Epidemiology, Etiology and Prevention
In 2018, approximately 570,000 women developed cervical cancer and 311,000 women died from it. Worldwide, cervical cancer was the fourth most common cancer and also the fourth leading cause of cancer death among women (Arbyn et al., 2020).
Markers of sexual activity, such as a younger age at first intercourse and a higher number of sexual partners, are consistently the most important risk factor for cervical cancer, which lead to research for sexually transmissible microbial agents as the cause. There is overwhelming evidence, both biologic and epidemiologic, that cervical infection by certain Human Papilloma Virus (HPV) types is a precursor event in the genesis of cervical cancer. HPV is a DNA virus capable of inducing malignant transformation of epithelial cells and causing cervical, anal, vulvar, penile and some oral cancers. HPV types are classified according to their oncogenic potential based on the frequency of the association with cancer and squamous intraepithelial lesions. There are over 60 types which infect the anogenital mucosa, of which 12 types (HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) are designated as high-risk HPV, and an additional 13 types are considered “probable” high-risk HPV (HPV-26, 30, 34, 53, 66, 67, 68, 69, 70, 73,82, 85, 97). The low-risk types cause subclinical infections or clinically visible benign lesions known as flat and acuminate condylomas. Over 80% of sexually active individuals will be infected by a genital HPV at some point in their lifetime. The majority of genital HPV infections are asymptomatic and clear within 1-2 years without consequences when immune function is normal. Persistent infection by a high-risk HPV is a necessary cause of cervical cancer, detected in 99.7% of cervical neoplasia (squamous and adenocarcinoma). Prevention of cervical cancer is possible through vaccines (primary prevention) and also screening with cervical cytology (secondary prevention), because progression from infection to cancer is usually slow, in the order of decade (De Pokomandy & Mayrand, 2017).
Primary Prevention: HPV Vaccines
Ever since HPV was identified as the necessary cause of cervical cancer and other tumors, intense research and development activities focused on the development, testing and licensure of HPV vaccines. As of 2015, three HPV vaccines are commercially available: a bivalent vaccine (CervarixTM) targeting types 16 and 18; a quadrivalent vaccine (GardasilTM) targeting types 16, 18 and also 6 and 11 responsible for most genital lesions; a nonavalent vaccine (Gardasil-9TM) targeting the quadrivalent types plus 31, 33, 45, 52, 58. These vaccines utilize virus-like particles comprised from the L1 capsid protein of HPV to induce seroconversion, and are usually given in three separate injections over a 6 month period. The vaccines are associated with frequent local reaction, but generalized or severe reactions are rare. Recent data of literatures show early decreases of infections by vaccine-targeted HPV types, condylomas, abnormal cervical cytology results and cervical HSIL (High grade Squamous Intraepithelial Neoplasia) at the population. Some decrease was also seen in unvaccinated individuals from the vaccine program eligible age groups, indicating some herd immunity. However, as with any new intervention, some aspects are still to be clarified. There is a theoretical risk of a gradual change in the distribution of HPV types in vaccinated population due to empty niches when HPV 16 and 18 are eliminated. Type-specific immunity conferred by vaccination may also wane over time and the duration of protection is unknown. Finally, HPV vaccine prices make it currently impossible to implement large-scale vaccination programs in resource-poor countries (De Pokomandy & Mayrand, 2017).
Secondary Prevention: Cervical Cytology and HPV DNA – Testing
Cervical cytology (Pap test) can detect cellular changes typical of cervical cancer, high-grade squamous intraepithelial lesion (HSIL) or HPV infection. Women with abnormal screening cytology then undergo diagnostic evaluation by colposcopy. Histological examination of colposcopy-directed biopsies of such lesions confirms the diagnosis. This procedure is the primary reason of reduction in cervical cancer mortality in most high-income countries. However, Pap test is based on subjective interpretation of morphologic alterations and also depends on the correct sampling of cervical cells. In the last years, liquid-based cytology has improved the efficiency of smear processing, but did not overcome the limitations of poor test sensitivity and reproducibility.
There is a considerable interest in the use of HPV DNA testing as a cervical cancer screening tool. An important advantage of this procedure is that it is amenable to automation. Moreover, the HPV DNA testing is more reproducible, more sensitive and has a higher negative predictive value compared to Pap test (De Pokomandy & Mayrand, 2017).