Affiliations of authors: M. Frisch, J. Wohlfahrt, M. Melbye, Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institut, Copenhagen, Denmark; B. Glimelius, Department of Oncology, Radiology, and Clinical Immunology, University Hospital, Uppsala, Sweden; H.-O. Adami, Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden, and Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard University, Boston, MA.
Correspondence to present address: Morten Frisch, M.D., Ph.D., visiting scientist, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Executive Plaza South, Rm. 8015, Bethesda, MD 20892 (e-mail: frischm{at}mail.nih.gov).
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ABSTRACT |
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INTRODUCTION |
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SUBJECTS AND METHODS |
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A total of 417 patients with invasive or in situ anal cancer (324 women and 93 men,
84% invasive), 554 population control subjects (349 women and 205 men), and 534
cancer control subjects (343 women and 191 men) participated in telephone interviews about
possible risk factors for anal cancer. Participation rates and selected characteristics for the study
participants are shown in Table 1. Other aspects of the study have been
presented in separate reports on the impact of sexual behavior and venereal diseases (1) and on the impact of benign inflammatory anal lesions (9).
The study was approved by the scientific ethical committees in both participating countries.
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Multivariate logistic regression analyses identified independent predictors of risk. In
multivariate analyses, we adjusted for potential confounding by age, country, year of diagnosis,
years of school attendance (<10 years or 10 years), years of postgraduate education
(none,
3 years, or >3 years), smoker status (current smoker, former smoker, or lifelong
nonsmoker), and major sexual and venereal factors. In men, the sexual and venereal factors
included marital status (ever married versus never married), lifetime number of female sexual
partners (0, 1, 2 or 3, 4-9, or
10 partners), anogenital warts (yes or no), gonorrhea (yes or
no), and syphilis or hepatitis (yes or no). In women, sexual and venereal factors included marital
status (ever married versus never married), lifetime number of male sexual partners (0, 1, 2 or 3,
4-9, or
10 partners), practice of anal intercourse (yes or no), anogenital warts (yes or no),
gonorrhea (yes or no), and history of a sexually transmitted disease in the spouse (yes or no).
Previous observations that led to the present working hypothesis of a stronger role of
smoking in premenopausal than in postmenopausal women were based on the use of age as a
proxy for menopausal status (5,6). In an attempt to separate the effects of
the highly collinear variables age and menopausal status, we performed separate sets of
age-stratified analyses of the risk associated with current smoking in premenopausal women (age
groups: <45 years and 45 years) and postmenopausal women (age groups: <60 years,
60-69 years, and
70 years).
To evaluate whether smoking variables and hormonal factors were associated only with the
risk of those anal cancers containing high-risk HPV, we first compared the distributions of these
variables by use of likelihood ratio 2 tests or, for categorized continuous
variables, by use of Mantel-Haenszel
2 tests among patients whose anal
cancers were positive (272 women and 55 men) and patients whose anal cancers were negative
(32 women and 29 men) in a polymerase chain reaction-based test for the presence of 14
high-risk types of HPV (1). We also calculated two sets of ORs for
associations with smoking and hormonal variables, with the case group restricted to high-risk
HPV-positive and high-risk HPV-negative anal cancer patients, respectively.
All regression analyses were performed with likelihood ratio tests (10). In tests for linear trend, we treated categorical variables as continuous variables, and the numeric value assigned to a given category was chosen as the median value within the category. The log-linear assumptions inherent in these trend tests were checked by likelihood ratio tests. Statistical significance was set at the 5% level, and all P values presented are two-sided.
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RESULTS |
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In women, tobacco smoking was statistically significantly associated
with anal cancer risk (multivariate OR = 1.9; 95% confidence
interval [CI] = 1.3-2.8, for current smoking versus lifelong
nonsmoking), with a monotonic dose-response relationship between
pack-years of smoking and the risk (Table 2). No
consistent association was present between age at smoking initiation
and the risk. Multivariate analyses stratified by menopausal status
showed that current smoking was strongly linked to anal cancer risk for
premenopausal women (OR = 5.6; 95% CI = 2.4-12.7) but not for
postmenopausal women (OR = 1.3; 95% CI = 0.8-2.0) (Table
3).
The risk increased linearly by 6.7% (95%
CI = 3.0%-10.7%) per pack-year of smoking for premenopausal
women (P for trend <.001), as opposed to 1.4% (95%
CI = -0.2% to 3.0%) for postmenopausal women (P for
trend = .08). The smoker status was not statistically significantly
different between women whose anal cancer contained high-risk HPV (n =
272) and the few women (n = 32) whose anal cancer did not
(
2 = 1.46, 2 df; P = .48). For all
smoking variables, ORs calculated separately with high-risk
HPV-positive and high-risk HPV-negative anal cancer groups were rather
similar (data not shown).
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Current male smokers were not at statistically significantly higher risk than nonsmokers
(multivariate OR = 1.6; 95% CI = 0.8-3.3), and former male smokers
appeared to be at even lower risk than lifelong male nonsmokers (Table 2). For the 84 men whose anal cancer was examined for HPV, lifelong nonsmokers
harbored high-risk HPV in their tumor statistically significantly more often (89%) than
current smokers (60%) and former smokers (57%) (
2 =
6.50, 2df; P = .04). Thus, for men, any possible difference in virus-associated
anal cancer risk by smoking status became even more unlikely after we restricted the case group
to those 55 male patients (including 26 current smokers) whose anal cancer was positive for
high-risk HPV (multivariate OR = 1.0; 95% CI = 0.4-2.6, for current
smoking versus lifelong nonsmoking).
Menstrual and Reproductive Factors
Prompted by the support for the a priori hypothesis of a
stronger effect of smoking in premenopausal women than in
postmenopausal women, we did additional analyses to explore the role of
menstrual history, reproductive factors, and body composition. We found
a strong positive association with age at menarche. Univariate analyses
showed that women whose menstrual periods started at or after the age
of 17 years were at 2.6 times higher relative risk than women who
started menstruating at age 12 years or earlier (P for trend
<.001). This trend was further strengthened after control for
confounding by sexual and other variables (Table 4).
Menopausal age appeared not to be associated with risk, but women with
a short fertile period (interval between menarche and menopause) were
at increased risk (multivariate OR = 2.8; 95% CI = 1.2-6.7, for
<25 years versus
35 years) (Table 4)
. When entered
simultaneously in the multivariate model, both age at menarche and
length of the fertile period retained statistical significance (P<.05).
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A comparison between case women with high-risk HPV types in the tumor tissue and case
women without detectable high-risk HPV DNA revealed no statistically significant differences in
distributions of any of the menstrual and hormonal variables in Table 4.
Accordingly, ORs obtained with the case group restricted to either high-risk HPV-positive or
high-risk HPV-negative anal cancer patients were almost identical (data not shown).
Body Mass Index
Participants were divided in groups according to the quartile
distribution of body mass index (BMI) among population control subjects
(Table 1). Women, but not men, with anal cancer were leaner than
control subjects in multivariate analysis (P for trend = .04),
and they statistically significantly more often belonged to the two
lowest than the two highest categories of premorbid BMI (multivariate
OR = 1.8; 95% CI = 1.3-2.4; P<.001). Further
adjustment for age at menarche did not materially change this
association (multivariate OR = 1.7; 95% CI = 1.2-2.4).
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DISCUSSION |
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We found strong associations between tobacco smoking and anal cancer risk that were confined to premenopausal women. In previous studies, relative risks for anogenital cancers were consistently higher among women younger than 60 years than among women 60 years old or older (5), and women diagnosed with anogenital cancers before the age of 45 years were at higher relative lung cancer risk than were older women with such cancers (6). In an attempt to disentangle the potential modifying effect of age from that of menopausal status, we found no age modification of the multivariate relative risk associated with current smoking in separate analyses of premenopausal and postmenopausal women. This result suggests that menopausal status rather than age is a major discriminator between women whose anal cancer risk is affected by tobacco smoking and women whose risk is not.
How could our observations of a strong effect of smoking restricted to premenopausal women be explained? Previous discussions as to how smoking may alter the risk of anogenital cancer have focused on the possible role of chemical carcinogens in tobacco smoke, smoke-mediated immunologic changes, or low levels of nutritional antioxidants in smokers (13). However, such mechanisms should plausibly entail a similar effect in premenopausal and postmenopausal women and in men. Our observations that smoking is an important risk factor only among women who are not estrogen deficient may reflect a mechanism in anogenital carcinogenesis that has not been considered so far. Although the involved molecular mechanisms are complex and far from settled, it is generally recognized that smoking has antiestrogenic effects in women, possibly mediated through changes in the production or metabolism of ovarian estrogens and adrenal androgens (14).
For sex hormones to be involved would require the presence of sex hormone receptors in the anal mucosa. Embryologically, the mucosa of the anal canal and the vagina derive from the same part of the distal hindgut termed the "cloaca" (15). Thus, the involvement of female sex hormones in the maintenance of a sound anal mucosa, as in the maintenance of the vaginal mucosa (16), would be plausible. It is interesting that both estrogen and androgen receptors were recently demonstrated in the anal squamous epithelium and its supportive tissues among premenopausal and postmenopausal women and men, and such receptors were consistently absent in rectal columnar epithelium and its supportive tissues (17). This novel observation strongly suggests a physiologic role of sex hormones, including estrogens, in the normal anal mucosa. The absence of detectable sex hormone receptors in tumor cells from 11 elderly women with anal cancer (18) is not in conflict with this view because that finding may reflect conformational changes or loss of hormone receptors during the cancerous process. Successively decreasing levels of estrogen receptors have been detected in normal, dysplastic, and cancerous tissues from the uterine cervix (19,20).
If the role of smoking is truly mediated through some antiestrogenic action, why is the impact of smoking not particularly strong among postmenopausal women whose circulating estrogen levels are already low? Although smoking probably will not reduce mucosal problems that prevail in postmenopausal women, the effects of low circulating estrogens may already be present. By contrast, smoking and other agents with antiestrogenic action might produce changes in the anogenital epithelia of premenopausal women in the direction of what occurs physiologically around and after menopause. The resulting mucosal vulnerability and the accompanying dryness, atrophy, and fissures could be one mechanism through which exogenous antiestrogenism acts as a cofactor in anogenital neoplasia among women. Histories of anal fissures and fistulae are statistically significantly more common among patients with high-risk HPV-positive anal cancer than among patients with high-risk HPV-negative anal cancer, possibly because such mucosal lesions may facilitate viral access to basal epithelial layers (9).
Because most cases of anal cancer appear to be caused by sexually transmitted HPV (1) and the notion that girls who mature early will also tend to engage in sexual activity at an early age, we anticipated an inverse association between age at menarche and anal cancer risk. The converse was seen. Age at menarche was strongly and positively associated with the risk, and adjustment for sexual and other confounding factors further strengthened this trend. Although this association and the statistically significant impact of low premorbid BMI among women were not a priori expectations, they may reflect the importance of constitutional hypoestrogenism. Combined with the proposed antiestrogen mechanism of smoking, these observations suggest that hypoestrogenism, whether constitutional or induced, may be a cofactor in anal carcinogenesis.
Other findings related to menstrual or reproductive factors and to the use of oral contraceptives and hormone replacement therapy should be interpreted cautiously. Even after age at menarche was taken into consideration, a short fertile period remained associated with elevated risk, but we unfortunately had no information to determine whether menopause was natural or iatrogenic. The association with abortions or miscarriages also could reflect a role for female sex hormones, but we cannot exclude the possibility that this association may be the result of residual confounding by uncontrolled sexual behavior or social factors related to induced abortion. In light of our hypothesis of a role for antiestrogenic agents, the use of exogenous female sex hormones might have been protective. We saw no such protective effect of oral contraceptive use or hormone replacement therapy. This result may be because the levels of supplemental estrogens beyond those of endogenous estrogen were too low to induce a protective effect or, alternatively, because endogenous and artificial estrogens act through different mechanisms. Moreover, the group of women using oral contraceptives may have differed from nonusers with respect to uncontrolled sexual behavior patterns in a way that outweighed a protective effect of exogenous estrogen. Finally, women receiving postmenopausal hormone replacement therapy may have included a high proportion of women treated because of symptoms related to constitutional hypoestrogenism. If so, this might have masked a protective effect of hormone replacement therapy.
In conclusion, the impact of tobacco smoking on anal cancer risk appears to be restricted to premenopausal women. Combined with strong statistical associations with late menarche and lean body composition and the recent demonstration that the anal mucosa is a hormone-sensitive area, we suggest that tobacco smoking may be involved in anal carcinogenesis among women through its antiestrogenic action. Given the considerable epidemiologic, histopathologic, and molecular biologic similarities between anal cancer and other squamous cell carcinomas in the anogenital region, this hypothesis should be addressed in other studies of anal cancer as well as in studies of HPV-associated cancers of the female genital organs.
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NOTES |
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We thank the pathology, surgery, oncology, and gynecology departments and private practitioners throughout Denmark and Sweden for their assistance.
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Manuscript received September 23, 1998; revised January 21, 1999; accepted February 12, 1999.
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