Human papillomavirus
Cervical cancer remains a serious problem affecting public health in Europe, despite the fact that some effective methods of prevention and treatment are now available. According to the lowest estimates in 2001, about 52,000 European women developed cervical cancer and 27,000 women died of cervical cancer each year.
Risk factors
For the development of cervical cancer, persistent infection with one subtype of human papillomavirus (HPV) alone is necessary, but ultimately causing cervical cancer is the result of multiple factors. Recent cohort studies have shown that HPV16 has a strong potential oncogenic effect, and it can cause malignant transcription of infected cervical cancer cells. The conventional route of transmission of HPV is through sexual transmission, and cervical cancer without HPV infection is an extremely rare phenomenon. However, HPV infection is very common after sexual intercourse and will resolve itself without any intervention. The determinants of HPV infection, progression to high cervical lesions and up to cancer formation are not yet well studied. Other risk factors for the development of cervical cancer include smoking, oral contraception, excessive childbearing, and immune deficiency, including HIV infection and Chlamydia trachomatis infection.
Pathophysiology
Cervical cancer begins with HPV virus infiltration into the epithelial basal cell layer in the junctional zone of the cervix. Early expression of viral proteins E1 and E2 ensures low viral replication, migration of HPV-infected cells to the superficial layer, and continued DNA synthesis, however, normal cells undergo programmed apoptosis. The viral oncogenes E6 and E7 are able to interact with a number of cellular regulatory processes and also inactivate the tumor suppressors P53 and RB. Persistent expression of these oncogenes eventually causes chromosomal instability as well as causing cellular mutations. These molecular changes are accompanied by morphological and cytological alterations.
Most HPV infections are cleared by cell-mediated immune responses (CMI), which are triggered by intraepithelial dendritic cells and Langerhans giant cells that recognize HPV-infected cells and activate Th1 cells to cause the production of cytotoxic T lymphocytes. These cytotoxic T-lymphocytes attack HPV-infected cells, ultimately leading to the clearance of the infection and intraepithelial lesions.
When the CMI response is inadequate, the lesions continue to develop into invasive cervical cancer.
Epidemiology
HPV infection is most common in young women who are sexually active. In Europe, the peak prevalence population is in the late teens to early twenties; subsequently, it declines with age; and the second peak occurs in women over the age of fifty. The increased prevalence of HPV infection in the last decades may have contributed to the increased incidence of cervical cancer in women born after the 1940s in most industrialized countries. In European countries, there is a wide variation in cervical cancer incidence and mortality rates. Cervical cancer mortality rates are lowest in Finland and highest in Romania, with world age-standardized rates of 1.1/100,000 and 13.7/100,000, respectively, in 2004.
Interventions
Cytological screening
Recently, the World Agency for Research on Cancer (IARC) confirmed that the incidence of cervical cancer can be reduced by 80% by performing cytological screening of good tissues every 3-5 years. Nevertheless, the coverage and quality of cytologic screening varies, and successful screening programs are currently only available in the Nordic countries and parts of Italy.
Liquid cytology (LBC) reduces the use of defective smear methods, has a shorter microscopic examination time compared to conventional smear methods, and allows for the continuation of ancillary molecular tests (e.g., HPV testing if cytology is not qualitative). However, LBC lacks sufficient sensitivity and specificity for the detection of histologically confirmed high cervical precancerous lesions.
HPV testing
The increased awareness of the close association between HPV infection and cervical cancer has led to the creation of multiple systems that can detect HPV nucleic acids, as well as to the creation of preventive and therapeutic vaccines.
HPV testing can be used for
Initial cervical screening
Cytologically detectable suspicious lesions
after treatment of high cervical intraepithelial neoplasia (CIN)
As a secondary and tertiary application, there is sufficient evidence to recommend HPV testing in current medical practice.
European Union (EU) guidelines acknowledge that initial HPV screening under good control can be used as an experimental test, but oppose universal application. The EU policy on HPV screening and cytology screening may be modified once the results of randomized controlled trials are available.
For HPV-based screening to become possible in the future, the following two points are necessary.
A significant reduction in the cumulative incidence of CIN3 among HPV screening test negatives is observed
Limited proportion of screen-positive women requiring further subsequent treatment
HPV vaccine for prophylaxis
Prophylactic trials have demonstrated that vaccines containing virus-like particles (VLPs) are safe and induce the production of subtype-specific antibodies in the body and are effective for 5 years. When applied to women who have not yet been infected with HPV, the vaccines provide good protection against recurrent infection with the same type of HPV and precancerous lesions caused by related types of HPV infection.
One of the vaccines, manufactured by Merck Sharp & Dohme (MSD), was approved in the United States and the European Union in 2006.
The other approved vaccine will be released in 2007 and will be produced by GlaxoSmithKline (GSK)
Both vaccines contain VLPs for HPV 16 and 18, which are responsible for 70% of cervical cancers caused by HPV 16 and 18 infection, and MSD’s vaccine also contains VLPs for HPV 6 and 11, which are responsible for more than 90% of condylomata. GSK’s vaccine has also been reported to provide partial protection against HPV infections associated with genetic levels of HPV types.
The vaccine does not protect women who are already HPV-infected, so the vaccine is mainly applied before sexual intercourse occurs, for example in girls aged 11-13 years. For women over 25 years of age, screening policies should not be modified by vaccination. And because the vaccine does not prevent all cancer-causing HPV types, screening cannot be excluded, but can be started later and less frequently. However, no data have been found to modify screening strategies for vaccinated women.
Summary
A high level of cervical cancer prevention can be achieved with well-organized preventive measures through the implementation of evidence-based, acceptable, and affordable policies. Opportunistic screening, which is costly and ineffective, is not advocated. Population coverage and quality of screening should be maximized and effectively monitored. HPV vaccination offers a new approach to primary prevention, but screening cannot be ruled out for the next 20 years.
For other HPV-associated cancers, such as vaginal, vulvar, and oropharyngeal cancers, prophylactic transmission of the virus appears to be the best strategy. There is no evidence yet that HPV vaccines protect against cancers other than cervical cancer.