cervical cancer ( cc ) is the third most common cancer in women , and the seventh overall , with an estimated 530  000 new cases in 2008 . more than 85% of the global burden occurs in developing countries , where it accounts for 13% of all female cancers . cervical cancer is responsible for 275  000 deaths in 2008 , about 88% of which occur in developing countries : 53  000 in africa , 31  700 in latin america and the caribbean , and 159  800 in asia . however , cc is preventable disease , and much effort should be done to prevent it . it is now well - established that persistence of human papillomavirus   ( hpv ) infection is the strongest epidemiologic factor associated with intraepithelial neoplasia and cancer of cervix [ 25 ] , and it is considered a necessary cause for development of the disease but not sufficient . exogenous or endogenous factors had been identified to , in conjunction with hpv infection , influence the risk for cc . as castellsagu and muoz   suggested , cofactors may be classified into three groups : ( 1 ) environmental or exogenous cofactors , including use of oral contraceptives ( ocs ) , tobacco smoking , diet , cervical trauma , coinfection with human immunodeficiency virus ( hiv ) and other sexually transmitted agents ; ( 2 ) viral cofactors , such as infection by specific types , coinfection with other types , hpv variants , viral load , and viral integration ; ( 3 ) host cofactors , including endogenous hormones , genetic factors such as human leukocyte antigen and other host factors related to the host 's immune response . winkelstein jr .    in 1977 was the first to put the hypothesis that smoking is a risk factor for cervical cancer . since then , the action of tobacco on cervical carcinogenesis has been a matter of scientific debate . the objective of this paper is to update the state of the science about smoking and cancer of the cervix . it was checked up in pubmed / medline and embase databases , studies written in english with keywords : cervical cancer ; cervix ; cin ; hpv ; tobacco ; smoking and smoke . only meta - analysis and or multi - institutional studies plummer et al . reported the first multicentric case - control study in 2003 . in analyzing eight studies on invasive cancer and two on carcinoma in situ , conducted by international agency for research on cancer ( iarc ) , between 1985 and 1997 , the authors conclude that ever - smokers have an excess risk of cervical cancer that persists after controlling for the strong effect of hpv and for other potential cofactors of progression from infection to cancer , and they suggest that squamous cell carcinoma of the cervix should be added to the list of tobacco associated cancers , while for adenocarcinoma , further data should be warranted .   in 2004 , iarc revisited its previous conclusions and listed cervical cancer among those causally related to smoking .   in 2006 , a collaborative reanalysis of 12 studies on cc , enrolling 8,097 cases of squamous cell carcinoma , 1,374 women adenocarcinoma , and 26,445 women without carcinoma of the cervix , showed that there are no substantial differences between the two most common histological types of invasive cervical cancer with respect to the role of number of sexual partners , age at first intercourse , age at first birth , body mass index , and use of oral contraceptives . the exception was current tobacco smoking , which is associated with an increased risk of squamous cell but not for adenocarcinoma of the cervix , in agreement with other studies [ 11 , 12 ] . vaccarella et al .   in 2008 reported a pooled analysis of 13 iarc hpv prevalence survey in 11 countries worldwide , carried out between 1993 and 2005 . they concluded that current tobacco smoking was associated with a significant , although moderate , increased risk of prevalent hpv infection . among current smokers , the risk of being hpv - positive increased with increasing number of cigarettes smoked per day , and women who reported to smoke 15 or more cigarettes daily had a 2-fold risk of hpv positivity as compared with never - smokers . these results have shown that smoking habits interfere with prevalence of hpv infection in agreement with reported in previous studies [ 1416 ] . syrjnen et al . , in 2007 , in analyzing a cohort of 3,187 women , conclude that cigarette smoking was not an independent risk factor of cin2 + , except for those patients who tested for hr - hpv ( high - risk hpv ) , and current smoking remains an independent predictor for those patients in a multivariate model , in agreement with previous study of harris et al . in 2004 ,   that found among women with oncogenic hpv infection of the three smoking measures ( smoking status , pack years of exposure , and number of cigarettes per day ) , number of cigarettes per day ( > 10 cigarettes ) was the most strongly associated with risk for cin1 and cin2 - 3 . in this study , association between cigarettes smoked by day and cin did not appear to be mediated by an immunologic response . those studies suggest that smoking has a special adverse effect on hr - hpv driven cervical carcinogenesis . a recent study , published in 2010 , conducted on 2,011 women , 1519 years old , recruited from 1988 to 1992 then regularly followed until 1997 , concluded that there is no evidence to suggest that the risk of acquiring a hpv infection of any type , or a hpv16 or hpv18 infection , increases with either pack years of exposure to smoking or duration of current smoking episode , suggesting that smoking is not a important risk factor for hr - hpv infection . xi et al . in 2009   reported an analysis of 1,050 women hpv16 and/or hpv18 positives for viral dna load , enrolled into the ascus - lsil triage study . the authors concluded that higher hpv16 and hpv18 dna load was associated with status of current , but not former , smoker . among current smokers , the viral load did not appear to vary appreciably by the intensity and duration of cigarette smoking , in accordance , with previous study of gunnell et al .   in 2006 , that in testing for hpv16 dna presence in first archival cervical smears from 375 cases of in situ cervical squamous carcinoma ( cis ) and in 363 controls , it was found that current smokers with a high hpv16 viral load at time of first smear were at a particularly increased risk ( 27-fold ) compared with current smokers without hpv - infection . some molecular mechanisms have been suggested through why smoking may contribute towards cervical carcinogenesis : one involves direct exposure of the deoxyribonucleic acid ( dna ) in cervical epithelial cells to nicotine and cotinine , and the other involves exposure to metabolic products resulting from the reactions of other components of cigarettes such as aromatic polycyclic hydrocarbons and aromatic amines . cervical mucus of smokers contains measurable amounts of cigarette constituents and their metabolites such as benzo[a]pyrene ( bap ) , nicotine , and nicotine derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone . bap up regulation of hpv genome amplification may increase the probability of viral dna integration into the host genome , a milestone in the development of cervical cancer . the in vivo effects of long - term nicotine exposure could affect persistent cellular proliferation , inhibition of apoptosis , and stimulation of vascular endothelial growth factor , with increased microvessel density . other mechanisms that may explain smoking - related carcinogenesis are related with abnormalities in the systemic and peripheral immune systems of smokers , that include unbalanced systemic production of pro- and anti - inflammatory cytokines , elevated numbers of cytotoxic / suppressor t lymphocytes , suppression of t lymphocyte activity , diminished numbers of helper t lymphocytes , decreased numbers of natural killer lymphocytes and low levels of immunoglobulins other than immunoglobulin e ( ige ) . these effects may result from substantial decreased numbers of langerhans cells in the cervix of smokers [ 30 , 31 ] . aberrant hpv - induced dna methylation may be another mechanism to explain cervical smoking - related carcinogenesis . in vitro studies in untransformed and transformed cell lines show that short - term exposure to nicotine or cigarette smoke extract is followed by changes in the expression of the dna methyltransferases dnmt1 , dnmt3a , and dnmt3b . aberrant methylation of the tumour suppressor gene , p16 ( cdnk2a ) , is strongly associated with current smoking in women with squamous cell cervical cancers and high - grade cin . intriguing studies analyzing wood - smoke effect on cervical carcinogenesis have shown that , among hpv - positive women , a dose - response relationship is observed for exposure to wood smoke and cervical cancer that persisted in multivariate analysis , and chronic exposure to wood smoke significantly increased the risk of cin iii , suggesting that chronic inhalation of carcinogens derived from wood smoke could have an effect on the progression to cervical cancer , similar to that observed for cigarette smoking . the regression of low squamous intraepithelial lesions ( lsil ) within 2 years is significantly lower in smokers than in never - smokers . for some authors , smoking have no influence in duration of hpv infection , for others tobacco delays the clearance of hpv infection [ 36 , 37 ] . covalent alteration of dna to form dna adducts is considered an early step in chemical carcinogenesis and , therefore , detection of dna adducts provides evidence of exposure of the cervix to carcinogens . had shown , in accordnce with previous studies , that significantly higher dna adduct levels are present in the cervix of smokers as compared with nonsmokers , providing molecular evidence of smoking - related carcinogenic agents that affects the dna of the cervical epithelium . however , the authors reported no significant differences in smoking - related dna damage ( dna adduct levels ) between hpv - positive and hpv - negative smokers , suggesting that smoking dna damage is not related with hpv infectivity . genetic susceptibility to smoking cervical cancer risk in smokers may be modified by genetic variants , as that described to interleukin 2   or to 8q24 chromosome polymorphisms . in a recent study , the tumor suppressors p53 , the fragile histidine triad and the interleukin-10 were under - expressed , and the cyclooxygenase-2 and the ki-67 were over - expressed in smoking , compared with nonsmoking women with cin . being older , being divorced , having friends / family who smoke , and having parents who smoke are all associated with ever smoking , and friends are the primary factor influencing ever smoking , especially among younger women . smokers seem to have lower compliance for cervical cancer screening , the most powerful weapon against cervical cancer mortality . smokers held less positive attitudes towards cervical screening than did nonsmokers , and the level of nicotine dependence is also significantly related to compliance with screening recommendations ; women with higher levels of dependence are less likely to be compliant . unhealthy life style , negatively rated life events , lack of social support , coping style , and distress , often associated with smoking , alcohol abuse , and illegal drugs addition , have been reported as risk factors for cervical cancer [ 4547 ] , especially among low - educated women [ 48 , 49 ] . in analyzing 24 studies worldwide that included 16,573 women with cervical cancer and 35,509 without cervical cancer , concluded that the relative risk of cervical cancer is increased in current users of oral contraceptives , and that increased risk is higher in current smokers women . oxidative stress induced by deficiencies in antioxidant micronutrients is likely to change normal redox balance and transform the hpv - infected cells toward a carcinogenic process in the cervix . reduced immunocompetence associated with deficiencies of folate and vitamin b12 could increase the risk of infection and persistence with multiple types or higher viral loads of hr - hpvs [ 5254 ] . higher prevalence rates of hpv have also been found in hiv - seropositive women , proportional to their level of immunosuppression [ 5557 ] . hiv - seropositive women , and particularly the current smokers , are at significantly elevated risk for the development and recurrence of precancerous and cancerous cervical disease [ 58 , 59 ] , especially those who have lower levels of th cells . it has been shown that th cells are involved in the defense against hpv - transformed cells . hence , immunosuppression in general , and depletion of th cells in particular , may interact with hpv infection to increase the risk of cervical cancer . recently , coker et al . , in analysing 2661 women diagnosed with invasive cervical cancer from 19952005 , found that , after adjustment for age and stage at diagnosis , cell type , rural residence , race , insurance coverage , and treatment - received , current smoker , were 35% more likely to die of any cause and 21% more likely to die of cervical cancer compared with known nonsmoking cases , in accordance with previous studies . all meta - analyses and multi - institutional studies point out that smoking is an important cofactor for cervical squamous cancer and probably also for cervical adenocarcinoma . acquisition of hr - hpv infection seems to be a smoking independent event ; however , progression of the acquired infection is negatively affected by current smoking . the action mechanisms of smoking on hpv driven cervical carcinogenesis seem to be complex and multifactorial . in current smokers , genetic , immunologic , and dietary factors may be associated with cervical epithelium susceptibility for hpv carcinogenic effect , but womens unhealthy lifestyles seem to be major factors associated with cervical carcinogenesis . what is much determinant for cervical cancer susceptibility : tobacco action by its own or women health or behaviour associated with smoking habits ? epidemiologic , clinical , and laboratorial research is needed to elucidate this unsolved topic .    in order to prevent cervical cancer and to improve therapy results , the practitioner should understand negative effects of tobacco on cervical carcinogenesis , and in those current smoking women with diagnosis of cervical hpv infection or cin , and he must have an active intervention to invite them to quit smoking habits . the researchers on cervical cancer should be aware that smoking habits are a major cofactor on cervical hpv driven carcinogenesis , and an important confounder factor for research .
cervical cancer ( cc ) is the third most common cancer in women worldwide ; however , cc is a preventable disease , and much effort should be done to prevent it . 
 persistence of high - risk hpv infection is the strongest epidemiologic risk factor for cc , however it is not sufficient for development of the disease it cofactors should be present . in 2004 ; iarc listed cervical cancer among those causally related to smoking . 
 smoking interferes with incidence and prevalence of hpv infection and is associated with cervical intraepithelial neoplasia and invasive cc . 
 multiple factors seem to intervene on cervical carcinogenesis related with tobacco , especially by direct local carcinogenic effect and local immunosuppression . 
 smoking addition is also closely related with other confounding factors , like unfavorable psychosocial events , systemic immunity , contraception , and nutrition , which got difficult epidemiologic evaluation of smoking role on cervical carcinogenesis . 
 smoking habits should be taken in account in clinical practice and in research concerning cc .