Human papillomavirus, warts and genital cancers

HPV causes warts on the skin and mucous membranes. These often disappear after a few weeks or months as the immune system fights off the viral infection. Some types of HPV can be spread sexually, causing genital warts in women at the cervix (the 'neck' of the womb at the top of the vagina) and vulva, on the penis in men, and around and inside the anus in both sexes. If genital warts are successfully treated the HPV becomes inactive, but remains in the body.

HPV is a very common infection, with prevalence rates of 30 to 40% in young adults: in 2004, there were around 80,000 cases in the United Kingdom, representing an increase of 4% on the previous year. Infection rates are higher in people with HIV.

There are many different strains of HPV, each of which is denoted by a unique number. Infection with oncogenic (cancer-causing) strains of HPV can cause cells to grow in abnormal ways, which can ultimately lead to cancer. In HIV-positive people, HPV is more likely to cause the cellular changes that may lead to cancer. Strains 16, 18, 31, 33 and 35 are more strongly associated with the development of genital cancers. Since many other non-oncogenic strains can cause genital warts, a history of genital warts does not necessarily mean a risk of anogenital cancer.

HPV has also been linked to some mouth and throat cancers.

There are several ways of classifying the severity of HPV-associated lesions and cellular changes:

• Dysplasia refers to any degree of cell abnormality. It is graded on the following scale: normal (i.e., absent), very mild, mild, moderate, and severe. Dysplasia is sometimes called 'pre-cancer'. Actual cancerous changes are referred to as carcinoma.
• Cervical or anal intraepithelial neoplasia (CIN or AIN), which refers to abnormal growth within the cells lining the cervix or the anus. CIN or AIN may be graded as condylomata (warts), grade 1, 2 or 3.
• Squamous intraepithelial lesions (SIL) also refers to an abnormal cell growth within the cell lining of the cervix or the anus, as well as the vagina or vulva (vulvovaginal lesions). SIL is classified as either low-grade or high-grade. Low-grade SIL is equivalent to CIN or AIN grade 1; high-grade SIL is equivalent to CIN or AIN grades 2 or 3.

Cervical or anal cytology techniques, such as a test called a Papanicolaou ('Pap') smear, can be used to identify abnormal or pre-cancerous cells, which then can be treated if necessary. Advanced immune deficiency is associated with a greater rate of abnormal Pap smear results.

Many people are infected with HPV but only a few develop HPV-related cancer. Although untreated abnormal cell growths may progress to life-threatening invasive cancer , in most cases they do not. Current research is trying to determine what factors lead to the development of cancer. There is evidence that abnormal hormone levels and viral mutations may play a role. Immune damage caused by HIV may increase the risk of developing cervical or anal cancer .

Despite assumptions to the contrary, two recent Dutch studies have shown that consistent condom use can help the clearance of HPV and the regression of CIN in women, as well as speed the regression of penile warts in men whose female partners have CIN.^{1 2}

Several vaccines against oncogenic (cancer-causing) strains of HPV are being developed. Of these, two (Gardasil and Cervarix) are currently approved in many countries including the UK and US, and others are nearing approval or under development. Thus far, such targeted vaccines have shown dramatic protective benefits against HPV infection when used prior to exposure, but very limited benefits in those already exposed. Most trials thus far have focused on cervical cancer in women; studies are beginning to examine effects on anal HPV infection in women and in men.

Genital warts are flattish, cauliflower-like protuberances which can be small or large and appear singly or in clumps. Other HPV-related abnormalities, such as cancerous changes in the cells of the cervix or rectum, may not cause any outwardly recognisable symptoms until the condition is advanced.

Warts are usually diagnosed visually by examination of the vagina, vulva, cervix, anal region, anal canal and penis. However, HPV infection can be present even if warts are not.

Pap smears (or liquid-based cytology tests) are designed to detect dysplasia early, before cancer develops. Screening involves³ a small scraping of cells from the cervix or anus, which are examined under a microscope for cellular abnormalities.

Cervical screening is recommended for HIV-positive women when they are first diagnosed with HIV, six months later, and then at least once a year. There is no equivalent screening service for men. It has been recommended that men with anal warts attend genitourinary clinics for regular clinical assessment.

Pre-cancerous changes in cervical cells can also be observed using a more precise procedure called colposcopy. This is an examination of the cervix using a magnifying instrument, and is often accompanied by a biopsy – removal of a small sample of tissue for examination. Studies in resource-poor countries have found that even very simple screening techniques, such as visual cervical inspection after applying acetic acid solution (vinegar) – which causes abnormalities to appear white or red – can identify many women at risk of progression to cervical cancer.³

The equivalent anal diagnostic procedures are anoscopy and anal biomicroscopy. Anoscopy is not yet used routinely in the diagnosis and classification of AIN, although it has been shown to be a simple and effective method in screening patients at high risk of the disease.⁴

A test to detect the presence of HPV infection is now marketed in the United Kingdom. HPV testing is not routinely used in clinical practice because the implications of the results have not yet been established.

Studies have reported that Pap smears are 100% sensitive in detecting SIL in a cohort of HIV-positive women when compared to colposcopy, confirmed by biopsy.⁵ Colposcopy was more effective at detecting very early cervical disease. An American study has found that Pap smears are as effective as colposcopy in detecting cervical abnormalities that merit treatment, although colposcopy is more effective at detecting very early cervical disease, and at detecting lesions of the vulva or vagina. However, Pap smears are generally less accurate in determining the grade of cervical or anal disease than analysis of biopsies.⁶

A prospective study found that anoscopy and cytology were fully successful at detecting high-grade anal intraepithelial neoplasia (AIN) in HIV-positive gay men with HPV.⁷