Causes

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Causes


Human papillomavirus

Persistent infection with human papillomavirus (HPV) causes an estimated 30% of the total global cancer burden.[1] HPV has been identified in 100% of cervical cancer cases[1] and a significant proportion of anal, vaginal, vulval, penile and oropharyngeal cancers.

HPV is a common, and usually asymptomatic, sexually transmitted infection. Almost all individuals become infected with HPV within two to five years of becoming sexually active.[2]

Of the more than 40 anogenital HPV types, 12 are classified as Group 1 carcinogens (‘high risk’) based on the strength of their association with cervical cancer and are responsible for nearly all cases of cervical cancer worldwide.[3][4] HPV types 16 and 18 are detected in more than 70% of cases of cervical cancer in Australia.[5]

While HPV infection is necessary for the development of cervical cancer, it is not sufficient, and a variety of factors influence whether cancer will develop.[3] Worldwide, there are estimated to be about 100 million adult women who are infected with high-risk HPV types.[6] This compares with approximately 528,000 new cases of cervical cancer worldwide each year.[7] Cervical cancer is a very rare outcome in relation to the high prevalence of HPV infection. However, the risk of developing cancer increases significantly with persistent HPV infection.[8]

HPV transmission

Genital HPVs are primarily transmitted through sexual contact (genital-genital or genital-anal). Other modes of transmission, including perinatal, digital, oral and autoinoculation, are thought to be less common.[9] HPV infections are thought to be established in the basal epithelium through abrasion or microtrauma of the superficial epithelium.[10]

Genital HPV infection is common in sexually active adults. Most infections are self-limiting or cleared by the immune system within one to two years.[11] HPV prevalence peaks soon after the average age of first sexual intercourse; prevalence among women aged over 30 years is much lower than among younger women.[12]

Table 1. Summary of levels of evidence for carcinogenicity of HPV types by cancer site

HPV type Sufficient Limited
HPV 16 Cervix, vulva, penis, vagina, anus, oral cavity, oropharynx and tonsil Larynx
HPV 18 Cervix Vulva, penis, vagina, anus, oral cavity and larynx
HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 Cervix 33: vulva and anus
HPV types 26, 53, 66, 67, 68, 70, 73, 82 Cervix


Source: IARC 2012 [13]

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HPV and cervical cancer

Research has distinguished between high-risk (oncogenic) and low-risk (non-oncogenic) types of HPV. Cervical cancer and its immediate precursor lesion (CIN3) only develop after many years of persistent infection with a high-risk type of HPV.[14] Australian data has shown that around 70% of squamous cell carcinomas and about 77% of adenocarcinomas are caused by high-risk HPV types 16 and 18.[5] HPV 16 accounts for about 55-60% of cervical cancers; HPV 18 accounts for a further 15-20% of cervical cancers.[5]

The four major steps in cervical cancer development are HPV infection/acquisition, viral persistence (versus clearance), progression to cervical precancer and invasion.[15] It is estimated that it takes an average of 10 years from HPV infection to malignant progression.[16]

Low and high-grade cervical lesions are distinct HPV processes.[17] It is now accepted that low-grade squamous intraepithelial lesions represent acute HPV infection (high- or low-risk) rather than cancer precursors,[4] most of which will resolve spontaneously within 12 months.[18] Most high-grade intraepithelial lesions (HSILs) also regress over time, but regression takes longer.[19]

Pre-cancerous lesions (CIN3) occur when oncogenic HPV is not cleared, infects immature cells and prevents maturation and differentiation, resulting in the replication of immature cells and the accrual of genetic changes that can lead to cervical cancer.[17] HSILs were indicated in 0.8% of cytology tests in Australia in 2009.

Other risk factors

Tobacco smoking, number of pregnancies and immunosuppression are established co-factors of HPV in cervical cancer.[13] Current cigarette smoking is associated with a significantly increased risk of squamous cell carcinoma, but not of adenocarcinoma.[20] Another co-factor that increases the risk of progression to cervical cancer in women who have a persistent high-risk HPV infection is early age at first full-term pregnancy.[21] Combined oestrogen-progestogen oral contraceptives have been classified as carcinogenic to humans and there is sufficient evidence that it causes cervical cancer, independent of HPV.[22]

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References

  1. 1.0 1.1 Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health 2016 Sep;4(9):e609-16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27470177.
  2. Wright TC, Bosch FX, Franco EL, Cuzick J, Schiller JT, Garnett GP, et al. Chapter 30: HPV vaccines and screening in the prevention of cervical cancer; conclusions from a 2006 workshop of international experts. Vaccine 2006 Aug 31;24 Suppl 3:S3/251-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16950014.
  3. 3.0 3.1 Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999 Sep;189(1):12-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10451482.
  4. 4.0 4.1 Guan P, Howell-Jones R, Li N, Bruni L, de Sanjosé S, Franceschi S, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer 2012 Nov 15;131(10):2349-59 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22323075.
  5. 5.0 5.1 5.2 Brotherton JML, Tabrizi SN, Phillips S, Pyman J, Cornall AM, Lambie N, et al. Looking beyond human papillomavirus (HPV) genotype 16 and 18: Defining HPV genotype distribution in cervical cancers in Australia prior to vaccination. Int J Cancer 2017 Oct 15;141(8):1576-1584 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28677147.
  6. Giles M, Garland S. Human papillomavirus infection: an old disease, a new vaccine. Aust N Z J Obstet Gynaecol 2006 Jun;46(3):180-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16704468.
  7. International Agency for Research on Cancer. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. Lyon, France: IARC; 2013 Dec Available from: http://globocan.iarc.fr/.
  8. Koshiol J, Lindsay L, Pimenta JM, Poole C, Jenkins D, Smith JS. Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis. Am J Epidemiol 2008 Jul 15;168(2):123-37 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18483125.
  9. International Agency for Research on Cancer. IARC handbooks of cancer prevention: volume 10 - cervix cancer screening. Lyon: IARC Press; 2005 Available from: http://www.iarc.fr/en/publications/pdfs-online/prev/handbook10/HANDBOOK10.pdf.
  10. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest 2006 May;116(5):1167-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16670757.
  11. Stanley M. Immune responses to human papillomavirus. Vaccine 2006 Mar 30;24 Suppl 1:S16-22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16219398.
  12. Franceschi S, Herrero R, Clifford GM, Snijders PJ, Arslan A, Anh PT, et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer 2006 Dec 1;119(11):2677-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16991121.
  13. 13.0 13.1 International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, volume 100 B. A review of human carcinogens: Biological agents. Lyon, France: IARC; 2012 Available from: http://monographs.iarc.fr/ENG/Monographs/vol100B/mono100B-11.pdf.
  14. Nobbenhuis MA, Walboomers JM, Helmerhorst TJ, Rozendaal L, Remmink AJ, Risse EK, et al. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Lancet 1999 Jul 3;354(9172):20-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10406360.
  15. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet 2007 Sep 8;370(9590):890-907 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17826171.
  16. Schiffman M, Kjaer SK. Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr 2003;(31):14-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12807940.
  17. 17.0 17.1 Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol 2005 Mar;32 Suppl 1:S16-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15753008.
  18. Proyecto Epidemiológico Guanacaste Group, Rodríguez AC, Schiffman M, Herrero R, Wacholder S, Hildesheim A, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008 Apr 2;100(7):513-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18364507.
  19. Schlecht NF, Platt RW, Duarte-Franco E, Costa MC, Sobrinho JP, Prado JC, et al. Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst 2003 Sep 3;95(17):1336-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12953088.
  20. International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, Berrington de González A, Colin D, Franceschi S, et al. Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 2006 Mar 15;118(6):1481-95 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16206285.
  21. International Collaboration of Epidemiological Studies of Cervical Cancer. Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. Int J Cancer 2006 Sep 1;119(5):1108-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16570271.
  22. International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, volume 100 A. A review of human carcinogens: Pharmaceuticals. Lyon, France: IARC; 2012 Available from: https://monographs.iarc.fr/wp-content/uploads/2018/06/mono100A-19.pdf.

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