Section 1: Epidemiology and aetiology
Cervical cancer is a major cause of morbidity and mortality worldwide, particularly in countries without organised screening programmes.
It is the second most common cancer and the third leading cause of death in women worldwide after breast and lung cancer.1 Each year, an estimated 400,000 women develop cervical cancer and 270,000 die of the disease. Cervical cancer is common between the ages of 30 and 45, thus affecting women with young families.
Infection with certain types of sexually transmitted human papillomavirus (HPV) is the main cause of cervical cancer.
HPVs are members of a large family of viruses. The so-called low-risk types (HPV 6 and 11) are responsible for genital warts, while the high-risk types (mainly HPV 16, 18, 31, 33, 35, 45, 52 and 56) are implicated in cervical cancer.
Among these, HPV 16 and 18 cause approximately 70% of cervical cancers worldwide, while the next most prevalent oncogenic type is HPV 45.2 It should be noted that HPV 45 is more frequent in adenocarcinoma (12% of cases) than squamous cancer (5% of cases).
Adenocarcinoma represents up to 25% of cervical cancers. It is more difficult to detect than squamous cancer and its incidence and mortality are rising considerably in many countries. Together, HPV 16, 18 and 45 cause 75% of squamous cell carcinoma (SCC) and 94% of adenocarcinoma. The next five most common oncogenic HPV types (HPV 31, 33, 35, 52 and 58) together cause another 15% of all cervical cancers.2
In addition, HPV types 16 and 18 together account for about 90% of anal cancers and approximately half of all vulval and vaginal cancers.1
In men, as well as anal disease, HPV causes penile intraepithelial neoplasia and about 50% of penile cancers.3 HPV can also cause non-genital disease; it can cause disease on the skin, and the mucous membranes of the head and neck, where it is increasingly being found in oropharyngeal cancers.4
Genital warts are caused by infection with low-risk HPV types, mainly 6 and 11. Genital warts are the most common viral STI in the UK, with 81,000 new diagnoses in 2005, and a 30% increase in the past 10 years.5
HPV types 6 and 11 are also responsible for virtually all cases of recurrent respiratory papillomatosis, a rare but extremely distressing condition in young children.5
Section 2: HPV transmission and identification
HPV infections are transmitted mainly by skin-to-skin contact. Male circumcision appears to significantly reduce male HPV infection and carriage, possibly due to the toughness of keratinised epithelium, thereby reducing transmission.6
Penetrative sexual intercourse is not strictly necessary for transmission and HPV types can apparently be transferred to the cervix from original infection at the introitus.
Risk factors for transmission are related predominantly to sexual behaviour, such as early age at first sexual intercourse, number of sexual partners, acquisition of new partners and the number of lifetime partners of the male partner. Infection with HPV is extremely common in young people, with a prevalence of 20-60%, but is usually transient. About 80% of sexually active women will be infected with HPV by the age of 50,7 but it appears the presence of HPV is more meaningful in older women (over 30), who have persistent infection.
Peak infection rates occur in young women (under 25), then fall in the 30s, and in some but not all populations, there is a slight rise in the late 40s and early 50s. The reasons for this rise in older women may relate to changes in sexual behaviour, such as increasing divorce rates in older age groups.
The male partner
It has been shown repeatedly that the risk of cervical cancer among monogamous women increases with the number of sexual partners of their male partner. One study reported that subsequent wives of husbands whose previous wife developed cervical cancer had an increased risk of cervical neoplasia, and other studies have shown that wives of men with cancer of the penis have a higher incidence of, and mortality rates for, cervical cancer.8
Testing for HPV
Liquid-based cytology (LBC) has enabled the introduction of testing for HPV, initially as a triage test following borderline and mildly abnormal cytology.
If high-risk HPV is found, these women will be referred for colposcopy. If HPV is not found, there is very little chance of any abnormality being present and they will be returned to routine screening. HPV testing also has practical advantages over cytology, in that it is carried out by machines, so is more reproducible and less subjective.
A number of HPV tests are available, whose characteristics are somewhat different. However, it should be remembered that a single HPV test of any kind does not discriminate between transient and chronic infection; such discrimination is important because it is the persistent infection that predisposes to progression to cervical neoplasia, not the transient one. In practice, therefore, many women who test positive for HPV will have no cervical abnormality.9
The HPV vaccines are composed of virus-like particles with the outward appearance of the virus (Photograph: SPL)
Section 3: Managing the condition
A feature of HPV is that it is very successful at avoiding the host immune system and therefore causing natural immunity.
HPV infects basal keratinocytes; it does not speed up or change the life cycle of the keratinocytes and there is no inflammation or provocation of immune messengers. As a result, the humoral immune system does not notice the virus, potentially allowing chronic, persistent infection to occur.10
When the epithelial cells containing HPV are shed as a natural event, the virus travels to a new destination. Despite this ability to impede host defences, a successful immune response to genital HPV infection does seem to occur in most people. The mechanism appears to be a local cell-mediated immune response associated with lesion regression and the generation of serum neutralising antibodies.10 However, after natural HPV infections, antibody levels are low and reinfection, even with the same HPV type, can occur.
Most cervical HPV infections are cleared within one to two years of exposure. Studies have shown that following infection, 50% of women will test negative at six months, 70%, negative at one year and 80-92%, negative at two years.11 If the infection is not cleared, it becomes persistent (in about 10% of cases) and this is associated with an increased risk of precancer.12
Risk of persistence
There are a number of risk factors for persistence. HPV type is the most important. HPV 16 is highly carcinogenic, with an absolute risk of a precancer approaching 40% after three to five years of persistent infection.13 Smoking, multiparity and long-term use of oral contraceptives are associated with double or triple the risk of precancer and cancer among women infected with high-risk HPV types.
Smoking has been found to be significantly associated with an increased risk of SCC, although not adenocarcinoma. Smoking may increase the risk of acquisition and persistence of HPV infection. Smokers tend to report more sexual partners than non-smokers, but smoking has also been reported to impair immune response and may therefore interfere with the clearance of HPV infection.14
An association between condom use and decreased persistence or progression has been seen in a few studies. Immunocompromised patients, such as those with HIV or those on immunosuppressive medication, are at greater risk of persistent infection and high-grade CIN.
In the UK, the incidence of cervical cancer has dropped substantially since 1988, when the UK national call-recall system began. However, approximately 2,800 women per year still develop cervical cancer. Meanwhile, the diagnosis and treatment of precancerous cervical abnormalities results in significant anxiety, as do inadequate cytology results.9
The UK now uses LBC, which greatly reduces the number of inadequate smears and allows the same sample to be used for other tests, such as HPV testing. This has allowed the introduction of 'reflex' HPV testing for triage - if a woman has a borderline or mildly abnormal smear, her LBC sample can be tested for HPV, without the need for another examination. If the HPV test is negative, this would be reassuring, because it almost completely rules out any possibility of disease.
A disadvantage is that transient HPV infections are very common in women under the age of 30 years. A single positive HPV test does not discriminate between transient and chronic infection, which is an important failing, because it is only the persistent infection that predisposes to progression to cervical neoplasia.
Vaccination against HPV
There are now two prophylactic HPV vaccines available.
Cervarix covers HPV types 16 and 18, and Gardasil covers 16, 18 and the two low-risk HPV types, 6 and 11.
Both vaccines are composed of virus-like particles, with the outward appearance of the virus (thus generating a powerful immune response), but are harmless because they contain no DNA. Gardasil offers protection against genital warts, which Cervarix does not, but Cervarix offers cross-protection against non-vaccine high-risk HPV types (for example, 31, 33 and 45), and therefore has been shown to give a higher degree of protection against high-grade cervical disease.15-17
The UK has had a national vaccination programme in place since 2008 for 12-13-year-old girls. Cervarix has been used in the programme until now, but from the autumn of 2012, the vaccine used will be Gardasil.
For both vaccines, the duration of protection is not known, so we do not know if a booster will be required, but there are data showing protection for up to 8.4 years for Cervarix and 4.5 years for Gardasil.
Section 4: Education
Although there has been some information accompanying the HPV vaccination programme, the introduction of HPV testing in the next couple of years will necessitate an improvement in knowledge among healthcare professionals and the public. Testing positive for HPV may be associated with feelings of anxiety, shame and stigma.9
Epithelial cells infected with HPV (Photograph: SPL)
Acquisition of information from the internet is common and likely to increase, with all of the problems that entails. A particular area of confusion is the difference between low-risk (genital warts) and high-risk (oncogenic) HPV types.
Doctors and nurses must be able to explain HPV in a way that is informed and culturally sensitive. The websites mentioned in the case study are most helpful in providing up-to-date information, phrased in a way that most people should understand.
Section 5: Case study
Susan, aged 32, came to the clinic in a terrible state. She had been for her routine three-yearly smear test and the result came back with borderline changes and a positive HPV result.
She was not so worried about the smear result, but had gathered from the internet that HPV was sexually transmitted and was now convinced her partner had been unfaithful.
This is a common concern, because it cannot be denied that HPV is sexually transmitted. However, HPV infection can lie dormant for some time, so it is impossible to be certain when it was acquired. Either she or her partner could already have been infected from a previous relationship.
Susan had many questions about the significance of the positive HPV test, such as whether she would have HPV forever. The answer is probably not. HPV infection is very common, but it usually clears, or is suppressed by the immune system, within one to two years.
Did it mean she was more likely to have cancer? How would she know if she did? If she had it, was her partner infected and could he reinfect her? She also asked if she had warts or dysplasia, and if so, did that mean she would have recurrences for the rest of her life? Warts and dysplasia do recur in some cases, but by no means all, and when they recur, show varying persistence.
These are just a selection of the many questions a patient might ask. In these cases, it is very useful to direct patients to Jo's Trust (www.jotrust.co.uk/)and the American Social Health Association (www.ashastd.org/std-sti/hpv.html) where they can find information and think about it, perhaps coming back for an appointment to discuss remaining or further concerns.
Section 6: Evidence base
- Kelly RS, Patnick J, Kitchener HC et al on behalf of the NHSCSP HPV Special Interest Group. HPV testing as a triage for borderline or mild dyskaryosis on cervical cytology: results from the Sentinel Sites study. Br J Cancer 2011: 1-6. doi:10.1038/bjc.2011.326.
Cervarix: phase III trials
- Lehtinen M, Paavonen J, Wheeler CM et al. For the HPV PATRICIA Study Group. Overall efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical intraepithelial neoplasia grade 3 or greater: end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2011; 13(1): 89-99.
- Wheeler CM, Castellsague X, Garland SM et al. For the HPV PATRICIA Study Group. Cross-protective efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: end-of-study (4-year) analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2011; 13(1): 100-10.
Gardasil: phase III trials
- FUTURE II Study Group. Four year efficacy of prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine against low-grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ 2010; 340: c3493.
- Kjaer SK, Sigurdsson K, Iversen O-E et al. A pooled analysis of continued prophylactic efficacy of quadrivalent HPV (types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. Cancer Prev Res 2009; 2: 868-78.
- Dr Szarewski has received conference sponsorship, honoraria and consultancy fees from GSK and Merck, Sharp and Dohme. She is an investigator in two GSK phase III HPV 16/18 vaccine trials
- Women's Health conference, 27 September 2012, London.
- Visit the GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum
- Contributed by Dr Anne Szarewski, clinical senior lecturer at the Wolfson Institute of Preventive Medicine, Queen Mary, University of London.
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