- Email: [email protected]
Carcinoma of the cervix and smoking
Biomed. & Phvnacorher., 43 (1989) 161-165 0 Msevier, Paris
Carcinoma Of the cervix ad
SiZOhi~
P.M. LAYDE and SK. BROSTE Department of Epidemiology and Riostatistics, Marshfield Medical Research Foundation, 510 North St. Joseph Avenue, Marshfield, WI 54449, USA (Received 31-I-1989; accepted 6-2-1989)
Summary - There is considerable evidence from epidemiologic and clinical studies that cigarette smoking is associated with the risk of cervical cancer. Definitive clarification of whether this association is causal will likely have to await definitive identification of the sexually transmitted agent which is probably the most important cause of cervical cancer. Only then will it be possible to clarify the contributions of risk factors with weaker associations with cervical cancer, such as cigarette smoking and socioeconomic status. MMNtii tke cmtx / making / rhik factors RksumC -
Cancer du ad de h&us et tabagisme. Des argumentstds solides en faveur du fait que le tabagisme est associd B un risque QCCIUde cancer du co1 de h&us sont foumis par des dtudes $id&miologiques et cliniques. Pour r&pondre de fagon plus favorable d la question de savoir si cela correspond B une relation de cause i eflet, il faudra certainement attendre i’identifcation prkise de I’agent sexuelkment transmissible qui. vraisenrblablement. joue un tile ddtenninant dons la genhe de ce cancer, Alors seulement il sera possible d’dvaluer plus phisthent le tile des facteurs de risque montrant une association moins forte avec le cancer du co1 tels le tabagisme et les conditions socio-kconomiques.
In 1977, Winkelstein hypothesized that cigarette smoking might increase a woman’s risk of cancer of the uterine cervix [25]. He based his hypothesis on several factors. Because most smoking-associated cancers (such as carcinoma of the lung and larynx) are squamous cell cancers, he averred that “the cigarette smoking effect is most importantly manifested by a squamous cell oncogenic response.” While most cancers are adenocarcinomas; cervical dancer also arises from squamous cell tissues and hence might also be susceptible to this squamous cell oncogenic response. In analyzing data from the Third National Cancer Survey in the United States, Winkelstein and his colleagues had noted that the geographical distribution of cervical cancer in the United States was similar to that of lung cancer in men [241. In addition, Winkelstein identified 4 previous epidemiologic studies of cervical cancer or smoking
which provided incidental information on the association of these 2 factors [2, 14, 20, 231. All the studies reported an increased risk of ce.rvical cancer in cigarette smokers, but the authors of each of these reports had not focused on these incidental findings, but had rather attributed them to confounding or other biases. Since the time of Winkelstein’s original article, considerable evidence has accumulated supporting his hypothesis. To date, almost 20 epidemiologic studies have been conducted that provide useful information regarding the association of cigarette smoking with cervical cancer. With few exceptions, the studies noted an increased risk of cervical cancer among women who smoke cigarettes (Table I). In general, the results of these studies are compatible with a causal association between cigarette smoking and cervical neoplasia. Current cigarette smokers have generally had a higher risk of cervical cancer than former cigarette smokers (Table I), which is similar to the
and SK. Bmte
P.M. Hyde
162
neoplasia; smokers have an increased risk of both mild and severe cervical dysplasia, carcinoma in situ, invasive cervical cancer, and deaths attributable to cervical cancer (Tables I, II). Another
&xling for lung cancer and is compatible with a role for cigarette smoke as a promoter of cervical ~ci~ogen~is. Cigarette smoking has been linked to the entire pathogenetie spectrum of cervical Td&
i
&ociation
Reference
14 20 2 2 4 16 11 E 19 IS 8
of cigarette smoking and cervical neoplasia.
Errant
CIS L invasive CIS Cervical ca death Cervical ca reg. Invasive CIS $ invasive Invasive Invasive CIS Cervical ca, NOS Invasive Cervical ea death
Reference SouP Never smoker
Fomer booker CRR *
ARR’
1.26
Ever ~~okeF~ CRR * 1.95 1.71
-‘I-
ARR+
2.14 1.472
-I’-
1.7
-“_
3.58
-- .*_
ARR+
CRR *
-“_ -“_
Current S?tiObS
2.08 5.16 2.3
3.0’ 2.2’
1.90
1.984
1.35 3.83* 2.16
-“_
2.1’
-‘I_
3.61’
4.2’ 1.28
-I’-
1.54
-“_
1.21’
Current non1.7Y
12 I
22 22 13
Invasive Invasive Invasive CIS CIS $ invasive & severe dysplasia
Never smoker _“_ _“_ _‘I_ _“_
0.67 1.93 1.0 13 2.94
0.76’
1.34
1.92’
2.93
1.69 6.14 2.0 3.68’
*cRR = Crude relative risk. “A&F= Adjusted relative risk adjusted for : ’ Direct measure of sexual activity, other miscellaneous factors. ’ Surrogate measures of sexual activity, other miscellaneous factors. 3 Age only. 4 Religion only (Moslem vs. non-Moslems.
Table BE.Association of cigarette smoking and cervical dysplasia. Reference
14 20 21 21 5 12 1 13
Endpoint
Reference m=P
Cervical dysplasia Never smoker -“_ Cervical dysplasia Mild or moderate -“_ dysplasia -II__ Severe dysplasia -.fl_ Cervical dysplasia -“_ CIS $ dysplasia -“_ CIS & dysplasia CIS & invasive & any _“_ dysplasia
Former
ARR+
StTtOkS
Ever
ARR+
S#tiOiCtW
CRR *
CRR *
4.63
5.95 1.23
6.87 1.072 I
::;i
;:;I 2.52 1.76
4.84 1.27
+ CRR = Crude relative risks. * ARR = Adjusted relative risks. Adjustments for : ’ Direct measures of sexual activity, other miscellaneous factors.
’ Surrogatemeasures of sexual activity, other miscellaneous factors.
1.67
ARR+
CRR *
1
1.26
Current smokers
3.13 I .35’ 6.76 1.87
2.6’ 3.0’ 1.9’
Carcinoma of the cervix and smoking
hallmark of a causal association is a “‘doseresponse trend”, that is, an increased risk of cervical cancer with an increasing exposure to cigarette smoke. The risk of cervical neoplasia has been associated with the number of cigarettes smoked per day [2,8,26], the number of years that a woman has smoked cigarettes [3, 151,as well as the most common summary of cumulative exposure to cigarette smo~ng, the pack years of cigarettes smoked 121, 221. Epidemiologic studies have also provided further suggestive evidence supporting this association. Among women who smoked, the greatest risk of cervical cancer appears to accrue to women who started smoking relatively early in their teenage years, when the cervix is undergoing the metaplastic changes of puberty and may be particularly sensitive to carcinogenic insults [12, 14, 211.Those epidemiologic studies that controlled for the influence of other risk factors for cervical cancer (such as sexual activity and socioe~nomi~ status) generally found that ~ntrolling for these factors reduced, but did not eliminate, the association of cervical cancer with cigarette smoking (Table I) Since the original hypothesis by Winkelstein, considerable evidence has also accumulated supporting the biologic plausibility of a carcinogenic effect of cigarette smoking on the cervix. Apart from the histologic similarities of cervical cancer to cancer of the lung and other smoking-related tumors, biochemical studies have shown that an important constituent of cigarette smoke, nicotine, and its major metabolite, cotinine, are concentrated in the cervical mucus compared with the blood 17, 171.In one study, 39% of the cervical mucus in 36 cigarette smokers was found to be mutagenic in a standard Salmonella assay compared to 12% in 42 non-smokers [9]. These findings may, however, have been an artefact of different rates of infection among smokers and non-smokers for an unidentified microorganism that interferes with interpretation of results on the microbiological mutagenicity test [ 181. Research on mechanisms of carcinogenesis have also supported the notion that there may also be a synergistic interaction of chemical carcinogens with viruses 161;this observation may be applicable to the situation in cervical cancer. In reviewing published literature, the possibility of publication bias must be considered. This bias would be of concern if only those studies showing a positive association were published, leaving a body of studies with negative associations unavailable for review. This could certainly
163
be a criticism of the older articles, since an observed positive association between smoking and cervicai cancer would have been considered particularly noteworthy, but weak or negative associations would not. Later studies on cervical cancer, however, would almost certainly have included measures of smoking behavior, due to the earlier articles and to the increased awareness of smoking and cancer following the Surgeon General’s report. In particular, one would expect that those studies conducted after Winkelstein’s review in 1977 would have included measures of smoking history. With these considerations in mind, the articles which were included in this review were classified according to the year published and the overall focus of the study. Nine of the studies were designed to investigate factors, in general, that were associated with cervical cancer, and not exclusively smoking. Of those 9 studies, 5 [l, 3, 5, 16, 261 were published after Winkelstein’s 1977 article. It is reasonable to expect that these and similar studies would have been published even if no association between smoking and cervical cancer had been found, and that either positive or negative findings with regard to smoking would have been reported. The studies designed primarily to study the association of smoking and cervical cancer 14, 12, 13, 15, 19, 211 were published after 1977, and it is also likely that any such study showing lack of association with smoking would have been of sufficient interest in light of the earlier findings to warrant publication. Thus, while there is no assurance that publi~tion bias has not skewed the results, it seems unlikely. Despite the accumulating evidence, the causality of the association of cigarette smoking with cervical cancer is not yet widely accepted. The concerns of skeptics have been well stated by an International Agency for Research on Cancer (IARC) Working Group which reviewed the carcinogenic risk of tobacco smoking in humans [lo]. In their summary of the association of cigarette smoking and cervical cancer, the working group stated “for cervical cancer, it is reasonable to suppose that there is a specific causal agent - most probably an infective agent transmitted sexually. Since this agent has not been unequivocally identified, and, in particular, was not included in the studies under review, surrogate measures have been included to reflect the degree of sexual activity. Smoking is positively related to sexual activity. Any observed crude association between smoking and risk of cervical
P.M. tayde
164
cancer may be confounded. Since the specific factor by which the analysis should be adjusted is not known, the ~nfou~ding effect can be removed only partially.” In essence, the concern of the IARC working group is that there could be other differences between smokers and non-smokers apart from their consumption of cigarettes. There is evidence that women who smoke cigarettes are more sexually active than non-smokers and have a greater likelihood of sexually transmitted diseases. There is a substantial amount of evidence developing that the human papiiloma virus (HPV) may be the causal agent in cervical carcinogenesis [s]. None of the epidemiology studies of cigarette smoking in cervical cancer have controlled for differences in HPV infections between smokers and non-smokers. Indeed, because of difficulties in making a definitive diagnosis of HPV infection with current diagnostic tests, adequate studies of HPV infection in cervical cancer are only now beginning to be conducted with both the traditional technique of reviewing pap smear specimens for histologic evidence of HPV infection, as well as modem DNA hybridization techniques to detect the presence of HPV genome in cervical cancer ~stologi~i or cytological specimens. Together these techniques may provide a reliable method of diagnosing previous HPV infection. As pointed out by Grubb [6] in his excellent review on HPV infection and cervical neopiasia, it is likely that ultimate resolution of the association of HPV in cervical cancer must await prospective studies in which the possibility that HPV infection occurs as a sequeia of the early changes in cervical neopiasia can be ruled out.
Buckley J.D., Harris R.W.C., Doll R & Vessey M.P. (1981) Case-control study of the husbands uf women with dysplasia or carcinoma of the cervix uteri. fAlncet ii, 1010 Cederlof R., Friberg L., Hrubec Z. Bt Lorich U. (1975) The relationship of smoking and some social covariables to mortality and cancer morbidity. Department of Environmental Hygiene, Karolinska Institute 1-91, Stockholm, Sweden Celentano D.D., Klassen A.C., Weisman C.S. & Rosenshein N.B. (1987) The role of contra~ptive use in cervical cancer : The Maryland Cervical Cancer Case-Control Study. Am. J. Epidemiol. 126, 592
and SK
Broste
Clarke E.A., Morgan R.W. C Newman A.M. (1982) Smoking as a risk factor in cancer of the cervix : additional evidence from a case cuntrol study. Am. J. Epidemiol. 115, 59 5 Clarke E.A., Hatcher J., McKrown-Eyssen G.E. & Lickrish G.M. (1985) Cervical dysplasia : association with sexual behavior, smoking and oral contraceptive use ? Am. J. O&et. Gynewl. 151, 612 6 Grubb G.S. (1986) Human papi~lomavi~s and cervical neoplasia : Bpidemio~ogi~i considerations. Znt. J. Epidemiol. 15, 1 7 Hellberg D., Nilsson S. & Haley NJ. (1988) Smoking and cervical intraepithelial neoplasia : nicotine and cotinine in serum and cervical mucus in smokers and non-smokers. Am. J. Obsre& Gyxecol. 158, 919 8 Hirayama T. (1974) Prospective studies on cancer epidemiology based on census population in Japan. Proceedings, XI Intl. Cancer Congress, Florence 30, 26 9 Holly E.A., Petrakis N.L. & Friend N.F. (1986) Mutagenic mucus in the cervix of smokers. J. Nazl. Cancer Inst. 76, 983 10 International Agency for Research on‘ Cancer (1985) In : Tobacco Smoking. ZARC Monographs on the Evaluation of the Carcinogenic R&k qf Chemicals to Humans 38, 282 11 Kessler LI., Kulcar Z. & Zimolo A. (1974) Cervical cancer in Yugoslavia II. Epidemiologic factors of possible etiologic signi~~an~e. J, ffatl. Cuncer Znsr. 53, 51 12 La Vecchia C., Pranceschi S., Dcaarli A., Fasoli M., Gentile A. 8t Tognomi G. (1986) Cigarette smoking and the risk of cervical neoplasia. Am. J. Epidemiol. 4
123, 22
13 Mayberry RM. (1985) Cigarette smoking, herpes simplex virus type 2 infection and cervical abnormalities. Am. J. Pub& Health 75, 676 14 Naguib S.M., Lundin F.E. 8t Davis H.J. (1966) Relation of various epidemiologic factors to cervical cancer as determined by a screening program. Obstet. Gynecol. 28, 451 15 Nischan P., Ebeling K. Br Sc~ndler C. (1988) Smoking and invasive cervical cancer risk; results from a case-control study. Am. J. Epidemiol. 128,74 16 Reeves W.C., Brinton L.A., Brenes M.M., Quiroy E., Rawls W.E. i$ DeBritton R.C. (1985) Case control study of cervical cancer in Gerrera province, Republic of Panama. Iat. J. Cancer 36, 55 17 Sasson I.M., Haley N.J. & Hoffmann D:‘(1985) Cigarette smoking and neoplasia of the uterine cervix : smoke constituents in cervical mucus. N. Engl. J. Med. 312, 315 18 Schiffman M., Brinton L. & Holly E. (1987) Regarding mutagenic mucus in the cervix of smokers. J. Nod. Cancer Ins?. 78, 590 19 Stellman S.D., Austin H. & Wynder EL. (1980) Cervix cancer and cigarette smoking : a case-control study. Am. J. Epidemiol. 111, 383
Carcinoma of the cervix and smoking 20 Thomas D.B. (1973) An epidemiologic study of carcinoma in situ and squamous dysplasia of the uterine cervix. Am. J. Epidemiol. 98, 10 21 Trevathan E.. Layde P., Webster L.A., Adams J.B., Benign0 B.B. 8c Ory H. (1983) Cigarette smoking and dysplasia and carcinoma in situ of the uterine cervix. J. Am. Med. Assoc. 250, 499 22 Wigle D.T., Mao Y. Jr Grace M. (1980) Re : smoking and cancer of the uterine cervix : hypothesis. Am. J. Epidemiol. 111, 125 23 Williams R.R. & Horm J.W. (1977) Association of cancer sites with tobacco and alcohol consumption and socioeconomic status : interview study from the
165
Third National Cancer Survey. J. N&l. Cuncer Inst. 58, 525 24 Winkelstein W. Jr., Sacks ST. Br Emster V.L. (1977) Correlation of incidence rates for selected cancers in the nine areas of Third National Cancer Survey. Am. J. Epidemiol. 109, 407 25 Winkelstein W. (1977) Smoking and cancer of the uterine cervix : hypothesis. Am. J. Epidemiol. 106, 257 26 Wright N.H., Vessey M.P., Kenward B., McPherson K. & Doll R. (1978) Neoplasia and dysplasia of the cervix uteri and contraception : a possible protective effect of the diaphragm. Br. J. Cancer 38, 273
Carcinoma Of the cervix ad
SiZOhi~
P.M. LAYDE and SK. BROSTE Department of Epidemiology and Riostatistics, Marshfield Medical Research Foundation, 510 North St. Joseph Avenue, Marshfield, WI 54449, USA (Received 31-I-1989; accepted 6-2-1989)
Summary - There is considerable evidence from epidemiologic and clinical studies that cigarette smoking is associated with the risk of cervical cancer. Definitive clarification of whether this association is causal will likely have to await definitive identification of the sexually transmitted agent which is probably the most important cause of cervical cancer. Only then will it be possible to clarify the contributions of risk factors with weaker associations with cervical cancer, such as cigarette smoking and socioeconomic status. MMNtii tke cmtx / making / rhik factors RksumC -
Cancer du ad de h&us et tabagisme. Des argumentstds solides en faveur du fait que le tabagisme est associd B un risque QCCIUde cancer du co1 de h&us sont foumis par des dtudes $id&miologiques et cliniques. Pour r&pondre de fagon plus favorable d la question de savoir si cela correspond B une relation de cause i eflet, il faudra certainement attendre i’identifcation prkise de I’agent sexuelkment transmissible qui. vraisenrblablement. joue un tile ddtenninant dons la genhe de ce cancer, Alors seulement il sera possible d’dvaluer plus phisthent le tile des facteurs de risque montrant une association moins forte avec le cancer du co1 tels le tabagisme et les conditions socio-kconomiques.
In 1977, Winkelstein hypothesized that cigarette smoking might increase a woman’s risk of cancer of the uterine cervix [25]. He based his hypothesis on several factors. Because most smoking-associated cancers (such as carcinoma of the lung and larynx) are squamous cell cancers, he averred that “the cigarette smoking effect is most importantly manifested by a squamous cell oncogenic response.” While most cancers are adenocarcinomas; cervical dancer also arises from squamous cell tissues and hence might also be susceptible to this squamous cell oncogenic response. In analyzing data from the Third National Cancer Survey in the United States, Winkelstein and his colleagues had noted that the geographical distribution of cervical cancer in the United States was similar to that of lung cancer in men [241. In addition, Winkelstein identified 4 previous epidemiologic studies of cervical cancer or smoking
which provided incidental information on the association of these 2 factors [2, 14, 20, 231. All the studies reported an increased risk of ce.rvical cancer in cigarette smokers, but the authors of each of these reports had not focused on these incidental findings, but had rather attributed them to confounding or other biases. Since the time of Winkelstein’s original article, considerable evidence has accumulated supporting his hypothesis. To date, almost 20 epidemiologic studies have been conducted that provide useful information regarding the association of cigarette smoking with cervical cancer. With few exceptions, the studies noted an increased risk of cervical cancer among women who smoke cigarettes (Table I). In general, the results of these studies are compatible with a causal association between cigarette smoking and cervical neoplasia. Current cigarette smokers have generally had a higher risk of cervical cancer than former cigarette smokers (Table I), which is similar to the
and SK. Bmte
P.M. Hyde
162
neoplasia; smokers have an increased risk of both mild and severe cervical dysplasia, carcinoma in situ, invasive cervical cancer, and deaths attributable to cervical cancer (Tables I, II). Another
&xling for lung cancer and is compatible with a role for cigarette smoke as a promoter of cervical ~ci~ogen~is. Cigarette smoking has been linked to the entire pathogenetie spectrum of cervical Td&
i
&ociation
Reference
14 20 2 2 4 16 11 E 19 IS 8
of cigarette smoking and cervical neoplasia.
Errant
CIS L invasive CIS Cervical ca death Cervical ca reg. Invasive CIS $ invasive Invasive Invasive CIS Cervical ca, NOS Invasive Cervical ea death
Reference SouP Never smoker
Fomer booker CRR *
ARR’
1.26
Ever ~~okeF~ CRR * 1.95 1.71
-‘I-
ARR+
2.14 1.472
-I’-
1.7
-“_
3.58
-- .*_
ARR+
CRR *
-“_ -“_
Current S?tiObS
2.08 5.16 2.3
3.0’ 2.2’
1.90
1.984
1.35 3.83* 2.16
-“_
2.1’
-‘I_
3.61’
4.2’ 1.28
-I’-
1.54
-“_
1.21’
Current non1.7Y
12 I
22 22 13
Invasive Invasive Invasive CIS CIS $ invasive & severe dysplasia
Never smoker _“_ _“_ _‘I_ _“_
0.67 1.93 1.0 13 2.94
0.76’
1.34
1.92’
2.93
1.69 6.14 2.0 3.68’
*cRR = Crude relative risk. “A&F= Adjusted relative risk adjusted for : ’ Direct measure of sexual activity, other miscellaneous factors. ’ Surrogate measures of sexual activity, other miscellaneous factors. 3 Age only. 4 Religion only (Moslem vs. non-Moslems.
Table BE.Association of cigarette smoking and cervical dysplasia. Reference
14 20 21 21 5 12 1 13
Endpoint
Reference m=P
Cervical dysplasia Never smoker -“_ Cervical dysplasia Mild or moderate -“_ dysplasia -II__ Severe dysplasia -.fl_ Cervical dysplasia -“_ CIS $ dysplasia -“_ CIS & dysplasia CIS & invasive & any _“_ dysplasia
Former
ARR+
StTtOkS
Ever
ARR+
S#tiOiCtW
CRR *
CRR *
4.63
5.95 1.23
6.87 1.072 I
::;i
;:;I 2.52 1.76
4.84 1.27
+ CRR = Crude relative risks. * ARR = Adjusted relative risks. Adjustments for : ’ Direct measures of sexual activity, other miscellaneous factors.
’ Surrogatemeasures of sexual activity, other miscellaneous factors.
1.67
ARR+
CRR *
1
1.26
Current smokers
3.13 I .35’ 6.76 1.87
2.6’ 3.0’ 1.9’
Carcinoma of the cervix and smoking
hallmark of a causal association is a “‘doseresponse trend”, that is, an increased risk of cervical cancer with an increasing exposure to cigarette smoke. The risk of cervical neoplasia has been associated with the number of cigarettes smoked per day [2,8,26], the number of years that a woman has smoked cigarettes [3, 151,as well as the most common summary of cumulative exposure to cigarette smo~ng, the pack years of cigarettes smoked 121, 221. Epidemiologic studies have also provided further suggestive evidence supporting this association. Among women who smoked, the greatest risk of cervical cancer appears to accrue to women who started smoking relatively early in their teenage years, when the cervix is undergoing the metaplastic changes of puberty and may be particularly sensitive to carcinogenic insults [12, 14, 211.Those epidemiologic studies that controlled for the influence of other risk factors for cervical cancer (such as sexual activity and socioe~nomi~ status) generally found that ~ntrolling for these factors reduced, but did not eliminate, the association of cervical cancer with cigarette smoking (Table I) Since the original hypothesis by Winkelstein, considerable evidence has also accumulated supporting the biologic plausibility of a carcinogenic effect of cigarette smoking on the cervix. Apart from the histologic similarities of cervical cancer to cancer of the lung and other smoking-related tumors, biochemical studies have shown that an important constituent of cigarette smoke, nicotine, and its major metabolite, cotinine, are concentrated in the cervical mucus compared with the blood 17, 171.In one study, 39% of the cervical mucus in 36 cigarette smokers was found to be mutagenic in a standard Salmonella assay compared to 12% in 42 non-smokers [9]. These findings may, however, have been an artefact of different rates of infection among smokers and non-smokers for an unidentified microorganism that interferes with interpretation of results on the microbiological mutagenicity test [ 181. Research on mechanisms of carcinogenesis have also supported the notion that there may also be a synergistic interaction of chemical carcinogens with viruses 161;this observation may be applicable to the situation in cervical cancer. In reviewing published literature, the possibility of publication bias must be considered. This bias would be of concern if only those studies showing a positive association were published, leaving a body of studies with negative associations unavailable for review. This could certainly
163
be a criticism of the older articles, since an observed positive association between smoking and cervicai cancer would have been considered particularly noteworthy, but weak or negative associations would not. Later studies on cervical cancer, however, would almost certainly have included measures of smoking behavior, due to the earlier articles and to the increased awareness of smoking and cancer following the Surgeon General’s report. In particular, one would expect that those studies conducted after Winkelstein’s review in 1977 would have included measures of smoking history. With these considerations in mind, the articles which were included in this review were classified according to the year published and the overall focus of the study. Nine of the studies were designed to investigate factors, in general, that were associated with cervical cancer, and not exclusively smoking. Of those 9 studies, 5 [l, 3, 5, 16, 261 were published after Winkelstein’s 1977 article. It is reasonable to expect that these and similar studies would have been published even if no association between smoking and cervical cancer had been found, and that either positive or negative findings with regard to smoking would have been reported. The studies designed primarily to study the association of smoking and cervical cancer 14, 12, 13, 15, 19, 211 were published after 1977, and it is also likely that any such study showing lack of association with smoking would have been of sufficient interest in light of the earlier findings to warrant publication. Thus, while there is no assurance that publi~tion bias has not skewed the results, it seems unlikely. Despite the accumulating evidence, the causality of the association of cigarette smoking with cervical cancer is not yet widely accepted. The concerns of skeptics have been well stated by an International Agency for Research on Cancer (IARC) Working Group which reviewed the carcinogenic risk of tobacco smoking in humans [lo]. In their summary of the association of cigarette smoking and cervical cancer, the working group stated “for cervical cancer, it is reasonable to suppose that there is a specific causal agent - most probably an infective agent transmitted sexually. Since this agent has not been unequivocally identified, and, in particular, was not included in the studies under review, surrogate measures have been included to reflect the degree of sexual activity. Smoking is positively related to sexual activity. Any observed crude association between smoking and risk of cervical
P.M. tayde
164
cancer may be confounded. Since the specific factor by which the analysis should be adjusted is not known, the ~nfou~ding effect can be removed only partially.” In essence, the concern of the IARC working group is that there could be other differences between smokers and non-smokers apart from their consumption of cigarettes. There is evidence that women who smoke cigarettes are more sexually active than non-smokers and have a greater likelihood of sexually transmitted diseases. There is a substantial amount of evidence developing that the human papiiloma virus (HPV) may be the causal agent in cervical carcinogenesis [s]. None of the epidemiology studies of cigarette smoking in cervical cancer have controlled for differences in HPV infections between smokers and non-smokers. Indeed, because of difficulties in making a definitive diagnosis of HPV infection with current diagnostic tests, adequate studies of HPV infection in cervical cancer are only now beginning to be conducted with both the traditional technique of reviewing pap smear specimens for histologic evidence of HPV infection, as well as modem DNA hybridization techniques to detect the presence of HPV genome in cervical cancer ~stologi~i or cytological specimens. Together these techniques may provide a reliable method of diagnosing previous HPV infection. As pointed out by Grubb [6] in his excellent review on HPV infection and cervical neopiasia, it is likely that ultimate resolution of the association of HPV in cervical cancer must await prospective studies in which the possibility that HPV infection occurs as a sequeia of the early changes in cervical neopiasia can be ruled out.
Buckley J.D., Harris R.W.C., Doll R & Vessey M.P. (1981) Case-control study of the husbands uf women with dysplasia or carcinoma of the cervix uteri. fAlncet ii, 1010 Cederlof R., Friberg L., Hrubec Z. Bt Lorich U. (1975) The relationship of smoking and some social covariables to mortality and cancer morbidity. Department of Environmental Hygiene, Karolinska Institute 1-91, Stockholm, Sweden Celentano D.D., Klassen A.C., Weisman C.S. & Rosenshein N.B. (1987) The role of contra~ptive use in cervical cancer : The Maryland Cervical Cancer Case-Control Study. Am. J. Epidemiol. 126, 592
and SK
Broste
Clarke E.A., Morgan R.W. C Newman A.M. (1982) Smoking as a risk factor in cancer of the cervix : additional evidence from a case cuntrol study. Am. J. Epidemiol. 115, 59 5 Clarke E.A., Hatcher J., McKrown-Eyssen G.E. & Lickrish G.M. (1985) Cervical dysplasia : association with sexual behavior, smoking and oral contraceptive use ? Am. J. O&et. Gynewl. 151, 612 6 Grubb G.S. (1986) Human papi~lomavi~s and cervical neoplasia : Bpidemio~ogi~i considerations. Znt. J. Epidemiol. 15, 1 7 Hellberg D., Nilsson S. & Haley NJ. (1988) Smoking and cervical intraepithelial neoplasia : nicotine and cotinine in serum and cervical mucus in smokers and non-smokers. Am. J. Obsre& Gyxecol. 158, 919 8 Hirayama T. (1974) Prospective studies on cancer epidemiology based on census population in Japan. Proceedings, XI Intl. Cancer Congress, Florence 30, 26 9 Holly E.A., Petrakis N.L. & Friend N.F. (1986) Mutagenic mucus in the cervix of smokers. J. Nazl. Cancer Inst. 76, 983 10 International Agency for Research on‘ Cancer (1985) In : Tobacco Smoking. ZARC Monographs on the Evaluation of the Carcinogenic R&k qf Chemicals to Humans 38, 282 11 Kessler LI., Kulcar Z. & Zimolo A. (1974) Cervical cancer in Yugoslavia II. Epidemiologic factors of possible etiologic signi~~an~e. J, ffatl. Cuncer Znsr. 53, 51 12 La Vecchia C., Pranceschi S., Dcaarli A., Fasoli M., Gentile A. 8t Tognomi G. (1986) Cigarette smoking and the risk of cervical neoplasia. Am. J. Epidemiol. 4
123, 22
13 Mayberry RM. (1985) Cigarette smoking, herpes simplex virus type 2 infection and cervical abnormalities. Am. J. Pub& Health 75, 676 14 Naguib S.M., Lundin F.E. 8t Davis H.J. (1966) Relation of various epidemiologic factors to cervical cancer as determined by a screening program. Obstet. Gynecol. 28, 451 15 Nischan P., Ebeling K. Br Sc~ndler C. (1988) Smoking and invasive cervical cancer risk; results from a case-control study. Am. J. Epidemiol. 128,74 16 Reeves W.C., Brinton L.A., Brenes M.M., Quiroy E., Rawls W.E. i$ DeBritton R.C. (1985) Case control study of cervical cancer in Gerrera province, Republic of Panama. Iat. J. Cancer 36, 55 17 Sasson I.M., Haley N.J. & Hoffmann D:‘(1985) Cigarette smoking and neoplasia of the uterine cervix : smoke constituents in cervical mucus. N. Engl. J. Med. 312, 315 18 Schiffman M., Brinton L. & Holly E. (1987) Regarding mutagenic mucus in the cervix of smokers. J. Nod. Cancer Ins?. 78, 590 19 Stellman S.D., Austin H. & Wynder EL. (1980) Cervix cancer and cigarette smoking : a case-control study. Am. J. Epidemiol. 111, 383
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