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

Source: IARC 2012 ^[13]

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]