classical HL
(codes 9650–9655,
9661–9667; N ¼ 34).
George et al. 483,338 NIH- 1918 6.9 1995–2003 USA (California, 59.6 NR 50–71 Cases were identified through
(2009) AARP Diet Florida, Louisiana, probabilistic linkage with
and Health New Jersey, North state cancer registry data-
Study Carolina, and bases, certified by the
participants Pennsylvania, North American
Atlanta, GA, and Association of Central
Detroit, MI) Cancer Registries. Incident
cancer cases were only
those who were both
invasive and the first
malignancy diagnosed
during the follow-up
period. Cancers were
defined on the basis of
criteria from the SEER pro-
gram and the ICD-O.
Hosnijeh et al. 477,325 EPIC 333 11.34 1992–2010 Europe 28.9 51.21 35–70 Incident lymphatic cancers
(2014) subjects were identified by either
population cancer regis-
tries (Denmark, Italy, the
Netherlands, Norway,
Spain, Sweden, and the
UK) or other methods,
such as health insurance
records, pathology regis-
tries, and active contact of
study subjects or next of
kin (France, Germany and
Greece). The diagnosis,
tumor site classification,
and morphology of each
case were based on ICD-
O-2 which was reclassified
according to the recently
published ICD-O-3.
Iso et al. (2007) 109,778 partici- 149 12.7 1988–2003 Japan 41.9 56.87 40–79 The sex-specific relative risks FFQ, 35 items
pants in of total mortality and
health screen- cause-specific mortality
ing were defined as the death
examinations rate among participants
according to the responses
to the diet questionnaire.
FFQ, 124 items A cup equivalent is 1 cup Age, smoking, energy
of raw or cooked fruit intake (log-trans-
or vegetable, 1 cup of formed kcal), BMI,
100% juice, 2 cups of alcohol consumption,
raw leafy greens, or physical activity, edu-
0.5 cup of dried fruit. cation, race, marital
Fruit intake in cup status, family history,
equivalents/1000 kcal: menopausal hormone
Q1 (0–0.60) (ref), Q2 therapy, and vege-
(0.60–0.97), Q3 table intake.
(0.97–1.35), Q4
(1.35–1.90), Q5
(1.90–5.58) for
females and Q1
(0–0.44) (ref), Q2
(0.44–0.75), Q3
(0.75–1.09), Q4
(1.09–1.59), and Q5
(1.59–5.13) for males
FFQ for each partici- Quartiles: 73.2 (0–109.7) Body mass index, educa-
pating country ref.  140.9 tion, smoking, alcohol
(109.8–175)  220.5 intake, physical activ-
(175.1–276)  410.3 ity and total energy
(276.1–2979.3) g/d intake and stratified
by (gender), center,
and age at
recruitment
Citrus fruits, other fruits Age and area of study
(excluded citrus fruits)
intake: <3/week (ref-
erence); 3–4/week;
> ¼5/week;
(continued)
Table 1. Continued
Incidence Follow-up Mean Age Categorization of fruit/
Study (Author, cases (years, median Study age range Definition and of hemato- Dietary assessment vegetable intake in the
year) Cohort size in Cohort or mean) period Country, Region Males (%) (years) (years) logical cancer cases in cohort method study Adjusting factors
Ma et al. (2010) 491,163 338 7.5 1995–2003 USA 59.5 62 – Incident cancer cases were FFQ, 124 items Quintiles of fruits intake: Age at baseline (continu-
NIH–AARP identified through linkage < ¼0.7 ous), gender, smoking
Diet and with state cancer registry ref.  (0.7–1.2] - status (never, former
Health Study: databases. Incident, first (1.2–1.7]  (1.7–2.5] - smoker of1 pack/day,
members primary AML cases were >2.5 servings/ current smoker of 1
identified based on the 1000 kcal pack/day, and
International Classification unknown), and total
of Diseases for Oncology. energy intake
(continuous).
Rohrmann et al. 411,097 EPIC 801 6.4 1992–2003 Europe NR NR 35–70 Cancer diagnoses were based FFQ for each partici- Quartiles of fruits intake: The analyses were strati-
(2007) subjects on population registries in pating country Fruits: <105 fied by center, gender,
Denmark, Italy, The ref.  (105–193) - and age at recruit-
Netherlands, Norway, (194–319) – >319 g/ ment in one-year cat-
Spain, Sweden, and the d, Citrus fruits: <8 egories. Adjustment
UK. An active follow-up ref.  8–8  29–71– for smoking, alcohol
through study subjects as >71 g/d, Hard fruits: consumption at base-
well as next-to-kin infor- <17 ref.  17–55– line, energy intake,
mation, the use of health 56–110 ->110 g/d and education.
insurance records and can-
cer and pathology regis-
tries were used in
Germany and Greece.
Mortality data were also
obtained from either the
cancer or mortality regis-
tries at the regional or
national level. Cases were
classified according to
ICD-O-3 In the current
analysis, the following
groups were considered:
all lymphoma combined,
HL, and NHL; within NHL
the B-NHL T-NHL, and
among B-NHL the entities
DLBCL, FL, BCLL, and MM.
Ross et al. (2002) 35,221 female 138 12.7 1986–1999 USA(Iowa) 0 NR 55–69 Deaths were ascertained FFQ. Tertiles of fruits intake: Level of intake of various
IWHS subjects using Iowa death certifi- <13.1 food groups, adjusted
cates and the NDI. ref.  (13.1–20.9) - for age, energy intake,
Incident cancers were >20.9 servings/week blood transfusion sta-
ascertained through the tus, education, BMI,
State Health Registry of and smoking status.
Iowa, one of the National
Cancer Institute’s SEER
program sites. SEER sites
achieve at least 98% case
ascertainment. Incident
cases were identified
through computer match-
ing on name, zip code,
birth date, and social
security number between
the 1986 and 1999 regis-
try cases and the study
FRUITS, VEGETABLES, AND HEMATOLOGICAL CANCER

participants. Topographic
and morphological data
from the ICD-O were used
to classify incident leuke-
439

mia in the cohort.

(continued)
Table 1. Continued
440

Incidence Follow-up Mean Age Categorization of fruit/

Study (Author, cases (years, median Study age range Definition and of hemato- Dietary assessment vegetable intake in the
year) Cohort size in Cohort or mean) period Country, Region Males (%) (years) (years) logical cancer cases in cohort method study Adjusting factors
Thompson et al. 35,159 female 415 17 1986–2005 USA(Iowa) 0 62 55–69 NHL incidence was ascer- FFQ with 127 items. Quartiles of fruits intake: Age and total energy
(2010) IWHS subjects tained by annual linkage All fruits: <45 intake
to the Iowa Cancer ref.  (45–68) -
Registry, which is part of (69–96) - >96 serv-
the SEER program. ings per month, Citrus
Analyses were conducted fruits: <11
for all NHL, as well as for ref.  11–26 –27–38 -
the two most common >38 servings per
subtypes of DLBCL and FL. month, Tertiles of fruit
T. N. SERGENTANIS ET AL.

Topographic and morpho- intake: Apple juice/

logic data were coded cider: 0 ref. –
using the ICD-O-2/3. These 1–2  >2 servings per
codes were grouped into month.
the two most common
subtypes of DLBCL and FL,
according to the approach
advocated by the
InterLymph Consortium.
Tsai et al. (2010) 525,982 partici- 1129 10.5 1993–2007 USA 58.8 63 50–74 Incident CLL/SLL cases were The Diet History Quartiles of fruits intake: Age, gender, body mass
pants identified by linkage to Questionnaire 42.1 (0.0–79.8) ref. - index.
recruited state cancer registries in (DHQ). 112.5
from the NIH the NIH-AARP Diet and (79.8–146.9)  185.2
AARP Diet Health study and through (146.9–234.8)  314.9
and Health study screening centers (234.8–1895.2) g/
Study and and annual study ques- 1000 kcal
the PLCO trial tionnaires in the PLCO
trial.
Zhang et al. 88,410 females 199 13.2 1980–1994 USA 0 NR 30–55 Women who reported the FFQ with 61 items Quartiles of fruits intake: Age (5-year categories),
(2000) in the NHS diagnosis of lymphoma on Fruits <1 total energy (quin-
cohort each biennial question- ref.  (1–1.9)  (2–2.9) tiles), length of fol-
naire from 1982 to 1994 - > ¼3 g/day. low-up (seven
(or their next of kin if Quintiles of fruits periods), geographic
they had died) were asked intake: Citrus fruits: region (Northeast,
for permission to obtain <2 ref. 2–4  5–6 Midwest, South,
their hospital records and savings/week - 1 - California), smoking
pathology reports. > ¼2 servings/day (never, past, present
Physicians without know- smoking of 1–14 ciga-
ledge of dietary intake of rettes and > ¼15 cig-
participants reviewed hos- arettes/d), and height
pital records and path- (<62 inches, > ¼62
ology reports to document to <64 inches, > ¼64
NHL. to <66 inches, > ¼66
to <68 inches, or
> ¼68 inches).
NR: not reported; NHL: non-Hodgkin lymphoma; CLL/SLL: chronic lymphocytic leukemia/small lymphocytic lymphoma; DLBCL: diffuse large B-cell lymphoma; DL: diffuse lymphoma; FL: follicular lymphoma; HL:
Hodgkin lymphoma; MM: multiple myeloma; USA: United States of America; FFQ: food frequency questionnaire; CTS: California teachers’ study; NIH-AARP: National Institutes of Health-American Association of
Retired Persons; NHS: nurses’ health study; NIH: The National Institutes of Health, JACC: Japan collaborative cohort study, IWHS: Iowa women’s health study, PLCO: prostate, lung, colorectal, and ovarian; SEER:
National Cancer Institute Surveillance, epidemiology and end results; ICD-O-2: International Classification of Diseases for Oncology, 2nd edition; ICD-O-3: International Classification of Diseases for Oncology, 3rd
edition.
 FRUITS, VEGETABLES, AND HEMATOLOGICAL CANCER 441

Study %

ID RR (95% CI) Weight

Chang Overall B−Cell NHL current Fruits >=2.0 ms (2011) 1.05 (0.84, 1.32) 21.04

George NHL females fruit intake 1.90−5.58 cup equivalents/1000 kcal (2009) 1.15 (0.87, 1.53) 14.43

George NHL males total fruit intake 1.59˘5.13 cup equivalents/1000 kcal (2009) 1.14 (0.94, 1.39) 26.48

Rohrmann B−NHL current Fruits >319 g/day (2007) 1.04 (0.81, 1.33) 18.03

Rohrmann T−NHL current Fruits >319 g/day (2007) 1.59 (0.48, 5.25) 0.91

Thompson NHL current all Fruits >96 s/m (2010) 0.78 (0.58, 1.04) 13.59

Zhang NHL current Fruits >=3 g/day (2000) 0.79 (0.49, 1.27) 5.51

Overall (I−squared = 12.1%, p = 0.337) 1.03 (0.92, 1.16) 100.00

NOTE: Weights are from random effects analysis

.191 1 5.25

Figure 2. Forest plot describing the association between risk of NHL and fruit consumption.

Table 2. Results of the meta-analyses examining the associ- 95% CI: 0.57–2.71, respectively) [32], and the second
ation between fruit and vegetable consumption and risk of one to total leukemia alone (RR ¼ 0.69, 95% CI:
hematological malignancies. Bold cells denote statistically sig-
0.44–1.07) [31]. Concerning the ALL subtype of leuke-
nificant associations.
mia, no eligible studies were retrieved.
n§ RR (95% CI) Heterogeneity I2, p
Fruits
NHL 7 1.03 (0.92–1.16) 12.1%, .337 Vegetable consumption and risk of MM
DLBCL 3 0.96 (0.72–1.28) 0.0%, .774
FL 3 0.93 (0.59–1.46) 42.3%, .177 The synthesis of the three eligible studies regarding
CLL/SLL 5 1.03 (0.85–1.23) 19.1%, .293
AML 3 1.23 (0.94–1.61) 0.0%, .645 vegetable consumption and MM risk [8,29,34] pointed
ML 3 1.15 (0.90–1.47) 0.0%, .464 to a null association (pooled RR ¼ 1.05, 95% CI:
MM 4 1.05 (0.72–1.55) 60.0%, .054
Citrus fruits 0.84–1.31) (Supplemental Figure 12, Table 2). Null asso-
NHL 6 0.85 (0.73–1.00)a 0.0%, .845 ciations were also reported regarding vegetable sub-
Vegetables
NHL 7 0.89 (0.79–1.00)b 16.2%, .306
groups [30].
DLBCL 3 0.90 (0.60–1.36) 45.3%, .161
FL 3 0.78 (0.53–1.15) 16.0%, .304 Vegetable consumption and risk of HL
CLL/SLL 5 1.00 (0.84–1.18) 8.3%, .359
AML 3 0.93 (0.68–1.26) 13.0%, .317
MM 4 1.05 (0.84–1.31) 0.0%, .536 Neither of the studies regarding HL risk and vegetable
Cruciferous vegetables consumption reported a significant association
NHL 3 0.84 (0.71–1.00)c 0.0%, .645
Leafy vegetables (HR ¼ 1.60, 95% CI: 0.60–4.24 [34], RR ¼ 1.05, 95% CI:
NHL 4 0.94 (0.64–1.37) 62.9%, .044 0.52–2.13 [29]).
Fruits and vegetables combined
NHL 3 0.79 (0.65–0.96) 11.2%, .324
§number of study arms, Fruits and vegetables combined
a
p ¼ .044,
b
p ¼ .056; Among the eligible studies, three reported data on the
c
p ¼ .047.
association between combined consumption of fruits
and risk for AML (pooled RR ¼ 0.93, 95% CI: 0.68–1.26, and vegetables and the risk of hematological malig-
Supplemental Figure 11, Table 2). nancies [27,29,36]. Regarding NHL, the synthesis of
Two eligible studies were identified [31,32], one of them pointed to a protective association (pooled
which [32] reported data also on the CML subtype. RR ¼ 0.79, 95% CI: 0.65–0.96, Figure 6). Highest cat-
Both studies pointed to null associations with the first egory of fruit and vegetable consumption combined
study pertaining to total leukemia as well as its CML was not associated either with DLBCL or FL risk
subtype (HR ¼ 1.11, 95% CI: 0.86–1.42 and HR ¼ 1.24, according to Thompson et al. (HR ¼ 0.84, 95% CI:
442 T. N. SERGENTANIS ET AL.

Study %

ID RR (95% CI) Weight

Iso NHL females current citrus fruits >=5/wk (2007) 0.76 (0.38, 1.51) 5.18

Iso NHL males current citrus fruits >=5/wk (2007) 0.66 (0.34, 1.28) 5.61

Rohrmann B−NHL current Citrus fruits >71 g/day (2007) 0.92 (0.73, 1.16) 44.33

Rohrmann T−NHL current Citrus fruits >71 g/day (2007) 0.55 (0.18, 1.69) 1.96

Thompson NHL current Citrus fruits >38 s/m (2010) 0.81 (0.62, 1.06) 34.29

Zhang NHL current Citrus fruits >=2 servings/day (2000) 0.97 (0.57, 1.66) 8.63

Overall (I−squared = 0.0%, p = 0.845) 0.85 (0.73, 1.00) 100.00

NOTE: Weights are from random effects analysis

.179 1 5.59

Figure 3. Forest plot describing the association between risk of NHL and citrus fruit consumption.

Study %

ID RR (95% CI) Weight

Chang Overall B−Cell NHL current Vegetables >=2.0 ms (2011) 0.82 (0.65, 1.03) 20.94

George NHL females vegetable 1.43˘4.38 cup equivalents/1000 kcal (2009) 0.80 (0.61, 1.05) 16.12

George NHL males vegetable 1.10˘3.25 cup equivalents/1000 kcal (2009) 1.04 (0.86, 1.26) 26.70

Rohrmann B−NHL current Vegetables >275 g/day (2007) 1.01 (0.77, 1.32) 16.32

Rohrmann T−NHL current Vegetables >275 g/day (2007) 0.40 (0.11, 1.48) 0.84

Thompson NHL current Vegetables >112 s/m (2010) 0.84 (0.63, 1.12) 14.65

Zhang NHL current Vegetables >=3 g/day (2000) 0.65 (0.37, 1.14) 4.43

Overall (I−squared = 16.2%, p = 0.306) 0.89 (0.79, 1.00) 100.00

NOTE: Weights are from random effects analysis

.108 1 9.26

Figure 4. Forest plot describing the association between risk of NHL and vegetable consumption.

0.53–1.34 for DLBCL; HR ¼ 0.59, 95% CI: 0.32–1.08 for
FL) [27] and Chang et al. (HR ¼ 1.07, 95% CI: 0.65–1.77
for DLBCL; HR ¼ 0.93, 95% CI: 0.56–1.52 for FL) [29].
Furthermore, Chang et al. reported also on CLL/SLL,
HL, and MM risk, but no associations were revealed
(HR ¼ 0.90, 95% CI: 0.52–1.56 for CLL/SLL, HR ¼ 1.22,
95% CI: 0.61–2.46 for HL, HR ¼ 1.23, 95% CI: 0.68–2.24
for MM) [29].
Evaluation of quality of studies and risk of bias
The evaluation of quality of studies is presented in
Table 3. The quality of the included cohort studies was
mainly compromised by the non-representativeness,
due to the fact that most of them were based on
cohorts including specific subgroups of population
[8,27,29,31,33,35,36], as well as the suboptimal
 FRUITS, VEGETABLES, AND HEMATOLOGICAL CANCER 443

Study %

ID RR (95% CI) Weight

Chang Overall B−Cell NHL current Cruciferous Vegetables >=0.4 ms (2011) 0.90 (0.70, 1.16) 46.53

Thompson NHL current Cruciferous Vegetables >16 s/m (2010) 0.82 (0.63, 1.07) 42.31

Zhang NHL current Cruciferous Vegetables 5−6 servings/week (2000) 0.69 (0.41, 1.16) 11.16

Overall (I−squared = 0.0%, p = 0.645) 0.84 (0.71, 1.00) 100.00

NOTE: Weights are from random effects analysis

.412 1 2.43

Figure 5. Forest plot describing the association between risk of NHL and cruciferous vegetable consumption.

Study %

ID RR (95% CI) Weight

Chang NHL F+V medium>=3.5s (2011) 0.91 (0.71, 1.17) 50.11

Thompson NHL F+V >204s/m (2010) 0.69 (0.51, 0.94) 35.60

Zhang NHL F+V >=6s/d (2000) 0.69 (0.42, 1.14) 14.29

Overall (I−squared = 11.2%, p = 0.324) 0.79 (0.65, 0.96) 100.00

NOTE: Weights are from random effects analysis

.417 1 2.4

Figure 6. Forest plot describing the association between risk of NHL and combined consumption of fruits and vegetables.

ascertainment of exposure (fruit and vegetable
consumption), taking into account that self-reporting
prevailed. However, all studies had a long enough fol-
low-up period with nearly complete follow-up, except
for two [32,35].
Discussion
The results of this meta-analysis suggest a possible
protective association between citrus fruit as well as
cruciferous vegetable consumption and decreased
NHL risk; however, the finding was derived exclusively
from self-reporting questionnaires that inherently suf-
fer from reporting bias, whereas confounding bias
could also have affected the results. Combined con-
sumption of fruits and vegetables seemed to confer
protection in terms of NHL risk, nevertheless, not sig-
nificant associations were yielded regarding overall
consumption of fruit and vegetable and risk of NHL
and subtypes, AML, and MM. It has to be noted that
there were not enough studies to conduct a meta-ana-
lysis regarding HL, total leukemia, ALL, and CML risk, a
fact which implies a lack of available evidence con-
cerning the nutritional epidemiology of hematological
cancer.
There has been accumulating data suggesting that
both citrus fruits and cruciferous vegetables play an
important role in cancer prevention. It has been
 444 T. N. SERGENTANIS ET AL.

suggested that citrus fruit consumption confers a pro-

Adequacy (completeness)
of follow-up (85%
tective effect on bladder [37,38], breast [39], pancreatic

response rate)
[40], colon [41], and stomach [42] cancer risk.



–





–

Flavonoids that are found in citrus fruits may have
anticancer activity by counteracting several hallmarks
of cancer regarding both solid and hematological
malignancies [43–47]. Similarly, cruciferous vegetable
consumption has been associated with reduced risk of
Outcome

(median 5 years)

pancreatic [48], renal [49], ovarian [50], prostate [51],

Long enough
follow-up

lung [52,53], head, and neck [54] cancer. It has been











proposed that isothiocyanates and indoles resulting
from the hydrolysis of glucosinolates found in crucifer-
ous vegetables may have a multifaceted role against
carcinogenetic molecular cascades due to their potent
of outcome
Assessment

antioxidant activity [55–57]. Thus, it may be postulated










–

that the abovementioned mechanisms may also medi-

ate the observed protective effect of citrus fruit and
cruciferous vegetable consumption on NHL risk; never-
Comparability on
other risk factors

theless mechanistic, in vitro studies seem necessary to

this direction.











The research hypothesis about an overall protective

Comparability

effect of vegetables and fruits against cancer is based

on the fact that they comprise a dietary source of anti-
oxidants, phytochemicals and folate [23]. It is known
Comparability
on age

that oxidative stress plays a crucial role in carcinogen-












esis, as malignant cells have impaired antioxidant

mechanisms and tend to maintain a higher level of
reactive oxygen species (ROS) compared to normal
present at start

cells; lymphoma pathophysiology may be associated

Outcome not

with oxidative stress [58,59]. Antioxidants neutralize












free radical species and protect DNA from oxidative

damage [16,59]. Furthermore, studies suggest that
Table 3. Evaluation of the eligible studies with Newcastle–Ottawa scale.

folate may have a potential anti-cancer benefit

Ascertainment

due to its role in DNA repair and S-adenosyl methio-

of exposure

nine regulation [23,60]. Different studies have indi-

–
–
–
–
–
–
–
–
–
–

cated a potential protective effect of folate, which is

found abundant especially in vegetables, against lym-
Selection

phomas [23].
non-exposed
Selection of

Several observational studies have been held focus-

ing on the anti-cancer effect of vegetables and fruits











by examining either food components separately or

specific dietary patterns. For instance, Mediterranean
diet strongly encourages the consumption of vegeta-
Representative-ness

bles and fruits, while it is associated with a protective

effect against overall malignancies and specific sub-
–
–


–

–
–
–
–

types of solid tumors [61,62].

Our study has several strengths. This meta-analysis
was based exclusively on cohort studies; prospective
cohort studies are valuable for nutritional epidemi-
Thompson (2010)
Rohrmann (2007)
Hosnijeh (2014)

ology as they tend to be free from recall bias provid-

George (2009)
Chang (2011)

Zhang (2000)
Ross (2002)

Tsai (2010)

ing, thus, reliable data [17,23]. For this analysis, we

Ma (2010)
Iso (2007)
Study ID

used studies with a large number of cases and suffi-

cient follow-up period [8,27,29–36]; therefore, we were

able to conduct separate analyses for vegetables,
fruits, and subtypes of hematological malignancies.
Furthermore, we conducted an extensive literature
search by using a comprehensive algorithm and by
thoroughly screening the reference lists in order to
minimize the missing data.
Among the limitations of this study was the small
number of eligible studies concerning leukemia, HL,
and MM. The findings were based on self-reporting
questionnaires that inherently suffer from reporting
bias. Moreover, confounding bias may have affected
the results, as the studies varied considerably regard-
ing the adjusting factors; for example, some studies
did not adjust for alcohol consumption
[27,29–32,34–36]. Also the assessment of dietary intake
varied considerably across the eligible studies; some
studies used grams/day [26,29,31,32,34], others used
grams per caloric intake (g/kcal) [33,35], cup equiva-
lents per caloric intake [8], and servings/day [36];
therefore, dose-response analyses could not be reliably
performed and the comparisons between ‘highest’ and
‘lowest’ categories did not correspond to the same val-
ues. Similarly to our previously published meta-analy-
ses [12,19,20], our search strategy was based on the
combination of PubMed with a meticulous ‘snowball’
procedure, namely a thorough examination of the
references in the relevant studies and reviews for
potentially eligible studies; alternative databases (such
as Embase, Web of Science, or Google Scholar) were
not searched. However, given the nature of the eli-
gible studies (large cohort studies) and the meticulous
‘snowball’ procedure, it seems that the possibility for
unidentified eligible cohorts is minimal; indeed, four
additional eligible studies were identified through the
‘snowball’ procedure. Several studies did not meet the
criteria of representativeness during the quality evalu-
ation, rendering the generalization of the results prob-
lematic [8,27,29,31,33,35,36]. Finally, the small number
of eligible studies (seven at most; three or four in the
majority of analyses) did not allow us to perform a set
of subgroup analyses exploring heterogeneity, such as
analyses by adjusting factors, unit of measurement,
representativeness, geography, time, type and quality
of dietary assessment instrument, or overall
Newcastle–Ottawa Quality scores. Moreover, meta-
regression could not be used for the exploration of
heterogeneity, since the number of included studies
was smaller than 10, as recommended by the
Cochrane Handbook [63].
In conclusion, regarding NHL risk, our meta-analysis
suggests a possible protective effect of citrus fruit and
cruciferous vegetable intake, as well as a possible
beneficial role of combined fruit and vegetable
FRUITS, VEGETABLES, AND HEMATOLOGICAL CANCER 445
consumption. However, the findings were based exclu-
sively on self-reporting questionnaires where reporting
bias is inherently present; confounding bias could also
have affected the results. Elucidating the underlying
pathophysiological mechanisms and promoting
research on plausible ways that different components
act, may provide further insight into cancer preven-
tion. Additional observational studies with rigorous
methodology seem necessary, especially regarding HL,
leukemia, and MM.
Acknowledgments
We are extremely thankful to acknowledge the World Cancer
Research Fund (WCRF) for the grant named ‘Identifying the
role of nutrition, physical activity and body size in hemato-
logical malignancies through systematic reviews and meta-
analyses’, funded by Wereld Kanker Onderzoek Fonds (WCRF
NL) and administered by WCRF International as part of the
WCRF International program.
Funding
We are extremely thankful to acknowledge the World Cancer
Research Fund (WCRF) for the grant named ‘Identifying the
role of nutrition, physical activity and body size in hemato-
logical malignancies through systematic reviews and meta-
analyses’, funded by Wereld Kanker Onderzoek Fonds (WCRF
NL) and administered by WCRF International as part of the
WCRF International program.
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