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American Journal of Epidemiology
Copyright © 2002 by the Johns Hopkins Bloomberg School of Public Health
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Vol. 155, No. 12
Printed in U.S.A.
Fruits, Vegetables, and Adenomatous Polyps Smith-Warner et al.
Fruits, Vegetables, and Adenomatous Polyps
The Minnesota Cancer Prevention Research Unit Case-Control Study
Stephanie A. Smith-Warner,1 Patricia J. Elmer,1 Lisa Fosdick,2 Bryan Randall,2 Roberd M. Bostick,1 Greg
Grandits,2 Patricia Grambsch,2 Thomas A. Louis,2 James R. Wood,3 and John D. Potter1
Although high vegetable intakes have been associated with a lower risk of colorectal cancer, this relation is less
well established for the precursor lesions, adenomatous polyps. With a case-control design involving
adenomatous polyp cases (n = 564), colonoscopy-negative controls who were polyp free at colonoscopy (n =
682), and community controls (n = 535), this 1991–1994 Minnesota Cancer Prevention Research Unit study
investigated the relation between fruit and vegetable consumption and first incident adenomatous polyps. Dietary
intake was assessed using a food frequency questionnaire. For women, adenoma risk was approximately halved
in the highest versus lowest quintile of juice consumption (cases vs. colonoscopy-negative controls: odds ratio
(OR) = 0.50, 95% confidence interval (CI): 0.27, 0.92; cases vs. community controls: OR = 0.56, 95% CI: 0.30,
1.06). The association was stronger for adenomas with moderate or severe dysplasia compared with mild
dysplasia. Juice was not associated with adenoma risk in men. The results for fruits, vegetables, total fruits and
vegetables, green leafy vegetables, and several botanically and phytochemically defined subgroups generally
were not statistically significant. Because elevated vegetable consumption has been associated with a lower risk
of colorectal cancer, vegetables may have a stronger role in preventing the progression of adenomas to
carcinomas rather than in preventing the initial appearance of adenomas. Am J Epidemiol 2002;155:1104–13.
adenoma; colorectal neoplasms; diet; fruit; vegetables
Numerous epidemiologic studies have examined the association between diet and colorectal cancer (1–3). One of the
most consistent findings has been an inverse association
with vegetable intake, particularly cruciferous vegetable
intake (1, 4–7). Associations with fruit and juice consumption have been inconsistent (4–7).
For studies of adenomatous polyps (8–22) (precursor
lesions of colorectal cancer (23–25)), statistically significant
inverse associations have been observed rarely with fruit
(12, 20) or vegetable (8, 14, 18) consumption, and one study
has reported a significant positive association for fruit consumption (22). Associations between adenomas and fruit
and vegetable subgroups have been reported rarely. We
therefore examined the associations between intakes of a
variety of fruit and vegetable groups and risk of adenomatous polyps in a case-control study including two control
groups. Associations of fruit and vegetable intakes with ade-
noma subgroups based on pathology also were explored to
evaluate whether there may be differential risks for adenomas of low versus high malignant potential (26).
Received for publication April 29, 1999, and accepted for publication February 1, 2002.
Abbreviations: CI, confidence interval; OR, odds ratio; SD, standard deviation.
1
Division of Epidemiology, University of Minnesota, Minneapolis,
MN.
2
Division of Biostatistics, School of Public Health, University of
Minnesota, Minneapolis, MN.
3
Minnesota Gastroenterology, Digestive Healthcare, PA,
Minneapolis, MN.
Reprint requests to Dr. John Potter, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave. N., MP-900, P.O. Box 19024,
Seattle, WA 98109-1024 (current address) (e-mail: [email protected]).
Participant populations
MATERIALS AND METHODS
This case-control study of adenomatous polyps was conducted as part of the Minnesota Cancer Prevention Research
Unit, a collaboration between the University of Minnesota
and Digestive Healthcare, PA, a private gastroenterology
practice that, at the time of this study, performed approximately 60 percent of the colonoscopies in the Minneapolis
metropolitan area. The study was conducted between April
1991 and April 1994 and was approved by the institutional
review boards of the University of Minnesota and nine hospitals serving the 10 endoscopy units utilized by Digestive
Healthcare.
Recruitment of the cases and colonoscopy-negative controls was initiated by Digestive Healthcare staff during the
routine scheduling of colonoscopy appointments. The initial
eligibility assessment evaluated whether patients were
30–74 years of age, were residents of the Minneapolis/St.
Paul metropolitan area, spoke English, were free of genetic
syndromes associated with a predisposition to colonic neoplasia, and did not have a personal history of ulcerative colitis, Crohn’s disease, adenomatous polyps, or cancer (except
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Fruits, Vegetables, and Adenomatous Polyps 1105
nonmelanoma skin cancer). An introductory letter, a consent
form, and four study questionnaires were mailed to persons
who met these criteria. The questionnaires were completed
prior to the colonoscopy visit to minimize recall bias.
At the colonoscopy visit, the forms were collected and
blood was drawn. To be eligible as either a case or
colonoscopy-negative control, the participant received a
complete colonoscopy reaching the cecum, had all identified polyps removed (if applicable), and did not have a
new diagnosis of ulcerative colitis, Crohn’s disease, or
invasive cancer. The study participation rate was 68 percent among all patients receiving a colonoscopy.
Colonoscopy-negative controls (n 707) were polyp free
at colonoscopy; cases (n 574) had at least one adenoma
(defined as either adenomatous or mixed pathology).
Among the cases, polyp size was determined in vivo by
comparison of the polyp with fully opened standard-sized
flexible colonoscopy forceps. Polyps were removed and
examined by the study pathologist using diagnostic criteria
established for the National Polyp Study (27). If polyps
were removed during a sigmoidoscopy prior to the
colonoscopy, the relevant slides were evaluated by the
study pathologist.
Because the colonoscopy-negative controls may represent a special group of persons who have undergone routine screening for colorectal cancer or who may have gastrointestinal disorders, signs, symptoms, or anxieties that
prompted colonoscopy, they may have been too similar to
the cases in lifestyle factors or family history. Therefore,
we also recruited a community control group using the
state of Minnesota Drivers’ Registry. Community controls
were frequency matched to estimates of the age (5-year
intervals), sex, and zip code distribution of the cases to
minimize differences in access to health care. University
staff telephoned prospective community controls to determine eligibility using the same criteria specified for the
colonoscopy patients. However, the current polyp status of
the community controls was unknown, because receiving a
colonoscopy was not a criterion for participation in this
control group. A packet identical to that sent to the
colonoscopy patients was mailed to eligible participants.
Completed forms were returned by prepaid mail. The participation rate was 65 percent for the community controls
(n 550).
Data collection
Study participants provided information on personal
medical history, family history of cancer and polyps,
lifestyle factors, reproductive history (women only), and
sociodemographic characteristics. Dietary intake over the
previous year was assessed using a 153-item semiquantitative Willett food frequency questionnaire that was
expanded and modified for the Minnesota Cancer
Prevention Research Unit studies to include additional
vegetables, fruits, and low-fat foods. The nine response
categories for frequency of intake ranged from “never, or
less than once per month” to “6+ per day.” The nutrient
database and analysis program developed at Harvard
Am J Epidemiol Vol. 155, No. 12, 2002
University was used to estimate nutrient intake
(HarvardSSFQ.5/93).
Fruit and vegetable consumption was estimated by summing the number of servings per week of the 59 fruits and
vegetables included on the food frequency questionnaire.
Portion sizes for fruits and vegetables were defined as one
small can or 6 fluid ounces (0.18 liter) for juices, 1 cup
(0.24 liter) for raw, green leafy vegetables, and one-half cup
for most raw or cooked fruits and vegetables. Missing
responses for items were coded as never consumed. The
following fruit and vegetable categories were examined:
fruits without juice (referred to as fruits); vegetables without juice (vegetables); fruit and vegetable juice (juice); and
fruits, vegetables, and juice (total fruits and vegetables). We
also evaluated several fruit and vegetable groups on the
basis of botanical taxonomy and phytochemical content to
identify foods that may be potentially rich sources of bioactive phytochemicals (28). Correlations comparing the food
frequency questionnaire with 15 days of diet records collected over 1 year were 0.67 for fruit, 0.32 for vegetable,
and 0.82 for juice intakes (29).
Participants were excluded from analyses if their reported
energy intake was implausible (<600 or >5,000 kcal/day), if
their total fruit and vegetable intake exceeded 175 servings/week, or if more than 10 percent of the items on the
food frequency questionnaire were blank. On the basis of
these criteria, 50 participants (10 cases, 25 colonoscopynegative controls, 15 community controls) were excluded
from the analyses.
Statistical analysis
Analyses were conducted separately for women and men
because the neoplastic potential of adenomas (30) and gastrointestinal function may differ between women and men
(31–35). Associations between fruit and vegetable intake
and adenomatous polyps were assessed using unconditional
logistic regression in the Statistical Analysis System (SAS
Institute, Inc., Cary, North Carolina); all tests of statistical
significance were two sided. Participants were classified
into sex-specific quantiles of fruit and vegetable intake by
the combined distribution of cases and controls. Separate
analyses were performed for comparisons of the cases versus the colonoscopy-negative controls and for the cases versus the community controls. Sex-specific odds ratios were
adjusted for age, energy intake, fat intake, body mass index,
smoking status, alcohol intake, multivitamin supplement
use, nonsteroidal antiinflammatory drug use, and hormone
replacement therapy use (women only). Tests for trend were
conducted using the square root of the number of servings as
a continuous regressor (36).
To investigate the association between fruit and vegetable intake and adenoma pathology, we classified cases
into two subgroups: a mild dysplasia group and a moderate
or severe dysplasia group. If a participant had more than
one adenoma, the adenoma with the highest degree of dysplasia was used for classification. Logistic regression
analyses compared each dysplasia subgroup with each
control group.
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Smith-Warner et al.
community controls, 40.1 (SD, 23.0) for male cases, 40.2
(SD, 23.1) for male colonoscopy-negative controls, and 41.8
(SD, 20.9) for male community controls. The most commonly consumed fruits and vegetables were orange juice
(2.9 servings/week), bananas (2.6 servings/week), potatoes
(2.5 servings/week), iceberg lettuce (2.3 servings/week),
and apples (1.8 servings/week).
RESULTS
Population characteristics
Study participants generally were White (97 percent), had
an average age of 53–58 years, and had a mean body mass
index of 27 kg/m2 (table 1). Women made up a smaller proportion of cases than of either control group. The primary
reason for receiving a colonoscopy among cases was a
planned polyp excision (64 percent) and among the
colonoscopy-negative controls, a strong family history of
colorectal cancer (31 percent) or a positive fecal occult
blood test (30 percent). Among the cases, the majority of
adenomas were located in the distal colon and were smaller
than 10 mm (table 2). Approximately half of the adenomas
had mild dysplasia.
The mean fruit and vegetable intakes were similar across
the three study groups. The mean total fruit and vegetable
intakes (servings/week) were 45.8 (standard deviation (SD),
26.6) for female cases, 45.2 (SD, 24.4) for female
colonoscopy-negative controls, 47.0 (SD, 23.0) for female
Fruit and vegetable intake and adenoma risk
Most of the odds ratios for the four main fruit and vegetable groups did not reach statistical significance at the
p < 0.05 level for either women or men (table 3). For
women, only juice consumption showed a monotonic
decrease in risk with increasing consumption. For both
control group comparisons, women in the highest quintile
of intake had at least a 40 percent lower adenoma risk than
did women in the lowest quintile. Fruit, vegetable, and
total fruit and vegetable intakes were not associated with
adenoma risk.
TABLE 1. Selected demographic characteristics by group, Minnesota Cancer Prevention Research Unit case-control study,
1991–1994
Characteristic
Cases
Colonoscopy-negative controls
Community controls
Cases
Colonoscopy-negative controls
Community controls
No.
Age (years)
(mean (SD*))
Women
(%)
Education
(years)
(mean (SD))
Drink alcohol
(%)
No. of
drinks/week
(mean (SD))†
564
682
535
58 (10)
53 (11)
58 (10)
38
62
45
14 (3)
14 (3)
14 (3)
73
72
74
7 (9)
5 (8)
6 (9)
Smokers
(%)
Body mass index
(kg/m2)
(mean (SD))
Energy intake
(kcal/day)
(mean (SD))
Fat intake
(% kcal)
(mean (SD))
Dietary fiber
(g/day)
(mean (SD))
Total fruits
and vegetables
(servings/week)
(mean (SD))
27 (5)
27 (5)
27 (4)
2,091 (776)
2,011 (711)
2,048 (712)
31 (6)
30 (6)
30 (6)
21
15
16
22 (10)
22 (9)
22 (9)
42 (24)
43 (24)
44 (22)
* SD, standard deviation.
† Among drinkers.
TABLE 2. Distribution of adenoma pathology in cases by sex, Minnesota Cancer Prevention Research Unit case-control study,
1991–1994
Pathology*
Total
Women
Men
No. of
adenomas
(mean (SD†))
Adenoma
size (mm)
(mean (SD))
1.5 (1.0)
1.3 (0.6)
1.6 (1.2)
9.0 (8.0)
8.3 (6.8)
9.4 (8.7)
Total
Women
Men
Mild
(%)
49
50
48
51
50
52
Medium
(5–9 mm)
(%)
Large
(≥10 mm)
(%)
30
38
25
33
27
36
37
35
39
Location
Histology
Degree of dysplasia
Medium or
severe
(%)
Adenoma size
Small
(<5 mm)
(%)
Tubular
(%)
Tubulovillous
or villous
(%)
Proximal
colon
(%)
Distal
colon
(%)
Rectum
(%)
68
72
66
32
28
34
24
20
27
60
61
59
16
19
15
* For those persons with more than one adenoma, the pathology of the largest adenoma is described.
† SD, standard deviation.
Am J Epidemiol Vol. 155, No. 12, 2002
Fruits, Vegetables, and Adenomatous Polyps 1107
TABLE 3. Multivariate-adjusted odds ratios* for colorectal adenomas by quintile of fruit and vegetable intake for women and
men, Minnesota Cancer Prevention Research Unit case-control study, 1991–1994
Mean intake
(servings/week)
Cases vs. colonoscopy-negative controls
Food group quintile
Women
Women
3.3
7.4
11.2
15.8
27.5
2.1
5.9
9.6
14.7
26.9
1.00
0.95
0.91
1.10
1.34
p trend
Vegetables
1
2
3
4
5
10.1
17.6
23.8
31.6
51.4
8.8
15.1
20.2
27.1
44.7
1.00
1.12
1.16
2.26
1.70
0.52,
0.50,
0.59,
0.66,
1.72
1.63
2.05
2.69
OR
1.00
0.79
1.06
0.79
0.66
0.5
2.2
4.8
7.7
14.2
0.62,
0.62,
1.23,
0.87,
2.01
2.16
4.14
3.34
1.00
1.29
1.11
1.30
0.90
0.5
1.9
4.2
7.4
15.1
1.00
0.81
0.72
0.61
0.50
16.5
26.8
36.1
48.5
75.9
1.00
0.76
1.06
1.48
0.96
p trend
0.48,
0.41,
0.34,
0.27,
1.36
1.84
1.43
1.24
1.00
0.65
0.78
0.61
0.68
0.75,
0.64,
0.72,
0.48,
1.39
1.27
1.09
0.92
1.00
1.53
1.24
0.88
0.98
0.86,
0.73,
0.52,
0.55,
1.38
1.92
2.78
1.96
1.00
0.80
1.05
0.82
0.61
0.46,
0.60,
0.44,
0.31,
0.40
95% CI
0.34,
0.40,
0.30,
0.32,
1.25
1.52
1.20
1.43
OR
1.00
0.73
1.00
0.62
0.75
0.29
2.23
1.93
2.34
1.69
1.00
1.08
0.86
1.34
1.40
0.56,
0.44,
0.69,
0.67,
2.73
2.10
1.51
1.73
1.00
0.97
0.80
0.56
0.56
0.53,
0.43,
0.31,
0.30,
2.07
1.68
2.59
2.92
1.00
0.67
0.73
0.59
0.55
1.00
0.61
1.01
0.71
0.76
0.32,
0.52,
0.36,
0.34,
0.86
0.43,
0.59,
0.36,
0.41,
1.23
1.68
1.06
1.35
0.39,
0.43,
0.34,
0.30,
1.13
1.26
1.03
0.98
0.16
1.78
1.51
1.03
1.06
1.00
1.16
0.83
0.75
0.97
0.04
1.38
1.83
1.51
1.22
95% CI
0.44
0.24
0.97
0.42,
0.59,
0.79,
0.47,
0.79
0.46,
0.61,
0.44,
0.35,
OR
0.69
0.02
18.4
31.8
41.8
53.8
82.8
Men
Women
95% CI
0.16
0.10
p trend
Total fruits and vegetables
1
2
3
4
5
95% CI†
0.54
p trend
Juice
1
2
3
4
5
Men
Men
OR†
Fruits
1
2
3
4
5
Cases vs. community controls
0.67,
0.51,
0.45,
0.56,
2.01
1.35
1.26
1.67
0.58
1.18
1.94
1.38
1.66
1.00
0.76
0.95
0.46
0.60
0.45,
0.56,
0.27,
0.32,
1.30
1.61
0.80
1.12
0.20
* Adjusted for age (continuous), energy intake (continuous), fat intake (continuous), body mass index (continuous), smoking status (never,
current, former), alcohol status (nondrinker, former drinker, current drinkers consuming <1 drink/week, current drinkers consuming ≥1
drink/week), nonsteroidal antiinflammatory use (yes, no), multivitamin use (yes, no), and hormone replacement therapy use (yes, no in women
only).
† OR, odds ratio; CI, confidence interval.
For men, fruit, juice, and total fruit and vegetable intakes
were not associated with adenoma risk in comparisons with
either control group. However, high vegetable consumption
was associated with a 45 percent reduced adenoma risk for
men in comparison with the community controls but was not
associated with adenoma risk in comparison with the
colonoscopy-negative controls.
Because the glycemic index has been positively associated with the risk of colorectal cancer (37, 38), we repeated
our analyses for fruits, vegetables, and total fruits and vegetables after excluding bananas and potatoes, two commonly consumed foods in our study population that have a
high glycemic index (39). The results were essentially
unchanged from those presented in table 2. For example, for
comparisons with the colonoscopy-negative controls, the
odds ratios for women comparing the highest versus lowest
Am J Epidemiol Vol. 155, No. 12, 2002
quintile of intake were 1.34 (95 percent confidence interval
(CI): 0.57, 2.20) for fruits excluding bananas, 1.33 (95 percent CI: 0.70, 2.54) for vegetables excluding potatoes, and
0.84 (95 percent CI: 0.42, 1.67) for total fruits and vegetables excluding bananas and potatoes. For the same comparisons, the odds ratios for men were 0.61 (95 percent CI:
0.33, 1.14), 0.72 (95 percent CI: 0.38, 1.35), and 0.75 (95
percent CI: 0.33, 1.47), respectively.
Additional adjustment for dietary fiber intake did not materially change the results for fruits, vegetables, juice, and total
fruits and vegetables (data not shown). Simultaneous adjustment for fruits, vegetables, and juice on a continuous scale
(data not shown) also did not substantially change the results
observed when each group was included in a separate model.
Results restricted to cases with distal adenomas (data not
shown) were similar to those reported for all cases.
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Smith-Warner et al.
TABLE 4. Multivariate-adjusted odds ratios* for colorectal adenomas by tertile of botanical and phytochemical groups,
Minnesota Cancer Prevention Research Unit case-control study, 1991–1994
Mean intake
(servings/week)
Cases vs. colonoscopy-negative controls
Food group tertile
Women
Women
Cruciferae (broccoli, cabbage,
cauliflower)‡
1
2
3
1.0
2.4
6.7
0.6
1.7
4.9
95% CI†
OR
95% CI
OR
95% CI
OR
95% CI
1.00
0.82
1.39
0.51, 1.33
0.89, 2.19
1.00
0.97
1.00
0.63, 1.48
0.64, 1.54
1.00
0.66
1.37
0.40, 1.09
0.83, 2.25
1.00
0.81
0.84
0.55, 1.21
0.56, 1.25
0.19
0.2
1.2
3.7
0.0
0.7
2.8
1.00
0.97
1.16
1.0
2.2
5.0
1.00
0.96
1.08
p trend
Liliaceae (garlic, leeks, onions)
1
2
3
0.5
2.6
9.1
0.6
2.0
7.5
1.00
1.61
1.37
1.00
1.35
1.11
1.1
3.8
10.5
0.8
3.0
9.4
1.00
1.16
1.20
0.61, 1.50
0.68, 1.74
1.00
1.30
0.96
0.7
4.0
10.9
1.00
1.04
1.00
p trend
1.02, 2.54
0.86, 2.20
1.00
0.99
0.90
1.00
0.77
1.07
1.00
1.08
0.91
0.82, 2.05
0.62, 1.49
1.00
0.99
0.96
1.00
0.88
0.70
0.50, 1.19
0.70, 1.65
0.60, 1.62
0.58, 1.59
1.00
1.13
0.92
0.69, 1.85
0.56, 1.54
1.00
0.91
1.10
0.55, 1.50
0.64, 1.89
1.00
1.08
1.15
1.00
1.42
0.64
0.85, 2.36
0.38, 1.10
0.07
0.72, 1.62
0.77, 1.72
0.86
1.00
0.78
0.80
0.52, 1.19
0.54, 1.18
0.41
1.00
0.94
0.74
0.63, 1.40
0.48, 1.13
0.25
0.98
0.57, 1.36
0.44, 1.11
0.56, 1.30
0.43, 0.99
0.01
0.60
0.71, 1.66
0.57, 1.45
0.61
1.00
0.85
0.65
0.40
0.31
0.67, 1.62
0.61, 1.66
0.60, 1.63
0.55, 1.49
0.74
0.40
0.79
0.73, 1.85
0.73, 1.99
0.72
0.88, 2.08
0.70, 1.74
0.26
0.41
0.7
4.1
10.7
0.44
0.13
0.29
p trend
Rutaceae (grapefruits, oranges,
tangerines)
1
2
3
0.61, 1.55
0.73, 1.86
0.68
p trend
Rosaceae (apples, peaches, pears)
1
2
3
0.37
0.94
1.1
2.4
5.5
Men
Women
OR†
p trend
Leguminosae (alfalfa sprouts,
beans, peas)
1
2
3
Men
Men
p trend
Cucurbitaceae (cucumbers, melons,
squash)
1
2
3
Cases vs. community controls
1.00
1.19
0.85
0.79, 1.79
0.56, 1.29
0.67
Table continues
We classified fruits and vegetables into botanically and
phytochemically defined groups in an attempt to identify particular types of fruits and vegetables that have high cancerpreventive activity. For example, the fruits of the Rutaceae
family (i.e., citrus fruits) are rich sources of vitamin C and
monoterpenes (40). Tertiles were used to categorize persons
because of the narrow range of intakes reported for these
groups. Strong associations were not observed for most of the
groups, and those observed were generally limited to comparisons with only one control group (table 4). For women, the
Rutaceae family (citrus fruits, including juice) was the only
botanical family for which an association was suggested. In
the comparison with the community controls, adenoma risk
was approximately 40 percent lower for the highest versus
lowest tertile of intake of the Rutaceae family (odds ratio (OR)
0.64, 95 percent CI: 0.38, 1.10; p trend 0.07). No association was observed in the comparison with the colonoscopynegative controls. In contrast, elevated consumption of the
Solanacea family was associated with at least a 35 percent
higher risk (not statistically significant) in comparisons with
both control groups. For men, the strongest association was
observed for fruits and vegetables with a high level of
Am J Epidemiol Vol. 155, No. 12, 2002
Fruits, Vegetables, and Adenomatous Polyps 1109
TABLE 4. Continued
Mean intake
(servings/week)
Cases vs. colonoscopy-negative controls
Food group tertile
Women
Women
Solanaceae (peppers, potatoes,
tomatoes)
1
2
3
2.7
5.6
10.6
2.8
5.6
10.7
OR
95% CI
OR
95% CI
1.00
1.49
1.36
0.94, 2.36
0.83, 2.25
1.00
1.48
1.21
0.96, 2.28
0.76, 1.93
1.00
1.21
1.80
1.0
3.1
7.1
1.00
1.36
1.38
1.6
4.4
11.3
1.0
2.8
8.2
1.00
1.31
1.46
1.00
0.95
0.66
2.8
6.9
14.8
2.2
5.1
10.9
1.00
1.39
1.28
0.82, 2.10
0.89, 2.40
1.00
1.31
0.97
0.3
1.3
4.7
1.00
1.12
1.30
p trend
0.89, 2.17
0.78, 2.12
0.85, 2.03
0.61, 1.53
1.00
0.97
0.74
0.63, 1.49
0.47, 1.17
1.00
1.32
1.14
0.87, 2.02
0.72, 1.80
0.82
OR
95% CI
0.74, 1.97
1.04, 3.13
1.00
0.65
0.57
0.43, 0.99
0.36, 0.88
0.71, 1.94
0.61, 1.66
0.05
1.00
0.52
0.66
0.97
1.00
0.89
0.94
0.34, 1.48
0.54, 1.62
1.00
0.99
0.73
0.60, 1.64
0.42, 1.27
1.00
0.94
0.85
0.63, 1.76
0.61, 1.56
0.32
0.63, 1.42
0.55, 1.31
0.21
1.00
0.89
0.72
0.76
1.00
1.05
0.98
0.35, 0.78
0.43, 1.00
0.10
0.77
0.55
0.70, 1.78
0.84, 2.01
0.71
1.00
1.17
1.00
0.70
0.10
0.6
1.8
5.0
0.61, 1.46
0.43, 1.04
95% CI
0.08
0.22
0.36
p trend
High lycopene (tomatoes, tomato
paste, watermelons)
1
2
3
0.86, 2.14
0.86, 2.21
0.30
p trend
High lutein (broccoli, peas, spinach)
1
2
3
0.98
0.17
1.4
3.9
9.1
Men
Women
OR
p trend
High b-carotene (apricots, carrots,
sweet potatoes)
1
2
3
Men
Men
p trend
Green leafy vegetables (lettuce,
spinach, collard greens)
1
2
3
Cases vs. community controls
0.60, 1.33
0.48, 1.08
0.12
1.00
0.72
0.53
0.47, 1.09
0.34, 0.82
0.002
* Adjusted for age (continuous), energy intake (continuous), fat intake (continuous), body mass index (continuous), smoking status (never,
current, former), alcohol status (nondrinker, former drinker, current drinkers consuming <1 drink/week, current drinkers consuming ≥1
drink/week), nonsteroidal antiinflammatory use (yes, no), multivitamin use (yes, no), and hormone replacement therapy use (yes, no in women
only).
† OR, odds ratio; CI, confidence interval.
‡ Three fruits and vegetables from each botanical and phytochemical group are given as examples. For more detailed descriptions, see
Smith et al. (Cancer Causes Control 1995;6:292–302).
lycopene, with an odds ratio of 0.53 (95 percent CI: 0.34,
0.82; p trend 0.002), in a comparison of the highest versus
lowest tertile of intake in the comparison with the community
controls. Inverse associations also were observed for men for
the Cucurbitaceae and Solanaceae families and green leafy
vegetables in comparison with the community controls but not
in comparison with the colonoscopy-negative controls.
Intakes of fruits and vegetables and adenoma pathology
Because cases with adenomas of moderate or severe dysplasia may have a higher risk of developing recurrent adenoAm J Epidemiol Vol. 155, No. 12, 2002
mas or colorectal cancer (26, 41), we examined associations
separately for adenomas with mild dysplasia and adenomas
with moderate or severe dysplasia (table 5). For women, in
the comparison with the colonoscopy-negative controls, the
odds ratios for juice were stronger for cases having adenomas
of moderate or severe dysplasia than for cases having adenomas of mild dysplasia. A similar pattern of odds ratios was
observed for comparisons with the community controls (for
cases with moderate/severe dysplasia: OR 0.48 for highest
vs. lowest tertile, 95 percent CI: 0.25, 0.93; for cases with
mild dysplasia: OR 0.67, 95 percent CI: 0.35, 1.27). In contrast, a statistically significant, positive association was sug-
1110
Smith-Warner et al.
TABLE 5. Multivariate-adjusted odds ratios* for colorectal adenomas of differing dysplasia versus
colonoscopy-negative controls by tertile of fruit and vegetable intake, Minnesota Cancer Prevention
Research Unit case-control study, 1991–1994
Men
Women
Food group tertile
Fruits
1
2
3
Mild dysplasia
OR
95% CI
OR
95% CI
OR
95% CI
1.00
1.18
1.34
0.64, 2.18
0.67, 2.67
1.00
0.90
1.34
0.49, 1.63
0.67, 2.66
1.00
0.93
0.85
0.52, 1.64
0.45, 1.59
1.00
0.92
0.65
0.56, 1.52
0.36, 1.17
0.76
1.00
1.39
1.68
p trend
0.75, 2.55
0.86, 3.27
1.00
0.96
0.61
0.54, 1.71
0.33, 1.15
1.00
1.52
1.82
0.70, 2.39
0.58, 2.55
0.93
0.84, 2.77
0.93, 3.54
1.00
1.13
0.98
1.00
0.99
0.43
0.57, 1.72
0.22, 0.81
1.00
1.12
1.02
0.51, 1.74
0.72, 2.96
0.44
1.00
1.26
1.12
0.64, 1.97
0.59, 1.78
1.00
1.06
0.76
0.60, 1.88
0.38, 1.50
0.40
0.76, 2.07
0.64, 1.96
0.74
1.00
0.96
0.68
0.70
0.05
1.00
0.95
1.46
0.65, 1.97
0.52, 1.85
0.13
0.52
0.04
0.10
1.00
1.29
1.22
0.31
0.68
0.45
p trend
Total fruits and vegetables
1
2
3
Moderate/severe
dysplasia
95% CI†
p trend
Juice
1
2
3
Mild dysplasia
OR†
p trend
Vegetables
1
2
3
Moderate/severe
dysplasia
0.58, 1.58
0.41, 1.12
0.44
1.00
1.16
0.89
0.71, 1.92
0.45, 1.46
0.24
* Adjusted for age (continuous), energy intake (continuous), fat intake (continuous), body mass index
(continuous), smoking status (never, current, former), alcohol status (nondrinker, former drinker, current drinkers
consuming <1 drink/week, current drinkers consuming ≥1 drink/week), nonsteroidal antiinflammatory use (yes,
no), multivitamin use (yes, no), and hormone replacement therapy use (yes, no in women only).
† OR, odds ratio; CI, confidence interval.
gested for vegetable consumption in both groups of cases in
comparisons with the colonoscopy-negative controls.
Weaker, nonsignificant associations were observed in comparisons with the community controls. For men, stronger
associations with fruit and juice consumption were suggested
for cases having adenomas with moderate or severe dysplasia
in comparisons with both control groups (data not shown for
comparisons with the community controls).
DISCUSSION
Although fruits and vegetables contain a multitude of
compounds that have been shown to have potential cancerpreventive activity (40), our study adds to the evidence
suggesting that fruits and vegetables are not strongly associated with the risk of adenomatous polyps. In comparisons with each control group, a statistically significant
reduction in the risk of adenomas was observed only for
juice intake in women. The association was stronger
among cases with moderate or severe dysplasia versus
mild dysplasia. Because orange juice (the most commonly
consumed fruit and vegetable in this population) is a pri-
mary contributor to folate intake in the United States (42),
the inverse association observed for juice is consistent
with our previous report that higher levels of dietary folate
are associated with a lower risk of adenomas (43). Results
for fruits, vegetables, total fruits and vegetables, green
leafy vegetables, and the botanically and phytochemically
defined subgroups generally were not statistically significant. If significant associations were observed for these
groups, they were restricted to either women or men in
comparison with only one of the control groups; thus, it is
likely they may be chance findings.
As in our study, most studies of adenomatous polyps have
reported that fruit and vegetable consumption is not associated with the risk of adenomas, although the risk estimates
generally have been in the protective direction (4, 7). For
fruit intake, only two (12, 20) of 12 (8–10, 12–15, 18–22)
studies have reported statistically significant inverse associations. In one study, women in the highest quartile of fruit
consumption had about half the risk of adenomas as did
women in the lowest quartile (OR 0.44, 95 percent CI:
0.20, 0.95) (12). A somewhat weaker, but statistically nonsignificant association was observed for men in this study
Am J Epidemiol Vol. 155, No. 12, 2002
Fruits, Vegetables, and Adenomatous Polyps 1111
(OR 0.60, 95 percent CI: 0.24, 1.52). Fruit consumption
was associated with a modest reduction in adenoma risk in
a cohort of 51,529 male health professionals (relative risk 0.73 for comparison of the highest vs. lowest quintile of
intake, 95 percent CI: 0.54, 1.00) (20). In contrast, in a
Norwegian case-control study, in comparison with the
colonoscopy-negative control group, fruit consumption was
associated with a fivefold higher risk of adenomas and, in
comparison with the population-based control group, with a
nonsignificant threefold higher risk (22). Juice rarely has
been evaluated as a separate category (18).
Vegetable intake has been significantly, inversely associated with adenoma risk in three (8, 14, 18) of nine (8, 9, 11,
12, 14, 15, 18–20) studies. In two (8, 18) of the three studies with statistically significant results, the risk of developing adenomas was 50–75 percent lower in the highest versus
lowest vegetable consumers; in the third study (14), the
association was slightly weaker and statistically significant
only for adenomas in the distal colon. The null results generally observed in the adenoma studies contrast with the
consistent inverse association observed in case-control studies of colorectal cancer risk and vegetable intake (1, 2, 4, 5,
7). A potential explanation for the discrepancy between the
adenoma and colorectal cancer studies may be that vegetables have a more pronounced effect in later stages of colorectal carcinogenesis. The cases in two (8, 14) of the three
(8, 14, 18) adenoma studies that reported significant inverse
associations for vegetable intake had advanced adenomas.
In the study by Benito et al. (8), most adenomas were larger
than 1 cm in diameter, and in the study by Kato et al. (14),
stronger associations were observed for cases with multiple
adenomas compared with single adenomas. In contrast, the
polyps in our study were generally isolated, small, tubular
adenomas.
Alternatively, recall bias in case-control studies of colorectal cancer may contribute to the discrepancies in the
associations observed among case-control studies of colorectal cancer and studies of adenomatous polyps, as well
as cohort studies of colorectal cancer. In cohort studies,
dietary information is collected prior to the development
of the disease, thereby reducing recall bias. Case-control
studies of adenomas also may be less susceptible to recall
bias than are case-control studies of colorectal cancer,
because adenomatous polyps frequently are asymptomatic
(44). In contrast, because symptoms of colorectal cancer
(45) may result in dietary changes prior to diagnosis, recall
bias may be more problematic in case-control studies of
colorectal cancer. A study comparing dietary intakes covering the same time period but collected 7 years apart
found lower correlations in persons who had changed their
diet over the 7-year period compared with persons whose
diets had not changed (46).
In our analyses, we evaluated associations separately for
women and men. Men have a higher risk of colorectal cancer (1, 47) and adenomas (30) than women have. In addition, it has been hypothesized that adenomas in women
may have more neoplastic potential than do adenomas in
men because the difference in adenoma prevalence
between women and men is believed to be greater than the
Am J Epidemiol Vol. 155, No. 12, 2002
difference in colorectal cancer incidence (30). Other studies examining fruit and vegetable intakes have indicated
differences in the associations observed for women and
men for both colorectal cancer (48, 49) and adenomas (12,
17). Differences in hormone levels, including the use of
exogenous hormones, colorectal epithelial cell proliferation, transit times, fecal mass, and fecal bile acid composition may contribute to these differences in risk between
women and men (31–35).
Multiple control groups were included in our analyses to
enable comparisons of cases with control groups with
inherently different advantages and disadvantages. The primary advantage of the colonoscopy-negative control group
is that all colonoscopy-negative controls had received a
complete colonoscopy and were determined to be polyp
free, thereby reducing misclassification in the outcome.
Recall bias also was probably minimized for comparisons
of cases with colonoscopy-negative controls, because both
sets of participants completed the study questionnaires
prior to receiving their colonoscopy and diagnosis.
However, because participants in these groups had an indication for receiving a colonoscopy, lifestyle factors, including diet, may have been too similar between the
colonoscopy-negative controls and cases, resulting in attenuation of the associations observed. This type of attenuation should not have occurred in comparisons with the
community control group. However, because the current
polyp status of the community control group participants
was unknown, associations may have been attenuated by
the inclusion of persons with polyps in this control group.
Thus, with either control group, some attenuation of associations is possible but for different reasons.
Most limitations of this study are specific to using a casecontrol study design. Because the response rate was 65–68
percent across the three study groups, selection bias could
affect the validity of our results. Generalizability also is limited because study participants were relatively homogeneous for several sociodemographic variables. In addition,
participants may have overestimated their fruit and vegetable consumption as a result of increased awareness of the
potential cancer-preventive effects of fruits and vegetables
(4–7) or social desirability bias.
In conclusion, our results show that fruit and vegetable
intakes generally were not associated with the risk of adenomatous polyps, although we did show a statistically significant inverse association for juice consumption in
women in comparisons with each control group. Because
previous studies, as well as our study, suggest that fruits
and vegetables may be more strongly associated with adenomas with greater malignant potential and because elevated fruit and vegetable consumption has been associated
more consistently with a lower risk of colorectal cancer
than of adenomas (1, 2, 4, 5, 7), fruits and vegetables may
have a stronger role in preventing the progression of adenomas to carcinomas than in preventing the initial appearance of adenomas. Further research aimed at identifying
factors that lead to the progression of adenomas may help
to clarify the role of fruits and vegetables in colorectal cancer prevention.
1112
Smith-Warner et al.
ACKNOWLEDGMENTS
This research was supported by National Cancer Institute
grants P01 CA50305 and T32 CA 09607 to Dr. Potter.
The authors thank the physicians, nurses, and patient
coordinators of Digestive Healthcare, PA, for recruitment of
colonoscopy patients and Dr. Phyllis Pirie and the staff of
the Minnesota Cancer Prevention Research Unit Survey
Core for recruitment of community controls. They also are
grateful to Laura Sampson and Steven Stuart of Harvard
University for their assistance with analyses of the food frequency questionnaires.
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