REPORTS

Tobacco Smoking as a Risk Factor in Anal Carcinoma: an Antiestrogenic Mechanism?

Morten Frisch, Bengt Glimelius, Jan Wohlfahrt, Hans-Olov Adami, Mads Melbye

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).


    ABSTRACT
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
BACKGROUND: Human papillomavirus-associated anogenital carcinogenesis depends on poorly defined cofactors. Smoking was recently suggested to increase the risk of anal cancer more in premenopausal women than in postmenopausal women. Thus, we used our population-based anal cancer case-control study in Denmark and Sweden to test this hypothesis. METHODS: Our study included 417 patients (324 women and 93 men) who were diagnosed with anal cancer (84% invasive cancer) from 1991 through 1994; it also included five patients diagnosed in 1995. Two control groups were used: 1) 554 population control subjects (349 women and 205 men) and 2) 534 patients with rectal adenocarcinoma (343 women and 191 men). Odds ratios (ORs), calculated from logistic regression analyses, were used as measures of relative risk. All P values are two-sided. RESULTS: Compared with the risk for lifelong nonsmokers, the risk of anal cancer was high among premenopausal women who currently smoked tobacco (multivariate OR = 5.6; 95% confidence interval [CI] = 2.4-12.7) and increased linearly by 6.7% per pack-year smoked (one pack-year is equivalent to one pack of cigarettes smoked per day for 1 year) (P for trend <.001). Smoking was not statistically significantly associated with anal cancer risk in postmenopausal women or men. Women whose menstrual periods started late were at high risk (multivariate OR = 3.6; 95% CI = 1.8-7.3, for >=17 years of age versus <=12 years of age; P for trend <.001), and body mass index (weight in kg/[height in m]2) was inversely associated with risk among women (P<.001). CONCLUSIONS: Because the risk of anal cancer associated with smoking was restricted to premenopausal women and because higher risk was associated with late menarche and lean body composition, female sex hormones may be a factor in anal cancer development in women. Since the anal mucosa is an estrogen-sensitive area, we hypothesize an antiestrogenic mechanism of action for smoking in anal carcinogenesis.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Most cases of anal cancer are caused by certain types of sexually transmitted human papillomaviruses (HPVs) (1-3), but other risk factors required for malignant transformation remain poorly defined. Tobacco smoking may be such a risk factor (4,5). A previous study (6) found a higher relative risk for lung cancer (for which smoking is a risk factor) among premenopausal women with anogenital cancers than among postmenopausal women with anogenital cancers. This finding suggested to us that smoking may be a more important risk factor for anogenital cancer development in premenopausal women than in postmenopausal women (6). Using data from our large population-based case-control study of anal cancer, we tested this hypothesis and simultaneously evaluated whether smoking had an effect on the risk of anal cancer in men.


    SUBJECTS AND METHODS
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We identified all incident cases of histologically verified invasive and in situ anal and rectal epidermoid carcinoma (hereafter referred to as anal cancer) in Denmark and Sweden for the period from 1991 through 1994 (including five cases diagnosed in 1995; hereafter referred to as the year 1994-1995). Two control groups were included: 1) subjects drawn at random from central population registers in Denmark and Sweden (population control subjects) and 2) patients with adenocarcinoma of the rectum (cancer control subjects). We included cancer control subjects for two reasons. By including patients with adenocarcinoma of the rectum, we could evaluate the role of potential recall and reporting biases that might occur in comparisons between patients with anal cancer and population control subjects. We anticipated that patients with anal cancer and cancer control subjects would be equally motivated to participate and recall events and would perceive questionnaires similarly. Also, since most studies have not found a link between smoking and the risk of colorectal adenocarcinoma (7,8), we anticipated that the smoking behavior reported by the cancer control subjects would reflect the smoking behavior of the general population. Our plan was to combine the two control groups to gain statistical power if the anticipated similarities between the control groups could be confirmed. Each control group was frequency matched by country, sex, and age (±5 years) and, for cancer control subjects, also by year of diagnosis.

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.Go 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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Table 1. Participation rates and selected background characteristics of participants in the Danish-Swedish anal cancer case-control study

 
The statistical methods used were as follows: Initially, control group-specific odds ratios (ORs) and ORs obtained with the combined group of population control subjects and cancer control subjects were calculated by adjusting for age (<40 years, 40-49 years, 50-59 years, 60-69 years, 70-79 years, or >=80 years), country (Denmark or Sweden), and year of diagnosis (1991, 1992, 1993, or 1994-1995). Because these ORs were adjusted only for the frequency-matching design variables and not for any of the potential explanatory variables, they are referred to as univariate ORs. In all analyses pertaining to the role of tobacco smoking, one cigar, one cheroot, and 1 g of pipe tobacco were converted to four cigarettes, three cigarettes, and one cigarette, respectively. We made population control subjects and cancer patients comparable with respect to smoking and hormonal variables that may change over time (such as smoker status, pack-years of smoking [number of packs of cigarettes smoked per day x years of smoking], and menopausal status). We did this by attributing a pseudo-year of diagnosis to population control subjects according to the distribution of the year of anal cancer diagnosis in case subjects of the same sex. We performed a logistic regression analysis that compared cancer control subjects with population control subjects to examine whether combining the two control groups was justified. When our analysis was adjusted for differences in age, country, and calendar year, we found that none of the smoking variables (current smoker versus lifelong nonsmoker, age at smoking debut, or pack-years of smoking) and none of the menstrual and hormonal variables examined were associated with an increased risk of rectal adenocarcinoma. Furthermore, all univariate ORs, except one, obtained from comparisons of patients with anal cancer and either of the two control groups were of similar direction and size. The exception was for women who were former smokers; these women had a higher risk for anal cancer only when compared with the population control group. Moreover, the distribution of major sexual confounders was quite similar in the two control groups (1), so we maintained the original analysis strategy and combined the control groups to increase statistical power.

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 {chi}2 tests or, for categorized continuous variables, by use of Mantel-Haenszel {chi}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.


    RESULTS
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Tobacco Smoking

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).Go 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).Go 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 ({chi}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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Table 2. Tobacco smoking risk (odds ratios [ORs] [anal cancer case subjects versus all control subjects] and 95% confidence intervals [CIs]) in the Danish-Swedish anal cancer case-control study

 

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Table 3. Tobacco smoking risk among premenopausal and postmenopausal women (odds ratios [ORs] [anal cancer case subjects versus all control subjects] and 95% confidence intervals [CIs]) in the Danish-Swedish anal cancer case-control study

 
Within groups of premenopausal and postmenopausal women, we further examined whether the association with current smoking depended on age. For premenopausal women, current smoking was associated with a high relative risk for anal cancer among those aged less than 45 years (multivariate OR = 6.5; 95% CI = 2.2-19.3) and among those who were 45 years or older (multivariate OR = 3.9; 95% CI = 1.4-10.7). These risk estimates were not statistically significantly different ({chi}2 = 0.50, 1 df; P = .48). For postmenopausal women, the overall lack of an association with current smoking was seen for those aged less than 60 years (multivariate OR = 1.2; 95% CI = 0.6-1.4), 60-69 years (multivariate OR = 1.8; 95% CI = 0.9-3.5), or 70 years or more (multivariate OR = 0.6; 95% CI = 0.3-1.4). These estimates were not statistically significantly different either ({chi}2 = 4.36, 2df; P = .11).

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)Go. 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%) ({chi}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).Go 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)Go. 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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Table 4. Menstrual and hormonal factors* in women (odds ratios [ORs] [anal cancer case subjects versus all control subjects] and 95% confidence intervals [CIs]) in the Danish-Swedish anal cancer case-control study

 
Women who had their first sexual intercourse close to or even before menarche were at higher risk than women whose sexual debut was 10 years or more after menarche (P for trend <.001). However, this association became insignificant in multivariate analysis (P for trend = .07) (Table 4)Go and disappeared when confounding by age at menarche was controlled (P for trend = .71). In contrast, age at menarche retained statistical significance in this model (P for trend <.001). Respondents who first became pregnant 10 years or more after menarche were at low risk, but age at first pregnancy itself had no impact on the risk. Women with anal cancer had fewer children and more abortions or miscarriages (difference between parity and number of pregnancies) than control women. Having had three or more abortions or miscarriages was associated with increased risk (multivariate OR = 2.2; 95% CI = 1.1-4.6), but a trend was not apparent (P = .18) (Table 4)Go. Oral contraceptive use and hormone replacement therapy appeared not to be associated with risk.

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 4Go. 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)Go. 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).


    DISCUSSION
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Tobacco smoking has been suggested as a cofactor with HPV in the etiology of anal cancer (2-5,11), but findings in previous studies are not consistent and confounding by sexual factors has been difficult to rule out. In one study, currently smoking women and currently smoking heterosexual men were at seven to nine times higher relative risk of anal cancer than nonsmokers, but the confounder control included only terms for age and number (fewer than five or five or more partners) of sexual partners (2). Another study (3) revealed a fivefold increased risk associated with heavy smoking among homosexual men but not among women and heterosexual men after controlling for confounding by age and history of genital warts. Unlike previous studies, the present population-based study has shown strong and consistent associations for sexual, venereal, and sexual partner variables and anal cancer risk in both men and women (1). Because smoking and sexual activity are intimately linked (12), this study may be the first to control effectively for sexual and venereal confounding while examining the role of tobacco smoking in anal carcinogenesis.

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.


    NOTES
 
Supported by grants from the Danish Cancer Society (Nos. 90-7620, 94-004, and 96-100-17) and from the Swedish Cancer Society (No. 3258-B95-04XCC).

We thank the pathology, surgery, oncology, and gynecology departments and private practitioners throughout Denmark and Sweden for their assistance.


    REFERENCES
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

1 Frisch M, Glimelius B, van den Brule AJ, Wohlfahrt J, Meijer CJ, Walboomers JM, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med 1997;337: 1350-8.[Abstract/Free Full Text]

2 Daling JR, Weiss NS, Hislop TG, Maden C, Coates RJ, Sherman KJ, et al. Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. N Engl J Med 1987;317:973-7.[Abstract]

3 Holly EA, Whittemore AS, Aston DA, Ahn DK, Nickoloff BJ, Kristiansen JJ. Anal cancer incidence: genital warts, anal fissure or fistula, hemorrhoids, and smoking. J Natl Cancer Inst 1989;81:1726-31.[Abstract]

4 Daniell HW. Re: Causes of anal carcinoma [letter]. JAMA 1985;254:358.

5 Daling JR, Sherman KJ, Hislop TG, Maden C, Mandelson MT, Beckmann AM, et al. Cigarette smoking and the risk of anogenital cancer. Am J Epidemiol 1992;135:180-9.[Abstract]

6 Frisch M, Melbye M. Risk of lung cancer in pre- and post-menopausal women with ano-genital malignancies. Int J Cancer 1995;62:508-11.[Medline]

7 Schottenfeld D, Winawer SJ. Cancers of the large intestine. In: Schottenfeld D, Fraumeni JF Jr, editors. Cancer epidemiology and prevention. 2nd edition. New York (NY): Oxford University Press; 1996. p. 813-40.

8 Nyren O, Bergstrom R, Nystrom L, Engholm G, Ekbom A, Adami HO, et al. Smoking and colorectal cancer: a 20-year follow-up study of Swedish construction workers. J Natl Cancer Inst 1996;88:1302-7.[Abstract/Free Full Text]

9 Frisch M, Glimelius B, van den Brule AJ, Wohlfahrt J, Meijer CJ, Walboomers JM, et al. Benign anal lesions, inflammatory bowel disease, and risk for high-risk human papillomavirus-positive and negative anal carcinoma. Br J Cancer1998 ;78:1534-8.[Medline]

10 The GENMOD Procedure. In: SAS Institute Inc., SAS/STAT Software. Changes and enhancements through Release 6.11. Cary (NC): SAS Institute Inc.; 1996. p. 231-316.

11 Holmes F, Borek D, Owen-Kummer M, Hassanein R, Fishback J, Behbehani A, et al. Anal cancer in women. Gastroenterology 1988;95:107-11.[Medline]

12 Wadsworth J, Johnson A. Physical health and sexual behaviour. In: Johnson AM, Wadsworth J, Wellings K, Field J, editors. Sexual attitudes and lifestyles. London (U.K.): Blackwell Scientific Publications; 1994. p. 259-95.

13 Winkelstein W Jr. Smoking and cervical cancer—current status: a review. Am J Epidemiol 1990;131:945-57.[Medline]

14 Baron JA, La Vecchia C, Levi F. The antiestrogenic effect of cigarette smoking in women. Am J Obstet Gynecol 1990;162:502-14.[Medline]

15 Larsen WJ. Human embryology. 2nd ed. New York (NY): Churchill-Livingstone; 1997. p. 229-309.

16 Nilsson K, Risberg B, Heimer G. The vaginal epithelium in the postmenopause—cytology, histology and pH as methods of assessment. Maturitas 1995;21:51-6.[Medline]

17 Oettling G, Franz HB. Mapping of androgen, estrogen and progesterone receptors in the anal continence organ. Eur J Obstet Gynecol Reprod Biol 1998;77:211-6.[Medline]

18 Goldman S, Skoog L, Wilking N. Immunocytochemical analysis of receptors for estrogen and progesterone in fine needle aspirates from anal epidermoid carcinoma. Dis Colon Rectum 1992;35:163-5.[Medline]

19 Henry RJ, Goodman JD, Godley M, Raju KS, Coffer AI, King RJ. Immunohistochemical study of cytoplasmic oestradiol receptor in normal, dysplastic and malignant cervical tissue. Br J Obstet Gynaecol 1988;95: 927-32.[Medline]

20 Mosny DS, Herholz J, Degen W, Bender HG. Immunohistochemical investigations of steroid receptors in normal and neoplastic squamous epithelium of the uterine cervix. Gynecol Oncol 1989;35:373-7.[Medline]

Manuscript received September 23, 1998; revised January 21, 1999; accepted February 12, 1999.


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