**5. Discussion**

**3.3. HPV E6/E7 mRNA**

because the risk of carcinogenesis is high [85].

ylating compounds have been developed [87].

**4. Therapeutic vaccine for CIN**

**3.4. Epigenomic alterations**

The usefulness of HPV E6/E7 mRNA testing in secondary prevention of CC has already been established [77, 78]. Combined testing of LBC cytology and APTIMA® HPV (AHPV) has already been used in the US and Europe. HPV E6/E7 mRNA testing is useful because it can detect HPV infection and the transformation properties of cervical cells. In fact, HPV E6/E7 mRNA testing

ASC-US and LSIL on cytology are mainly caused by low-grade cervical lesions that often resolve spontaneously [82]. Currently, the HPV test is used for triage of women with ASC-US and LSIL; however, its low specificity has increased the number of unnecessary examinations and treatment [83]. On the other hand, HPV E6/E7 mRNA testing enables stratification of the risk of developing CIN2+ in women with both hrHPV-positive and hrHPV-negative cytology [84]. A recent meta-analysis to confirm usefulness of HPV E6/E7 mRNA testing for triage revealed that a positive HPV E6/E7 mRNA testing in women with mild cytology findings, such as ASC-US and LSIL, necessitates immediate colposcopy and intensive follow-up

Epigenetic events in the host and in viral genomic regions and genes are necessary during HPV-mediated cellular transformation and carcinogenesis [86]. DNA methylation is a typical epigenetic change and characterizes the molecular, cellular, and clinical features of HPVassociated neoplasia. Because hypermethylation is a stable and reversible process, detection of methylation marks is used for diagnosis. In addition, new targeted therapies with demeth-

Combined testing with DNA methylation and hrHPV is one of the promising screening options for CC. The Triage and Risk Assessment of Cervical Precancer by Epigenetic Biomarker (TRACE) study was conducted to examine the usefulness of human epigenetic biomarker testing in the primary prevention of CC. In this study, methylation of the POU4F3 promoter, which is a promising marker for CIN3, showed significantly higher sensitivity and similar specificity for detecting CIN3+, compared with LBC [88]. This finding suggested that detection of POU4F3 methylation is useful for early detection of CIN3. Another study assessed the correlation between CpG methylation of the HPV16 L1 gene and CC in 145 HPV 16-infected Uyghur women who were divided into five groups, as follows: transient infection (n = 32), persistent infection (n = 21), CIN1 (n = 21), CIN2–3 (n = 33), and CC (n = 38) [89]. After quantifying each CPG methylation by pyrosequencing, results revealed that methylation increased at 13 CpG sites in advanced lesions and that high methylation levels were associated with the risk of developing CIN2+ [89]. These findings may be applied to CC screening.

Currently, the standard therapy for CIN is surgical excision such as conization or LEEP. Although these treatments are very effective from the viewpoint of removing HPV-induced

was reported to detect high-grade CIN with high sensitivity and specificity [79–81].

64 Cervical Cancer - Screening, Treatment and Prevention - Universal Protocols for Ultimate Control

The mathematical model by a German group estimated that the incidence and mortality of CC will drastically decrease in the next 30 years due to the increasing number of screening participants since the 1990s [94]. Furthermore, even at a vaccination rate of only 50%, more than 40% of CC is considered to be preventable in the next 100 years [94]. Nevertheless, more effective primary prevention is necessary to eradicate CC. Currently, an effective vaccine can be used to inhibit a part of the hrHPV infection process that leads to cancer. However, several individuals cannot receive vaccination due to economic or geographical problems. In order to solve this problem, international cooperation and national policy are necessary to construct a CC prevention system. One possible problem in the future would be the changes in the distribution of hrHPV types due to an increase in the number of vaccinated cohorts; this would likely decrease the efficiency of the current screening system. Therefore, it may be necessary to monitor the distribution of hrHPV in each country and region, and to develop screening methods that are suitable for each situation.

of cost-effectiveness and expansion of screening services [101]. Therefore, HPV-DNA testing

Secondary Prevention of Uterine Cervical Cancer http://dx.doi.org/10.5772/intechopen.72144 67

CIN frequently regresses spontaneously within months or a few years [102, 103]. However, there is no biomarker to predict spontaneous regression of CIN. The standard treatment for CIN is still surgical resection such as conization; for a long time, there had been no other options for treatment. Although surgical excision is successful for CIN treatment most of the time, HPV infection cannot be completely eliminated. We reported that postsurgical hrHPV infection was a positive predictor of the recurrence of abnormal cytology (**Figure 3**). Furthermore, surgical procedure can lead to complications such as pregnancy problems, infertility, incontinence, and sexual dysfunction [104–106]. At the very least, overtreatment of women with fertility must be avoided. With the progression of CC screening, the importance of these problems has increased. In order to overcome this problem, development of a therapeutic vaccine as a new treatment option without surgery is urgently needed. The availability of low-cost therapeutic vaccines for patients with CIN or stage IA CC in the future will lead

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. To decrease the mortality rate of CC, early detection by screening will remain important for a while. The clinical application of simple biomarkers to stratify HPV-positive women is important for maintenance of medical economy and avoidance of overtreatment of women in the reproductive age. To overcome cancer deaths due to CC, the development of inexpensive treatment options or therapeutic vaccines that can be readily used worldwide is necessary.

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine,

[1] Saslow D. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Journal of Lower Genital Tract Disease. 2012;

by self-sampling has the potential to become the mainstream in cancer prevention.

to a long-term reduction in medical costs [107].

**6. Conclusions**

**Author details**

Iwate, Morioka, Japan

**16**(3):175-204

**References**

Seiya Sato and Hiroaki Itamochi\*

\*Address all correspondence to: itamochi@iwate-med.ac.jp

Secondary prevention remains important because vaccines only prevent infection with a limited number of HPV types. In order to reduce the mortality rate of CC, the coverage of a screening program needs to be increased and include patients with advanced CC. To address this issue, the usefulness of self-sampling for HPV testing has been studied [95, 96]. The US National Health and Nutrition Examination Survey in 2007–2010 on women aged 18–59 years revealed a 41.9% prevalence of genital HPV infection [97]. Multivariate analysis in this cohort revealed that HPV infection was related to age, number of sexual partners, smoking, educational level, income, and insurance status [97]. Similar results on the risk of persistent HPV infection have been confirmed in other studies [98, 99]. Therefore, populations with these risk factors require more rigorous and continuous monitoring for effective prevention; in these cases, self-sampling may be particularly useful. Importantly, the hrHPV detection rate by continuous self-sampling of vaginal fluid for 28 days was reported to be consistent regardless of the hormonal cycle [100]. In other words, hrHPV detection by selfsampling can be adapted to all women, even those in the nonmenstrual period, including menopause. A recent meta-analysis of 37 studies including 18,516 women revealed that HPV-DNA sampling screening was highly accepted compared with clinician's sampling. In the future, the importance of self-collection method will increase, especially from the viewpoint

**Figure 3.** Postoperative infection with high risk (hr) HPV and risk of abnormal cytology. The cumulative risk curves for (a) atypical squamous cells of undetermined significance (ASC-US) or higher and (b) low-grade squamous intraepithelial lesion (LSIL) or higher show that the cumulative risks for recurrence of abnormal cytology and LSIL or higher were significantly increased in postoperative hrHPV-positive patients than in hrHPV-negative patients.

of cost-effectiveness and expansion of screening services [101]. Therefore, HPV-DNA testing by self-sampling has the potential to become the mainstream in cancer prevention.

CIN frequently regresses spontaneously within months or a few years [102, 103]. However, there is no biomarker to predict spontaneous regression of CIN. The standard treatment for CIN is still surgical resection such as conization; for a long time, there had been no other options for treatment. Although surgical excision is successful for CIN treatment most of the time, HPV infection cannot be completely eliminated. We reported that postsurgical hrHPV infection was a positive predictor of the recurrence of abnormal cytology (**Figure 3**). Furthermore, surgical procedure can lead to complications such as pregnancy problems, infertility, incontinence, and sexual dysfunction [104–106]. At the very least, overtreatment of women with fertility must be avoided. With the progression of CC screening, the importance of these problems has increased. In order to overcome this problem, development of a therapeutic vaccine as a new treatment option without surgery is urgently needed. The availability of low-cost therapeutic vaccines for patients with CIN or stage IA CC in the future will lead to a long-term reduction in medical costs [107].
