**Secondary Prevention of Uterine Cervical Cancer**

**Secondary Prevention of Uterine Cervical Cancer**

DOI: 10.5772/intechopen.72144

Seiya Sato and Hiroaki Itamochi Seiya Sato and Hiroaki Itamochi Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72144

#### **Abstract**

Secondary prevention by cervical cytology has clearly improved the mortality rate of uterine cervical cancer (CC) by enabling early detection and treatment of high-grade squamous intraepithelial lesion (HSIL) or cervical intraepithelial neoplasia (CIN), which is a precancerous lesion. In the past two decades, HPV-DNA testing, including HPV typing, has clearly brought about positive effects on secondary prevention of CC. However, in practice, CC remains a fatal disease and is the second leading cause of cancer deaths in women aged 20–39 years. Although elucidation of the mechanisms of HPV carcinogenesis and development of a prophylactic vaccine have made CC a preventable disease, eradication of CC is expected to take several decades. Therefore, primary screening to decrease the mortality rate of CC will remain important for a while. In addition, the clinical application of simple biomarkers to stratify HPV-positive women is important for maintenance of medical economy and avoidance of overtreatment in women in the reproductive age. Therefore, the development of an inexpensive therapy or vaccine that can be used worldwide is necessary to overcome cancer deaths due to CC.

**Keywords:** uterine cervical cancer, cervical intraepithelial neoplasia, secondary prevention, human papillomavirus, carcinogenesis, biomarker, therapeutic vaccine

#### **1. Introduction**

Secondary prevention with the use of cervical cytology has clearly improved the mortality rate and early treatment of uterine cervical cancer (CC) by enabling early detection of high-grade squamous intraepithelial lesion (HSIL) or cervical intraepithelial neoplasia (CIN), which is a precancerous lesion [1]. In practice, however, CC was estimated to have 12,820 newly diagnosed cases and 4210 women dying of the disease in 2017 [2]. Moreover, according to the United States data in 2014, CC is the second leading cause of cancer deaths in women aged 20–39 years [2]. Therefore, improvement of screening efficiency remains an important issue.

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

The etiology of CC is persistent uterine cervical infection with the high-risk human papillomavirus (hrHPV). Therefore, HPV-DNA testing or HPV testing, has become widely used for primary screening of CC. Compared with conventional cytology, HPV testing has higher sensitivity and reproducibility in detecting lesions [3]. However, the specificity of HPV testing is low, with an increase in the number of false-positives, especially in women in their twenties who are highly sexually active [3, 4]. Therefore, HPV testing has been adopted in cancer screening for women over 30 years old. In fact, in the United States (US), the guidelines created by the American Cancer Society, American Society for Clinical Pathology, and American Society for Colposcopy and Cervical Pathology suggested CC screening by cytology starting at the age of 21 and every 3 years until 30 years old; beyond the age of 30, combined HPV testing and cytology for every 5 years was recommended [5]. Based on data from large-scale, longitudinal, randomized-controlled trials in European countries, HPV testing has been adopted as the primary screening tool for CC in women aged 30 years or older [6–9]; in those who are tested positive for HPV, cytology is used as the triage test. In ASC-US cases, HPV testing is performed for triage in the management of CIN, based on the results of available largescale clinical studies [10–13]. Furthermore, HPV typing has already been used as a biomarker for decisions on therapeutic interventions and subsequent follow-up of CIN [14–19]. Both the US and European guidelines recommended HPV testing to confirm the completion of treatment of CIN.

history of HPV and CC prevention. In this chapter, we will describe the recent developments

Secondary Prevention of Uterine Cervical Cancer http://dx.doi.org/10.5772/intechopen.72144 61

HPV is a virus with a double-stranded circular DNA in the icosahedral capsid. The genome size is about 8000 bases and contains eight protein-coding genes and a noncoding, regulatory long control region [31]. The early genes (E1, E2, E4, E5, E6, and E7) encode nonstructural proteins involved in replication, transcription, and transformation; whereas the late genes (L1 and L2) encode viral capsid proteins. Among these genes, E6 and E7 play a central role, particularly in carcinogenesis. Notably, a recent whole-genome sequencing study that assessed the risk of viral genetic variation showed that strict preservation of the 98 amino acids of E7, which destroys the function of the retinoblastoma protein (pRB),

HPV can infect the epithelial cells of the human mucosa and skin at least once in most women's lives. In other words, HPV infection is a common sexually transmitted disease. Because prophylactic vaccines prevent only initial infection, its value in women is most effective before the first sexual contact [33]. In the early stages of HPV infection, the host is asymptomatic, and in most cases, the virus is eliminated by the immune system within a few years [34]. However, HPV infection can persist in some patients. The reported risk factors for progression of cervical HPV infection to CIN or CC include persistent hrHPV infection, immunosuppression, age

Persistent hrHPV infection of the cervix is divided into three stages: latent, permissive, and transforming [36–38]. First, HPV invades the epithelial basal cells via minor breaches of the epithelium [39] and become latent as a nuclear episome; the infected cells usually die after virus multiplication. The E6 and E7 genes are rarely integrated into cellular DNA and cause HPV growth in the cells; however, this property also allows continued expression of E6 and E7 proteins at high levels. The expression of E6 and E7 oncogenes in basal cells is tightly controlled; therefore, HPV-infected cells can escape a host's immune defense. In fact, in a small percentage of HPV-infected women, HPV-specific antibodies and T cells are detected at low levels [40, 41]. Recently, it was suggested that the programmed death 1/programmed death 1 ligand (PD-1/PD-L1) pathway might be involved in the mechanism of this immune

When infected cells begin to differentiate in the epidermis, the E6 proteins degrade the tumor suppressor protein p53, while the E7 proteins inhibit the function of the pRB; these processes reactivate DNA synthesis and replication of the HPV genome. The cells with integrated E6 and E7 genes will have uncontrolled cell cycles because p53 and pRB are major cell cycle regulators. Furthermore, apoptosis and the tumor suppressor pathway are repressed. During this process, accumulation of genetic mutations and genomic instability ensue [45–50]. As a result, a large number of clones with intratumor heterogeneity are produced, some of which might be able to avoid the host antitumor response [51–54]. Ultimately, with the addition of external factors, these cells will be immortalized and can

was critical for HPV 16 carcinogenesis and development of CIN and CC [32].

in secondary prevention of CC.

over 30 years, and smoking [35].

evasion [42–44].

become cancerous [55].

**2. Biology and carcinogenesis of HPV**

HPVs are classified according to carcinogenic potential. In general, the frequently reported highrisk types are HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 [20]. Among these, HPV 16 and 18 are the most common types that are related to carcinogenesis worldwide; both HPV types are controllable by prophylactic vaccines that contain virus-like particles with antigenicity [21, 22]. Bivalent vaccines for HPV 16 and 18 are commercially available, but quadrivalent vaccines are also available for HPV 6, 11, 16, and 18. Although these vaccines have some cross-protective effects [23, 24], these are basically ineffective for infection by all HPV types. To overcome these limitations, a nonavalent vaccine containing HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 has been launched [25, 26].

As mentioned above, hrHPV testing has clearly brought about positive effects on early detection of CIN and prevention of CC in the past two decades [27–30]. Several researchers all over the world continue to pursue efforts to eradicate CC. **Figure 1** shows the schema of the natural

**Figure 1.** Natural history of HPV and prevention of cervical cancer. Persistent infection of the cervix with high-risk HPV causes cervical cancer (CC), which begins as cervical intraepithelial neoplasia (CIN). Primary prevention of CC can be achieved by prophylactic HPV vaccination. Secondary prevention consists of early detection of CIN and therapeutic vaccination to inhibit progression from CIN to CC.

history of HPV and CC prevention. In this chapter, we will describe the recent developments in secondary prevention of CC.
