Chapter Four - Human Papillomavirus and Its Testing Assays, Cervical Cancer Screening, and Vaccination

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Abstract

Human papillomavirus (HPV) was found to be the causative agent for cervical cancer in the 1980s with almost 100% of cervical cancer cases testing positive for HPV. Since then, many studies have been conducted to elucidate the molecular basis of HPV, the mechanisms of carcinogenesis of the virus, and the risk factors for HPV infection. Traditionally, the Papanicolaou test was the primary screening method for cervical cancer. Because of the discovery and evolving understanding of the role of HPV in cervical dysplasia, HPV testing has been recommended as a new method for cervical cancer screening by major professional organizations including the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology. In order to detect HPV infections, many sensitive and specific HPV assays have been developed and used clinically. Different HPV assays with various principles have shown their unique advantages and limitations. In response to a clear causative relationship between high-risk HPV and cervical cancer, HPV vaccines have been developed which utilize virus-like particles to create an antibody response for the prevention of HPV infection. The vaccines have been shown in long-term follow-up studies to be effective for up to 8 years; however, how this may impact screening for vaccinated women remains uncertain.

In this chapter, we will review the molecular basis of HPV, its pathogenesis, and the epidemiology of HPV infection and associated cervical cancer, discuss the methods of currently available HPV testing assays as well as recent guidelines for HPV screening, and introduce HPV vaccines as well as their impact on cervical cancer screening and treatments.

Introduction

Human papillomaviruses (HPVs) are a group of about 200 related viruses. More than 40 HPV types can cause sexually transmitted diseases through direct sexual contact such as vaginal, anal, and oral sex. Low-risk HPVs transmitted by sex may result in condylomata acuminata (skin warts) on or around the genitals, anus, mouth, or throat, while high-risk HPVs (hrHPVs) are responsible for HPV-induced cervical, anogenital, oropharyngeal, and other rarer cancers. The HPV genome is incorporated into the host genome, and in particular, the incorporation of E6/E7 genes and subsequent host expression maintains a transformed phenotype which has been linked to oncogenesis. HPV DNA testing is primarily used for the detection of high-risk type of HPV infections to screen for cervical cancer. Various HPV testing methods with different principles have been developed and some of them have been approved for clinical use. Major professional organizations have provided recommendation of using HPV testing for cervical cancer screening. In order to prevent HPV infections and subsequent HPV-associated cancers, HPV vaccines have been developed and used in many countries.

Section snippets

Molecular Biology, Pathogenesis, and Epidemiology of HPV

HPVs are nonenveloped viruses, which consist of an icosahedral capsid containing histone-associated dsDNA. About 200 genotypes have been identified to date, which are differentiated by their genetic sequences encoding the outer capsid protein. HPV infects epithelium of skin and mucosal origins and commonly induces benign self-limiting lesions, but is also known to be potentially oncogenic pathogens associated with cervical, anogenital, and oral cancers. HPV infection is currently one of the

Principles and Methods for HPV Testing

There are over about 200 different genotypes of HPV with around 40 of these types able to infect the anogenital mucosa of humans. Of these 40 types, 14 (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are considered high risk (HR) for the development of cervical cancer and/or precursor legions. HPV-16 is associated with approximately 60% of cervical cancers, while HPV-18 is associated with 15% of cervical cancers. In 2002, guidelines began inclusion of recommendations for

Cervical Cancer Screening

Historically cervical cancer screening recommendations have changed relatively rapidly since the introduction of the Pap test reflecting emerging data and understanding of the pathogenesis of cervical cancer. Prior to 1980 the ACS recommended a Pap test “as part of a regular checkup” [119]. From 1980 to 1987 the recommendation for cervical cancer screening was for annual Pap smears with cervical cytology for women over the age 20 (younger if sexually active) and if two negative Pap tests, this

HPV Vaccines and the Impact on Cervical Cancer Screening

HPV vaccines consist of type-specific HPV L1 proteins that are capable of self-assembly into VLPs. VLPs do not contain vDNA, and thus are noninfectious. The FDA currently licenses three HPV vaccines. Cervarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is a bivalent vaccine that provides protection against HPV types 16 and 18, which are responsible for approximately 70% of cervical cancer cases. A quadrivalent HPV vaccine, Gardasil (Merck, Kenilworth, NJ) adds protection against HPV types

Acknowledgments

Section 4, “Cervical Cancer Screening,” is adapted from a prior published article in Current Treatment Options in Oncology by M.R.D. and S.F. entitled “Making Sense of Cervical Cancer Screening” [227] with permission of Springer.

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