Cervical cancer - risk factors

This page presents risk factors for cervical cancer including, human papillomavirus (HPV), smoking, socioeconomic status and other factors. It is thought that 100% of cervical cancers are theoretically preventable, by preventing infection with HPV, which is present in all cervical cancers. Smoking also plays a part in causing some cervical cancer, increasing likelihood of infection with HPV or causing HPV infection to be more persistent. A study published in December 2011 estimated that around 7% of cervical cancers in the UK are caused by smoking.36

Cervical cancer risk factors:

 
 

Human papillomavirus (HPV) and cervical cancer risk

Members of the HPV family have been detected in cervical tumours worldwide with studies showing the presence of HPV in virtually all cervical tumours tested 1.

The highest risks are associated with HPV types 16 and 18. Most HPV infections will not progress to cervical intraepithelial neoplasia (CIN) . However, it is believed that cervical cancer will not develop without the presence of persistent HPV DNA and it has been proposed as the first ever identified “necessary cause” of a human cancer 2,37

Genital HPV is generally sexually transmitted through contact with infected cervical, vaginal, vulvar, penile or anal epithelium. Genital HPV infection may involve areas that are not easily covered by a condom so correct condom use may not protect against infection.

An analysis of studies on the prevalence of HPV infection in the population led to the conclusions that HPV is more common in younger women than older women, that HPV is rarely detected in women with no previous sexual activity and that there are no apparent geographical differences in HPV prevalence.

The percentage of the study populations who were HPV positive varied from 0% to 48% depending on the group studied. Results also show that HPV 16 infection is more common than any other classified type of HPV 3. Risk factors for HPV infection include number of sexual partners, a relatively recent new sexual relationship and a history of previous miscarriage 4.

A study has shown that the main risk factors for CIN 3 among HPV positive women are early age at first intercourse, long duration of the most recent sexual relationship and cigarette smoking. 4

For cigarette smoking there is a strong dose-response relationship. The risk of CIN 3 for women who were HPV positive and smoking 20 or more cigarettes a day was two and a half times that of women who had never smoked. The authors concluded that even though smoking was not a risk factor for HPV, smoking acted with HPV to cause cervical neoplasia (see also smoking section below).

Suggested co-factors for cervical cancer include age at first intercourse, number of life-time partners, co-infection with herpes simplex virus-2 or chlamydia trachomatis, parity, age at first birth, oral contraceptive use and family history 5,9,25-28. A lower risk has been shown in partners of men who have been circumcised. 29

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HPV vaccination

HPV vaccination for schoolgirls aged 12 to 13 in the UK was introduced in September 2008. The vaccine used, Cervarix, immunises against HPV types 16 and 18, which are the strains of the virus most commonly associated with cervical cancer.32 The vaccine was shown in a phase III clinical trial to provide 90% protection against CIN caused by either of these HPV types.33 The vaccine has also been shown to provide some protection against CIN caused  by other HPV types, and for women with evidence of previous infection with HPV 16 or 18 in blood samples.34, 35

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Smoking and cervical cancer risk

Cigarette smoking has been linked to inactivation in cervical tumours of the fragile histidine triad 6 putative tumour suppressor gene (which is also altered in most tobacco-associated lung cancers).

Smoking may also be associated with a decrease in the number of Langerhans’ immune cells in the cervix epithelium, suggesting a decrease in epithelial cell-mediated immune responses in smokers 7, 8.

The most recent meta-analysis showed that risk of squamous cell cervical cancer is increased by 50% in current smokers. 30 A study published in December 2011 estimated that around 7% of cervical cancer cases in 2010 (around 200 cases) were linked to smoking.38

Reduction in early cervical lesion size in women who gave up smoking after diagnosis has been reported 10. Also smokers have been found to have a 3-fold increased risk of treatment failure of CIN compared to non-smokers and therefore require more intensive follow-up after treatment 11.

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Socio-economic status and cervical cancer risk

In England and Wales 12, incidence and mortality from cervical cancer has been analysed by to Carstairs deprivation category ( Figure 4.1).

Figure 4.1: European age-standardised incidence of and mortality,cervical cancer by deprivation category, England and Wales, 1990-93

Download this chart (27KB)

Women living in the most deprived areas have rates more than three times as high as those in the least deprived areas. A strong positive association between cervical cancer and deprivation has also been described for incidence data from Scotland 13.

In addition a link has been demonstrated between social class and cervical cancer. Data from a longitudinal study, representing 1% of the England and Wales population, indicates that cervical cancer incidence is considerably higher among women of working age in manual than in non-manual classes 14.

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Other cervical cancer risk factors

As with smoking, the association between oral contraceptive (OC) use and cervical cancer is complicated by possible confounding with sexual behaviour 15. A meta-analysis found risk of invasive cervical cancer in current users of combined OCs increases by 7% for each year of use. The risk increase for five years of use is approximately 40%. The risk increase is temporary, and risk returns to the level of a never-user after 10 years of stopping use.17

A study published in December 2011 estimated that around 10% of cervical cancers in 2010 were linked to OCs. However, when the protective effect of OCs on ovarian and womb cancer were taken into account, OCs were estimated to have a net beneficial effect, reducing the number of cancers in women in the UK by almost 1,600.39

Other studies 20, 21 have investigated the use of hormone replacement therapy and cervical cancer, but there are no clear conclusions.

A recent meta-analysis showed that women with HIV/AIDS have a six-fold increased risk of cervical cancer and women who have undergone organ transplant have more than double the risk, strongly suggesting that immunosuppression plays a role. 22 The International Agency for Research on Cancer (IARC) states that HIV is a cause of cervical cancer.43

It has been estimated that around 1% of cervical cancers in women in the UK are linked to occupation.40,42 This estimate was based on exposure to tetrachloroethylene, which is classified by IARC as probably carcinogenic to humans.42,43 Exposure can take place in dry cleaning and metal degreasing.41

Diethylstilboestrol (DES) is a drug that was given to some women in the 1940s-60s to prevent miscarriage. IARC states that exposure to DES in the womb is a cause of cervical cancer.43

Risk of cervical cancer is approximately doubled in women with a mother or sister who has been diagnosed with the disease. 31

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References for cervical cancer risk factors

  1.  Walboomers, J.M.M. and C. Meijer, Do HPV-negative cervical carcinomas exist?[editorial]. Journal Pathology, 1997. 181: p. 253-254.
  2.  Bosch, F.X., et al., The causal relation between human papillomavirus and cervical cancer. Journal of clinical pathology, 2002. 55(4): p. 244-265.
  3.  International Agency for Research on Cancer, IARC Monographs on the evaluation of carcinogenic risks to humans: human papillomaviruses. Vol. 64. 1995, Lyon: World Health Organisation.
  4.  Deacon, J., et al., Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN 3 among those infected. A case-control study nested within the Manchester cohort. Br J Cancer, 2000. 83: p. 1565-1572.
  5.  Schottenfeld, D. and J. Fraumeni, eds. Cancer epidemiology and prevention. 2nd ed. 1996, Oxford University Press: Oxford.
  6.  Holschneider, C., et al. Lost fragile histidine triad (FHIT) gene expression may link cigarette smoking and cervical cancer [abstract]. in Program and Abstracts of the Society for Gynecologic Oncologists 31st Annual Meeting; February 5-9. 2000. San Diego, California.
  7.  Derchain, S., et al., Langerhans' cells in cervical condyloma and intraepithelial neoplasia in smoking and non-smoking adolescents. Acta Derm Venereol, 1996. 76(6): p. 493-494.
  8.  Poppe, W., et al., Langerhans' cells and L1 antigen expression in normal and abnormal squamous epithelium of the cervical transformation zone. Gynecol Obstet Invest, 1996. 41(3): p. 207-213.
  9.  Berrington de Gonzalez, A., et al., Comparison of risk factors for squamous cell and adenocarcinomas of the cervix: a meta-analysis. Br J Cancer, 2004. 90(9): p. 1787-91.
  10.  Szarewski, A., M.J. Jarvis, and P. Sasieni, Effect of smoking cessation on cervical lesion size. Lancet, 1996. 347: p. 941-943.
  11.  Acladious, N., et al., Persistent human papillomavirus infection and smoking increase risk of failure of treatment of cervical intraepithelial neoplasia (CIN). International Journal of Cancer, 2002. 98(3): p. 435-439.
  12.  Quinn, M., et al., Cancer Trends in England & Wales 1950-1999. Vol. SMPS No. 66. 2001: TSO.
  13.  Harris, V., et al., Cancer Registration Statistics: Scotland 1986-1995. 1998, Edinburgh: ISD Scotland Publications.
  14.  Brown, J., S. Harding, and A. Bethune, Incidence of Health of the nation cancers by social class. Population Trends, 1997.
  15.  Zondervan, K., et al., Oral Contraceptives and Cervical Cancer- Further findings from the Oxford Family Planning Association contraceptive study. British Journal of Cancer, 1996. 73: p. 1291-1297.
  16.  Beral, V., C. Hermon, and C. Kay, Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from Royal College of General practitioners' oral contraception study. British Medical Journal, 1999. 318: p. 96-100.
  17.  Appleby, P., et al., Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet, 2007. 370 (9599): p. 1609-21.
  18.  Hildesheim, A., et al., HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica. Br J Cancer, 2001. 84(9): p. 1219-1226.
  19.  Munoz, N., et al., Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet, 2002. 359: p. 1093-1101.
  20.  Parazzini, F., et al., Case-control study of ostrogen replacement therapy and risk of cervical cancer. British Medical Journal, 1997. 315: p. 85-88.
  21.  Lacey, J.J., et al., Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix. Gynecologic Oncology, 2000. 77: p. 149-154.
  22.  Grulich, A.E., et al., Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis.Lancet, 2007. 370(9581): p. 59-67.
  23.  Gallagher, B., et al., Cancer incidence in New York State acquired immunodeficiency syndrome patients.American Journal of Epidemiology, 2001. 154(6): p. 544-556.
  24.  Dal Maso, L., Serraino, D. and Franceschi, S. Epidemiology of AIDS-related tumours in developed and developing countries. European Journal of Cancer, 2001. 37(10): p. 1188-1201.
  25.  Smith, J.S., et al., Herpes Simplex Virus-2 as a Human Papillomavirus Cofactor in the Etiology of Invasive Cervical Cancer. JNCI, 2002. 94(21): p. 1604-1625.
  26.  Smith, J.S., et al., Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case-control study. Int J Cancer, 2004. 111(3): p. 431-9.
  27.  Madeleine, M.M., et al., Risk of cervical cancer associated with Chlamydia trachomatis antibodies by histology, HPV type and HPV cofactors. Int J Cancer, 2007. 120(3): p. 650-5.
  28.  Hemminki, K., et al., Familial risks for cervical tumors in full and half siblings: etiologic apportioning. Cancer Epidemiol Biomarkers Prev, 2006. 15(7): p. 1413-4.
  29.  Castellsague, X., et al., Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med, 2002. 346(15): p. 1105-1112.
  30.  Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer, 2007. 120(4): p. 885-91.
  31.  Familial clustering of cancer at human papillomavirus-associated sites according to the Swedish Family-Cancer Database. Int J Cancer, 2008. 122(8): p. 1873-8.
  32.  Clifford, G.M., Smith, J.S., Plummer, M. et al.Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer, 2003. 88(1): p. 63-73.
  33.  Paavonen, J., Jenkins, D., Bosch, F.X. et al.Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet, 2007. 369(9580): p. 2161-70.
  34.  Paavonen, J., Naud, P., Salmeron, J. et al.Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet, 2009. 374(9686): p. 301-14.
  35.  Szarewski, A., Poppe, W., Skinner, S. et al.Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18. Int J Cancer, 2011.
  36.  Parkin, D.M., Boyd, L., Walker, L.C. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Summary and conclusions. Br J Cancer, 6 Dec 2011; 105 (S2):S77-S81; doi: 10.1038/bjc.2011.489
  37.  Parkin, D.M. Cancers attributable to infection in the UK in 2010. Br J Cancer, 6 Dec 2011; 105 (S2):S49-S56; doi: 10.1038/bjc.2011.484
  38.  Parkin, D.M. Tobacco-attributable cancer burden in the UK in 2010. Br J Cancer, 6 Dec 2011; 105 (S2):S6-S13; doi: 10.1038/bjc.2011.475
  39.  Parkin, D.M. Cancers attributable to exposure to hormones in the UK in 2010. Br J Cancer, 6 Dec 2011; 105 (S2):S42-S48; doi: 10.1038/bjc.2011.483
  40.  Parkin, D.M. Cancers attributable to occupational exposures in the UK in 2010. Br J Cancer, 6 Dec 2011; 105 (S2):S70-S72; doi: 10.1038/bjc.2011.487
  41.  Siemiatycki, J, Richardson, L, Straif, K. et al.Listing occupational carcinogens. Environ Health Perspect, 2004. 112(15): p. 1447-59.
  42.  Rushton, L., Bagga, S., Bevan, R., et al. Occupation and cancer in Britain. Br J Cancer, 2010. 102: p. 1428-1437
  43.  Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human cancers. JNCI, 2011. 103: p. 1827-39