Causes

From National Cancer Control Policy


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Causes

Persistent infection with human papillomavirus (HPV) causes an estimated 5% of the total global cancer burden[1]. HPV has been identified in 99.7% of cervical cancer specimens[2], and a significant proportion of anal, vaginal, vulval, penile and head and neck 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[3].

Of the more than 40 anogenital HPV types, 15 are classified as ‘high risk’ based on the strength of their association with cervical cancer. HPV types 16, 18 and 45 are responsible for nearly all cases of cervical cancer worldwide[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 certainly not sufficient[2]. 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].

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Human papillomavirus

Species-specific papillomaviruses infect a range of animals, including humans. Over 100 different types of HPV have been identified. The majority of HPV types infect only epithelial cells of the skin and mucosa. Most produce no evident disease. Some HPV types have been associated with anogenital and aerodigestive diseases[9]. Some produce proliferative lesions (warts) of skin and genital skin, and these tend to be grouped as low and high risk based on their potential to cause malignancy.

Anogenital HPVs are the most common sexually transmitted infections. There are more than 40 anogenital HPV types, 15 of which are classified as ‘high risk’[10]. High risk types can establish persistent infection and cause abnormalities which, in rare cases, progress to cancer. A recent meta-analysis suggests some of these types have relatively low carcinogenic potential, and types 16, 18 and 45 are the cause of virtually all cases of cervical cancer worldwide[4].

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HPV transmission

Genital HPVs are primarily transmitted through sexual contact (genital-genital or genital-anal), though this need not include penetrative sexual intercourse. Other modes of transmission, including perinatal, digital, oral and autoinoculation, are thought to be less common[11]. HPV infections are thought to be established in the basal epithelium through abrasion or microtrauma of the superficial epithelium[12].

Genital HPV infection is common in sexually active adults. A study of cervical HPV prevalence found multiple infections were common in Australian women, with a wide range of HPV types detected (HPV 16 being the most common) and incidence peaking in the years following the start of sexual activity[13]. International data show prevalence is high even in young women who are with their first partner and are monogamous, with HPV infection rates of 30% within one year of becoming sexually active and 48% within three years[14]. Most infections are self-limiting or cleared by the immune system within one to two years[15]. 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[16].

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HPV infection and cancer

HPV infections can induce the development of either benign or malignant lesions. Benign lesions include non-genital and anogenital skin warts, oral and laryngeal papillomas and anogenital mucosal condylomata[12].

Persistent infection with high-risk HPVs are generally subclinical, but can result in the development of a range of anogenital tumours including cancers of the cervix, anus, penis, vulva and vagina[12]. HPV infection is associated with squamous cell carcinomas of the head and neck, particularly oropharyngeal cancers[17]. There is continuing research into the possible role of HPV infection in the development of cancers in other sites.

In 2007 the International Agency for Research on Cancer published an analysis of the evidence linking HPV infection to specific cancers, outlined in Table 1[10].


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

HPV type Sufficient Limited Inadequate
HPV 16 Cervix, vulva, penis, vagina, anus, oral cavity, oropharynx Larynx, periungual skin (squamous-cell carcinoma)
HPV 18 Cervix Vulva, penis, vagina, anus, oral cavity and larynx
HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 Cervix
HPV 6, 11 Squamous-cell carcinoma of the larynx and verrucous carcinomas of the vulva, penis and anus
HPV genus-beta types Skin (squamous-cell carcinoma)*
HPV Conjunctiva (squamous-cell carcinoma) Oesophagus, lung, colon, ovary, breast, prostate, urinary bladder and nasal and sinonasal cavities

* In the rare case of patients with epidermodysplasia verruciformis, there is compelling evidence for the carcinogenicity of HPV genus-beta types 5 and 8 in the skin (squamous-cell carcinoma)
Source: IARC 2007[10]

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HPV and cervical cancer

The association between HPV and cervical cancer was determined in the 1970s, but it was not until the mid-1990s that the primary role of HPV in the development of cervical cancer was definitively confirmed[18]. HPV has been identified in 99.7% of cervical cancer specimens[2].

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[19]. More than 70% of squamous cell carcinomas and about 78% of adenocarcinomas are caused by high-risk HPV types 16 and 18[20]. HPV 16 is the most carcinogenic, accounting for about 55-60% of cervical cancers; HPV 18 accounts for a further 10-15% of cervical cancers[21][22]. Women with persistent infections, especially with HPV 16, are at significantly higher risk of CIN3 and cervical cancer[23][24][25].

The four major steps in cervical cancer development are HPV infection/acquisition, viral persistence (vs clearance), progression to cervical precancer and invasion[26]. It is estimated that it takes an average of 10 years from HPV infection to malignant progression[27].

It previously was thought that the development of cervical cancer involved progression from low to moderate to high-grade intraepithelial lesions (HSIL), but studies have shown that low and high-grade cervical lesions are distinct HPV processes[9]. 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[28]. Most high-grade abnormalities also regress over time, but regression takes longer[29].

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[9]. HSILs were indicated in 0.8% of cytology tests in Australia in 2009. Histologically verified HSIL includes the subcategory CIN3 or pre-cancer.

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Other risk factors

Current cigarette smoking is associated with a significantly increased risk of squamous cell carcinoma, but not of adenocarcinoma[30].

Co-factors that increase the risk of cervical cancer progressing in women who have a persistent high-risk HPV infection include:

  • multiparity (more than five full-term pregnancies)[31];
  • early age at first full-term pregnancy[31]; and
  • the use of oral contraceptives[32].

Immunodeficiency (acquired through chronic immunosuppresion, for example HIV infection) contributes significantly to persisting HPV infection and cervical cancer risk[33].

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References

  1. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006 Jun 15;118(12):3030-44 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16404738.
  2. 2.0 2.1 2.2 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.
  3. 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.
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  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/.
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  9. 9.0 9.1 9.2 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.
  10. 10.0 10.1 10.2 International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, volume 90. Human papillomaviruses. Lyon, France: IARC; 2007 Available from: http://monographs.iarc.fr/ENG/Monographs/vol90/mono90.pdf.
  11. 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.
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  13. WHINURS study group, Garland SM, Brotherton JM, Condon JR, McIntyre PB, Stevens MP, et al. Human papillomavirus prevalence among indigenous and non-indigenous Australian women prior to a national HPV vaccination program. BMC Med 2011 Sep 13;9:104 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21910918.
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  29. 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.
  30. 31.0 31.1 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.
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  32. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007 Jul 7;370(9581):59-67 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17617273.

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