ANOGENITAL HPV AND CANCER

Cervical cancer

Epidemiology

Most sexually active women will acquire HPV infection at some point in their life, but only a few women will go on to develop cervical cancer. HPV infection typically occurs in the younger age groups whereas cervical cancer typically develops later in life. Hence it usually takes many years for a precursor lesion to develop into a cancer. This is reflected in the epidemiology of HPV and cervical cancer. Cervical cancer is the fourth most common cancer in women worldwide, with an Age Standardised Rate of over 30/100,000 women in high risk regions (Eastern Southern and Middle Africa, Melanesia).(66) The evidence linking HPV to cervical carcinoma is extensive, with HPV 16 accounting for approximately 50% of cases and HPV 18 for 20%. HPV 16 and 18 account for about 70% of all cervical cancers worldwide.(67-70) The prevalence of HPV 16/18 in confirmed high-grade disease in New Zealand is comparable to that observed in Australia and European countries.(71,72) The prevalence of HPV 16/18 is almost identical for both Maori and non–Maori populations in New Zealand.(73)

The most common HPV types in women with CIN-2/3 were HPV 16 (51%), 18 (21%), 31 (4%), 45 (3%) and 52 (3%).(72) Although cervical screening has reduced the incidence of cervical cancer by 70% or more where screening has been effectively implemented, cervical cancer remains a leading cause of death in countries without effective screening programmes. The incidence of cervical cancer in New Zealand is among the lowest in the world. In 2014 there were 144 new cervical cancer registrations.(74) The age-standardised registration rate was 5.5 per 100,000 population. The registration rate for Maori women was 10.8 per 100,000, 2.5 times greater than for non-Maori women.

Classification of abnormalities

Abnormalities are classified by whether it is a cytologic or histologic specimen and by its severity. For example, exposure to HPV results in productive viral infections that may cause mild abnormalities which are referred to as low-grade squamous intraepithelial lesions (LSILs) by cytologists or cervical intraepithelial neoplasia 1 (CIN-1) by pathologists. These can be caused by either lrHPV or hrHPV which indicate the presence of HPV infection. Most HPV infections, including high-risk genotypes, typically become undetectable within 6–12 months. Persistent (detectable) infection is associated with the development of CIN-2+.(75,76)

Risk of progression to cancer

CIN-3 (histologically confirmed) must be regarded as the precursor for cervical cancer. Many high-grade precursors will not progress to cancer even after protracted periods of follow-up of up to 30 years. It is important to stress to the patient that HPV infection does not equal cancer (indicator of risk). The median age of women with CIN-3 is 27–30 years. The median age for women with a cervical screen-detected invasive cancer is 10 years or more older than the median age of women presenting with CIN-3.(77)

New Zealand data have demonstrated that, in women with CIN-3 managed only with small diagnostic biopsy and who have persistent abnormal smears, the cumulative incidence of invasive cancer of the cervix was 50%.(78) Previously it was thought it took many years to progress from incident HPV infection to high-grade precursor lesion; however, intensive prospective follow-up of women in their early 20s has demonstrated that rapid development of CIN-2 and 3 can occur, often within a few months of incident infection.(79) It does however, take many years in most cases to progress from a high-grade precursor to invasive cervical cancer.

Some CIN-2 lesions, particularly in young women, will regress, while others persist with risk of progression. The risk of progression is considerably higher with a HPV 16 or 18 infection than with other high-risk genotypes. HPV 16 persists longer than other types, with an absolute risk of CIN-3 approaching 40% after 5 years’ persistence.(80)

Risk factors

Cigarette smoking,(81,82) and coinfection with HIV have been consistently demonstrated as co-factors for cervical cancer.(83) Long-term use of hormonal contraceptives,(84) high parity (85) are less important cofactors.

Anal cancer

Although a relatively uncommon cancer, the incidence of anal cancer in the United States has increased substantially in the last three decades. The incidence in the general population is approximately 2/100,000 and is more common in women than men. In contrast, the rate of anal cancer is estimated to be 35/100,000 among MSM and 137/100,000 among HIV-positive MSM.(86) The attributable fraction due to HPV is 88%.(65) HPV 16 and 18 cause 70% of AIN and anal cancers.

Vulval and vaginal cancers

Vulval and vaginal cancers are rare cancers globally. In Oceania, 40% of vulval cancers is estimated to be due to HPV (86% for warty/basaloid squamous cell carcinoma [SCC] and 14% for keratinising SCC).(87) 70% of vaginal cancer is estimated to be due to HPV.(65) New Zealand studies have demonstrated usual-type HSIL to have a significant invasive potential in women age 30 years and over with a mean transit time to invasion of 4 years.(88) Investigation of the role of co-factors for persistence and progression is difficult because of the ubiquitous and transient nature of HPV infection.

Penile cancer

Penile cancer is also rare, with an attributable fraction due to HPV at 50%.(65)