ICANCER RESEARCH56, 5192-5197. November 15.

19961

Gender Differences in Smoking and Risk for Oral Cancer'

Joshua E. Muscat,2 John P. Richie, Jr., Seth Thompson, and Ernst L. Wynder
Divisions

ofEpidemiology

(J. E. M., S. T., E. L. W.j and Nutritional

Carcinogenesis

If. P. RI,

ABSTRACT
Based on studies that show gender differences in cigarette smoking and
lung cancer risk, we hypothesized that sex differences also exist in the risk
for cancer of the oral cavity and pharynx. A hospital-based study of 1009
patients with oral neoplasla and 923 age-matched controls was conducted
from 19811990.
All subjects were interviewed directly with an extensive
questionnaire containing items on tobacco smoking, alcohol consumption,
and occupational exposures. Using a cumulative lifetime measure of ex
posure

to cigarette

tar,

the

adjusted

odds

ratio

for

men,

according

to

increasing quartile of tar consumption and relative to never smokers, was

1.0 195% confidence interval (CI), 0.61.6)for the lowest category, 0.9
(95%

CI, 0.61.6)for the second category,

1.6 (95%

CI, 1.02.5)for the

third category, and 2.1 (95% CI, 1.43.2)

for the highest category. Among
women, the corresponding odds ratios were 1.8 (95% CI, 1.13.0),
2.8

American

Health

Foundation.

New

York, New

York 10017

sex, age (five years), race, and date of admission (three months). Eligible
patients were identified from daily hospital admission logs. Ninety-one percent
of cases and 97% of controls who were approached agreed to be interviewed
by a trained

interviewer

and signed consent

forms. Within

each hospital,

cases

and controls were interviewed by the same interviewer.

The most detailed section of the questionnaire contained data on lifetime
smoking

history.

Subjects

were asked to provide

information

for each brand of

cigarette smoked, the age they started smoking, and the duration and frequency

of smoking. Never smokers were those who never smoked cigarettes regularly.
Current

smokers

were

defined

as subjects

who

had

smoked

at least

one

cigarette/day during the past year. Ex-smokers were quitters who had not
smoked within the past year. The tar content of the brand of cigarette was
obtained from the 1977 and 1988 Federal Trade Commission reports (14). A
cumulative tar yield measure was obtained by the following formula:

(95% CI, 1.64.9), 3.2 (95% CI, 1.95.6),and 4.6 (95% CI, 2.58.7). The

T=@(t1XDXC1)X

106

linear increase in risk was significantly higher for women than for men.
Among nonsmoking cases, there was a significantly higher proportion of
women than men over the age of 50 years. This was consistent for all
subsites within the oral cavity. These findings support the hypothesis that
there are gender differences in the smokiag-related risks for oral cancer
and in the risk for nonsmoking-related oral cancer as well. The role of
nutrition in relation to these findings is discussed.

where t = tar content in milligrams, D

days of smoking, and
C = number of cigarettes smoked (3). The cumulative tar yield was
divided into quartiles based on the distribution of smokers in the entire
control group (e.g., men and women combined), and subjects were
compared to never smokers when calculating ORs. Likewise, a pack
year measure was calculated by multiplying the years of smoking by
the number of packs smoked/day for each brand of cigarette. Detailed
INTRODUCTION
questions were asked on current alcohol consumption including beer,
wine, and hard liquor. Alcohol consumption was divided into several
Cigarette smoking is the predominant cause of cancer of the lung,
categories. Nondrinkers were classified as subjects who never con
oral cavity, and pharynx. The risk of lung cancer is higher in women
sumed alcohol or drank less than one drink/week. Occasional drinkers
than in men per cumulative dose ofcigarette smoking (18),and there
include subjects who drank > I drink/week and <1 drink/day. Sub
is limited evidence that women have a higher susceptibility to tobacco
jects were asked to give a detailed employment history including job
smoke carcinogens than men (9, 10). These observations, and a
title and type of occupation. For each job, subjects were asked
previous analysis of risk factors for oral cancer by our group showing
whether they had been exposed to one or more of 45 occupational
higher ORs3 for current smokers in women than in men (1 1), led us
exposures including hydrocarbon emissions and fumes, solvents, met
to hypothesize that female smokers are also at higher risk for oral
als, chemicals, dyes, dusts, and fibers for at least 8 h/week for one
cancer than male smokers. In the current paper, we examine the
year or more.
association of smoking by gender on the development of oral cancer.
Gender specific ORs and 95% CIs for tar quartiles were calculated.
Because alcohol consumption is a cofactor in oral carcinogenesis (12,
Unconditional multiple logistic regression analysis was performed to
13), the risk estimates were adjusted for levels of alcohol intake.
obtain maximum likelihood estimates of ORs, adjusted for the con
Subjects (men) who smoked pipes or cigars were excluded from the
tinuous covariates age (five ordinal levels) and education (four ordinal
analysis. In addition, we examine the epidemiology of oral cancers in
levels). Additional terms for religion, marital status, race, and body
nonsmokers.
mass index were tested by the likelihood ratio statistic. In models that
evaluated trends and interactions, T was treated as continuous by
assigning the median cumulative tar yield value for each of the four
MATERIALS AND METHODS
categories. The confounding or interaction effects of alcohol con
A hospital-basedstudy of oral cancer was conducted between 1981 and sumption were also modeled as a continuous variable by assigning
1990 (see Acknowledgments).
Case patients were men and women between
median values to each category of consumption. To determine
the ages of 21 and 80 years with newly diagnosed histologically confirmed whether the effects of smoking were significantly greater for women
cancer of the oral cavity and pharynx (lCD, 9th Revision, codes 141, 143146,
than for men, a model that combined all subjects was evaluated, and
148, and 149). Patients with cancer of the salivary gland (lCD 142) and
an interaction term for gender and tar was tested. The fit of the final
nasopharynx (lCD 147) were excluded. Controls were hospital patients admit
ted for conditions unrelated to tobacco use. Controls were matched to cases by models was evaluated by plotting the changes in the Pearson f
against the estimated logistical probabilities (15).
Received 5/31/96; accepted 9/19/96.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
I Supported

By

2 To

requests

whom

NIH

Grants
for

DE-09514,

reprints

should

CA-68384,
be

addressed,

CA-32617,
at

Division

and

CA-17613.
of

Epidemiology,

American Health Foundation, 320 East 43rd Street, New York, NY 10017.
3 The

abbreviations

used

are:

tional Classification of Diseases.

OR,

odds

ratio;

CI,

confidence

interval;

lCD,

Interna

RESULTS
Partial or complete information on brands of cigarettes smoked was
missing for 56 cases and 60 controls. This left a final sample of 1009
cases (687 men and 322 women) and 923 controls (619 men and 304
women). The subsite distribution among cases was similar for men

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GENDER AND ORAL CANCER

990MalesFemalesCases
Table1 Characteristics
of oral cancer

and women (tongue, 34.0 and 35.1%; floor of mouth, 27.5 and 27%;
palate, 11.5 and 11.2%; pharynx, 9.9 and 10.6%; tonsil, 10.8 and

Among women, 61 % of cases and 21 % of controls were current

smokers. There were some differences in the prevalence of smoking
when the case subjects were stratified by subsite. Male cases with
cancer of the tongue had the lowest prevalence of current smoking
(57%), and cases with cancer of the mouth floor had the highest
prevalence (74%). Among women, the smoking prevalence was also
lowest for the buccal mucosa (2 of 10 cases) and tongue (53%) and
highest for the floor of mouth (75%). The case-control differences in
alcohol consumption were even more marked than those for cigarette
consumption. Among men, 83% of cases and 70% of controls con
sumed at least one alcoholic drink/day, and 45% of cases and 16% of
controls took seven or more drinks/day. Among women, the corre
sponding figures were 47 and 20% for at least one drink/day and 14
and 1% for seven or more drinks/day.
Table 2 provides the adjusted ORs associated with cumulative tar
intake by quartiles relative to never smokers. Comparing men to
women, the OR was 1.0 (95% CI, 0.61.6) versus 1.8 (95% CI,
1.13.0)for the lowest quartile, 0.9 (95% CI, 0.61.6) versus 2.8
(95% CI, 1.64.9) for the second quartile, 1.6 (95% CI, 1.02.5)
versus 3.2 (95% CI, 1.95.6)for the third quartile, and 2. 1 (95% CI,
1.43.2)versus 4.6 (95% CI, 2.58.7)for the upper quartile. A linear
increase in risk was statistically significant for both men and women
(P < 0.01). When smoking-risk estimates were calculated according
to pack-years, similar results were found (Table 2). Combining men
and women together, the effect of cumulative tar intake and of
pack-years, as modeled by a gender X smoking interaction term, was
significantly higher for women than for men ((3 = 0.1 1; P < 0.01). In
contrast, there was no significant gender X alcohol interaction after
adjusting for tar.
The stratified analysis (Table 3) shows that for almost every smok
ing/alcohol category, the risks are higher for women than for men. In
men, there was no increased risk associated with smoking in never
drinkers. Elevated risks were observed only for high levels of lifetime

8.1%;buccalmucosa,2.3and3.1%;andretromolartrigone,3.9and

tar intake (>3.5

5.0%). Ninety-two percent of cases had a histological designation of

squamous cell carcinoma. Controls were patients with cancer (large
bowel, breast, prostate, skin, or lymphoma), 44.3%; benign neoplastic
disease, 7.3%; and a variety of nonneoplastic conditions, 48.4% (e.g.,
injuries, fractures, spinal disc problems, hernia, gall bladder disorders,
gemtounnary disorders, cataract, osteoarthritis, and so forth).
Table 1 shows that cases and controls were similar in age. Male
cases were less educated than their controls (P < 0.01). Eighty-nine
percent of cases and 92% of controls were white. Almost all other
subjects were black. A greater proportion of controls than cases
reported Jewish as their religious affiliation (P < 0.01). As expected,
cases were more likely to have smoked cigarettes than controls.
Among men, 67% of cases and 35% of controls were current smokers.

women, increased risks were observed for all levels of smoking and
alcohol intake. The one category where equivalent or higher ORs were
observed for men than women was the heaviest alcohol drinkers (>4
drinks/day). However, the ORs for women in this category were
highly unstable because there were only two female cases and one
female control who never smoked cigarettes. Further modeling of this
data revealed a significant interaction between smoking (ever versus
never) and alcohol consumption for both men and women. A separate
model revealed that each tar quartile X alcohol term was statistically
significant, although the (3 coefficient slopes did not vary. Regression
diagnostic plots did not reveal any large values that indicated a poor
fit.
In never smokers, there was no increased risk associated with

ControlsCharacteristic(n
%Age<5023.7

ControlsCases

= 687) %

(n = 619) %(n

19.4505935.4
32.2606931.3
31.37o9.6
17.1Education'@(yr)l229.8

22.318.0
35.133.9
32.330.8

19.41233.2
40.1131514.7
20.7l622.3
19.7ReligionProtestant39.9

26.321.7
25.539.4
20.221.7
28.017.1

32.6Catholic50.7

22.323.9

23.7Cigarettes/cla@12039.9

35.460.9
42.315.2

69.2213919.2
16.94041.0
13.9Alcohole0l/wk8.5

51.853.1
21.120.9
27.126.0

60.1Occasional8.1

28.636.4

19.814/thy23.6
16.246/day14.9
3.07/day44.9

18.016.9
26.824.7
26.67.8
16.414.1

b For

men,

X2

d Current

17.9;

@2=

C Excludes

pipe

304)

5.22.8

54.9Current66.8
21.4Former23.0

men,

(n

32.544.7
48.546.6
13.95.9

3.0SmokingcNever10.2

,For

322) %

10.317.4

45.4Jewish5.2
19.1Other/none4.1

parients and controls, 1980 1

33.1;
and

<

P <

cigar

1.0

0.01.

0.01;

for

women,

28.1;

P <

0.01.

smokers.

smokers.

e Occasional drinkers include >1 drink/week

and < 1 drink/day.

19801990MenWomenCases
Table 2

Variable

(n = 687) %

Cumulative tar (kg)

0
<1.4
1.43.5

Adjusted ORsfor smokingand

kg) and daily or greater

alcohol

consumption.

Among

oralcancer,

CICases

Controls (n = 619) %OR95%

(n = 322) %Controls

(n

304)

OR

95% CI

10.222.31.023.954.91.08.916.01.00.61.614.618.11.81.13.014.419.20.90.61.618.611.22.81.64.925.319.71.61.02.526.410.93.21.95.641.222.82.11.43.216.54.94

3.56.8
>6.8
Pack-years

10.2

22.3

1.0

23.9

54.9

1.0

119

10.0

21.2

0.7

0.51.1

15.1

21.8

1.6

1.02.6

2039

20.7

21.3

1.4

0.92.1

22.4

12.1

3.3

2.05.9

4059

27.1

17.5

2.0

1.33.1

23.7

6.8

5.5

2.910.1

>60

31.9

17.7

2.2

1.43.3

14.8

4.4

5.3

a Adjusted

for

age,

education,

alcohol,

religion,

and

body

mass

index.

Tests

for

linear

trend

in

tar

and

pack-years

were

statistically

significant

at

<

0.01

for

both

2.511.3
men

and

5193

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women.

GENDER

AND ORAL CANCER

Table 3 ORs of smoking and oral cancer by levels of alcohol consumption

Reference category is never smokers. All ORs adjusted for age and education. Numbers in parentheses are numbers of cases and controls.
A.MenCumulative
l/wkOccasional1-4/day>4/day<1.40.7
TarAlcohol0<
0.31.8
(8, 29)0.9

7)1.43.50.30.11.1

0.32.3
(10, 21)1.0

0.42.1
(21, 34)2.1

0.75.9
(14,
1.16.6

21)3.56.81

(4, 29)0.50.21.5
.0 0.52.6

(6, 24)1.50.73.2
.2 0.43.7

(27, 29)2.7
.8 0.83.8

(49,
2.01
1.3

25)>6.81.00.42.8

(12, 19)1

(10, 18)1

(34, 31)4.7
1.15.2
(57, 40)6.1

(88,
2.614.4
(145,

36)B.WomenAlcohol0<

(13, 19)2.5

(8, 7)1.60.64.7

1/weekOccasional1-4/day>4/day<1.41.2

0.62.4
2)3.56.82.0
2)>6.82.4

a Greater

b Crude

than

ORs

or

and

equal

to

1/week

exact

confidence

0.54.3

(17,29)1.4
1.37.0
(16,11)1.2
1.04.0
(19, 20)5.8
0.86.9
(8, 7)16.7

3)1.43.53.0

and

less

limits.

than

Only

(10,15)5.9
0.43.6
(8,14)9.5
1.720.3
(15, 5)14.0
1.8152.6
(9, 1)18.6

two

female

cases

and

one

female

control

(95%CI, 0.61.2)
for occasional
drinkers,1.4(95%CI, 0.73.1)
for
14drinks/day, and 1.6 (95% CI, 0.64.2) for >4 drinks/day. In
women, the corresponding ORs were 0.9 (95% CI, 0.42.1),0.6(95%
CI, 0.21.4),and 4.6 (95% CI, 0.452.2).
Oral snuff use and chewing tobacco were unrelated to oral cancer
risk. Among men, 9 cases (1.3%) and 10 controls (1.6%) reported
using snuff at least once a week for one or more years. Among
women, only two cases and one control reported snuff use. Thirty
eight cases (5.5%) and 33 controls (5.3%) reported using chewing
tobacco at least once a week for at least one year. Among the tobacco
chewers, there were no case-control differences in the frequency of
chewing. None of the women reported using chewing tobacco regu
larly.
Among cases, the percentage of nonsmokers was greater in women
than in men (24 versus 10%). Table 4 shows the age distribution in the
nonsmoking cases. There were relatively more women than men over
the age of 50 (71 versus 51%; P < 0.05). The employment history of
all nonsmoking cases and controls was examined to determine possi
ble gender differences in chemical, environmental, or other exposures.
No pattern of risk was evident with any single occupation, categories
of similar occupations (e.g. , construction workers), or any specific
occupational exposures.

Table4 Agedistributionin nonsmoking

controlsNS
casesand
casesMen

WomenSite
<50 yr

(60.0%)Floor

18 (56.3%)

50 yr
14 (43.7%)

<50 yr
14 (40.0%)

50
21

14(82.4%)Palate

6 (42.9%)

8 (57.1%)

3 (17.7%)

(75.0%)Tonsil

5 (45.5%)

6 (54.5%)

3 (25.0%)

(100.0%)Other
(75.0%)TOtal'

2 (22.2%)
3 (75.0%)

7 (77.8%)
1 (25.0%)

0 (0.0%)
2 (25.0%)

5
6

(71.4%)NS

81.4%a
controls

34 (48.6%)

29.0%

36 (5 1.4%)

7 1.0%

0.0127.9
(6,

2.832.0
(19,7)4.3
4.148.5
(24, 6)6.5
4.086.8
(16, 3)2.40.0-55.1

0.1116.9
(17,
0.1174.2
(26,
(19,4)

1/day.

drinking. The adjusted OR for men, relative to never drinkers, was 1.2

yrTongue

1.720.5
(13,8)1.0

22 (28.6%)

18.6%

smokers.b
NS,
never

percentages.Differences
Percentages
are row

in age between men and women; P < 0.05.

55

were

never

smokers

in this

category.

DISCUSSION
Few reports have had gender-specific risk estimates for smoking
and oral cancer. A recalculation of case-control data published in 1957
by Wynder et a!. (16) yields a higher crude OR for women than men
(8.1 versus 4.6) associated with
21 cigarettes/day. In contrast,
slightly higher smoking-related risks were reported for men than
women in Puerto Rico in 1969 (17) and in a hospital-based study in
1977 (18). These early studies were conducted when men smoked
cigarettes with much higher tar content than women, and findings
were unadjusted for the higher tar intake and alcohol consumption in
men. More recently, in a population-based study of 1114 oral cancer
cases conducted by Blot et a!. (19), the alcohol-adjusted ORs for
women and men were I .0 versus 0.8 for 119pack-years, 2.9 versus
1.9 for 2039pack-years, and 5.0 versus 1.8 for 40+ pack-years. In
a pooled analysis of three large case-control studies of oral cancer,
Macfarlane et a!. (20) reported that the smoking OR in nondrinkers,
among men, was 1. 1 for 133pack-years and 1.3 for >33 pack-years.
In women, the OR in nondrinkers was 2.6 (P < 0.05) for 118
pack-years and 4.6 for >18 pack-years (P < 0.05). Using part of the
data from the current study, Kabat et a!. (11) found higher ORs for
women than men among current (4.3 versus 3.3) and former smokers

(1.4versus1.1).Thecurrentfindings showa significantly highertrend

in the ORs for women than men for both the cumulative tar measure
and the pack-year measure after adjustment for alcohol and other
confounding variables. Our data and those described by Blot et a!.
(19) both show that 40 pack-years of smoking approximately in
creases the risk of oral cancer 2-fold in men and 5-fold in women
relative to nonsmokers.
The prevalence of smoking was highest for subjects with cancer of
the mouth floor and lowest for cancer of the tongue in both men and
women. These findings are consistent with the results from earlier
case-control studies (16). The percentage of mouth cancers that were
located in the tongue and mouth floor was equal for men and women.
No significant interaction between gender and alcohol consumption
was found after adjustment for smoking, although these findings
should be interpreted with caution because the heaviest drinkers were
predominantly men and because of possible misclassification. In a
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GENDER AND ORAL CANCER

controlsMalesFemalesCasesControlsORCasesControlsORFilter
Table 5 Types of cigarette smoked among ever-smoking cases and

22.8
17.2
16.11.0

28.7
12.4
21.844.0

SW 20+

SW 119'
Nonfilter37.1

1.5
0.9
1.649.8

27.9
13.1
9.360.2

20.3
9.8
9.81.0

1.7
1.6
1.1

a SW, switched from smoking nonfilter to filter.

b Switched

from

smoking

nonfilter

to filter

20 years

before

diagnosis.

Switched from smoking nonfilter to filter 10 years before diagnosis.

case-control study of oral cavity cancer in Italy, Franceschi et a!. (21)

observed similar alcohol-related risks for men and women. We did
observe a significant interaction between ever smoking and alcohol in
both men and women, although this effect did not vary by levels of
lifetime tar consumption.
The main limitations of this study are its hospital-based nature and
lack of information on nutritional factors. Possible biases that could
account for the current findings include a greater underreporting of
smoking consumption in women than in men. However, Wagenknecht
et a!. (22) found no gender differences in the misclassification rates
(under 3% for white subjects) in a study of 3445 healthy reported
nonsmokers when validated against serum cotinine. Previous studies
of the reproducibility of questions on smoking and hard liquor con
sumption in this data found very high intraclass correlation coeffi
cients in men and in women (23). Still, the validity of reported alcohol
consumption in heavy drinkers may be problematic. Women may tend
to underreport heavy alcohol consumption as social drinking, although
this may occur among men as well. Some studies have demonstrated
the unreliability of self-reported alcohol consumption among problem
drinkers (24). Because relatively few women drink heavily, misclas
sification of heavy drinkers as moderate drinkers would result in a
slightly spurious effect associated with moderate levels of alcohol
consumption but would result in a substantial underestimation of risk
in the heavy alcohol consumption category.
When interpreting gender-specific risks in case-control data, it is
necessary to consider the absolute rates of cancer in nonsmokers.
In a pooled analysis, Risch et a!. (25) calculated that the female:
male ratio of age-adjusted lung cancer rates was 0.7. This differ
ence, which may reflect a greater exposure to occupational carcin
ogens (26, 27), does not account for the 23-foldhigher relative
risks of lung cancer among female smokers than male nonsmokers
(25). However, there is little population-based data of oral cancer
rates in nonsmokers. In a 1960 study of one million men and
women, Hammond (28) calculated a oropharyngeal mortality rate
of 7 per 100,000 in nonsmoking men ages 6579.This was based
on five deaths after three years of follow-up. The rate for women
in this age group was also seven, although this number included
larynx and esophagus deaths as well. Some data indirectly suggest
that men do not have a higher baseline risk of oral cancer than
women. For example, several studies have found little evidence for
occupational oral carcinogens (2936). Occupation and occupa
tional exposures were unrelated to oral cancer risk in this study.
The use of oral snuff may be associated with increased rates of oral
cancer in men (37), although combined data from the Mortality
Followback Survey and National Health Interview Survey show no
increased risk of oral cancer from any form of smokeless tobacco.
There has been an increase in the incidence of snuff use among
young men (38) and an increase in the incidence of tongue cancers
in men under age 40 since the 1950s in the United States (39, 40)
and Scotland (41). In our data, snuff use was unrelated to oral
cancer risk. This did not seem to reflect the low prevalence of snuff
use in controls (1 .6%). There was 80% statistical power to detect

an OR of 2.8 given this level of exposure in controls. Among the

nonsmoking

cases,

there

was a slightly

higher

percentage

of men

than women under the age of 40 (26% versus 18%), although this
difference was not statistically significant. If the age differences
between nonsmoking male and female cases do reflect a male
specific

risk factor

besides

snuff,

it would

not seem to account

for

the differences in smoking-related risks between men and women

in this study.
Possible biological explanations for the higher risks of oral
cancer

in women

than

in men

include

nutritional

deficiencies.

There was a higher proportion of nonsmoking female cases than

nonsmoking male cases (24% versus 10%). In nonsmoking cases
over age 50, there was a significantly greater percentage of women
than men (Table 4). Ahlbom was among the first investigators to
relate the occurrence of Plummer-Vinson
syndrome in Sweden

(42), a precancerous condition resulting from chronic iron defi

ciency

and associated

anemia

during

the menstrual

years,

to an

increased risk of oral and other cancers in almost exclusively older

women. Riboflavin deficiency is also characteristic of Plummer
Vinson disease. In a study of 810 mostly nonsmoking patients with
a variety of alimentary tract cancers in Sweden, Wynder et a!. (43)
found a higher percentage of women with oral cancer in older age
groups

than men with oral cancer

and a significant

association

with

Plummer-Vinson symptoms in these women. The similar findings

with respect to the higher prevalence of older women than men in
the current data could reflect a subclinical condition, similar to
Plummer-Vinson syndrome, associated with iron depletion and low
intake of vitamins and minerals. Iron and riboflavin deficiency in
mice leads to cell atrophy
in upper alimentary
tract epithelium,
conditions
similar to patients with Plummer-Vinson
disease (44

46). Subsequent

hyperplasia

has been observed

with riboflavin

deficiency
(42). Rats fed diets deficient
in zinc also have
morphological
changes in the buccal mucosa (47).

similar

Populations that consume low amounts of fruits experience

elevated rates of oral cancer. Decreased blood nutrients of vitamins
A and B2 and /3-carotene have been detected in patients with oral
cancer (48). Similarly, vitamin A-deficient animals are more
susceptible to tobacco smoke polycyclic aromatic hydrocarbons
(49). Nutritional deficiencies associated with oral cancer may also
arise indirectly through excessive alcohol consumption because a
large percentage of daily caloric intake in alcoholics comes from
alcohol (50). Intake of fruits and vegetables is likely to be low in
persons with excessive alcohol consumption. Alcohol consumption
can also directly inhibit the absorption of nutrients and vitamins

(51).
The effects of a higher absolute risk of oral cancer in nonsmoking
older women resulting from menstrual-associated nutritional deficien
cies during the reproductive

years would result in an underestimate

of

the smoking effects in women by increasing the numbers of nonsmok

ing female cases relative to nonsmoking male cases. However, al
though nutritional deficiencies may be a risk factor for oral cancer, the
etiology

of nonsmoking-related

oral tumors

remains

largely

unknown.

5195

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GENDER AND ORAL CANCER

women:examinationof the evidence.J. Natl.CancerInst.,88: 183192,

1996.

Only beer consumption in men and low body weight in women have
also been identified as possible causes (52). It has been hypothesized
that human papilloma virus may cause oral cancer in nonsmokers (53,

9. Ryberg, D., Hewer, A., Phillips, D. H., and Haugen. A. Different susceptibility to
smoking-induced DNA damage among male and female lung cancer patients. Cancer

Res., 44: 833839,1989.

54).We did not find anydifferencesin educationallevelsbetween 10. Muscat,J., Carmella,S., Scott,D., Hecht,S. S., Richie,J. P.,Jr. Genderdifferences
postmenopausal
unidentified

in the metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-l-(3pyridyl)-1-butanone (NNK). Proc. Am. Assoc. Cancer Res., 37: 253, 1996.
11. Kabat, G. C., Chang, C. J., and Wynder, E. L. The role of tobacco, alcohol use, and body

nonsmoking cases and controls. There may be other

risk factors

that are gender-specific

and thus could have

confounded our results.

Another possible interpretation of this data is that there is a
greater exposure to tobacco juice among female smokers than male
smokers. Filter cigarettes reduce the contact with tobacco juice
relative to nonfilter cigarettes and reduce the risk for oral cancer.
In the previous report by Kabat et a!. (1 1), the independent effects
of filter use compared to nonfilter use on the risk of oral cancer
were similar for men and women. Table 5 shows that few women
have smoked nonfilter cigarettes exclusively, whereas more men
have smoked nonfilter cigarettes exclusively. Thus, the current
findings are unlikely to be due to a greater oral contact with
tobacco juice among women.
Estrogens may be involved in the promotion of oral cancer. Using
the Surveillance, Epidemiology, and End Results (SEER) Program
data, Begg et a!. (55) found that women also had a higher risk than
men of developing second primaries of the head and neck, as well as
lung, esophagus, urinary bladder, and kidney cancers.
We noted that the higher proportion of postmenopausal cases,
compared to male cases over age 50, was reported as early as 1957
(16) and have suggested that possible risk factors more specific to
women include iron, vitamin, and mineral deficiency. In addition,
glutathione, an active antioxidant, is found to be depleted in the
elderly (56) and associated with age-related morbidity (57). Low
blood glutathione levels and low dietary glutathione intake may
also play a role in oral cancer risk (58). Further investigations
should consider the effects of age in nonsmokers by subsite.
Cancer of the tonsil in nonsmokers occurs almost exclusively in
older individuals, and this may provide further clues to the origins
of mouth cancer.

Island

Jewish

Hillside

Medical

Center,

New Hyde Park,

NY); Drs. Elliot Strong and Stimson Schantz (Memorial Sloan-Kettering

Cancer

Center,

New

York,

NY);

Dr. Linga

Raju

(Nassau

County

Medical

Center, East Meadow, NY); Dr. James Colberg (Thomas Jefferson University
Hospital,

Philadelphia,

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cancers. Cancer Res., 37: 46084622, 1977.

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women. in: W. Haenszel(ed.), National Cancer Institute Monograph 19,pp. 127204.

We thank Dr. Edith Zang for statistical assistance and comments. We are
grateful to the following collaborators: Dr. Edward S. Garrity, Jr. (Loyola
University Hospital, Chicago, IL); Dr. John Sharp (Hines Veterans Hospital,
Hines, IL); Dr. Christine Johnson (Henry Ford Hospital, Detroit, MI); Dr.
R. Rai (Long

16. Wynder,E. L., Bross,I. J., andFeldman,R. M. A studyof theetiologicalfactorsin

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ACKNOWLEDGMENTS

Kanti

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Gender Differences in Smoking and Risk for Oral Cancer

Joshua E. Muscat, John P. Richie, Jr., Seth Thompson, et al.
Cancer Res 1996;56:5192-5197.

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