HPV has many types, and its infection is related to various diseases in humans. About 15 types of HPV (HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73, and HPV-82) are oncogenic and defined as high-risk HPV, which can cause cervical cancer as well as other HPV-related cancers such as of the vulva, vagina, penis, anus, and oropharynx. HPV is transmitted by sexual contact. HPV infections are common and generally asymptomatic, and it is estimated that 50–80% of healthy sexually active individuals are at risk of HPV infection within their lifetime. However, approximately 90% of women infected initially (incidentally) by HPV may eliminate the infection from their cervical epithelial cells within 2 years, and most women with this transient infection never develop cancer. In contrast, in the remaining 10% of women, persistent HPV infection may occur, and some of those could develop high-grade precancerous lesions, and some may subsequently develop invasive cancer (Fig. 5.1).

Nearly all patients with invasive cervical cancer show evidence of HPV infection. HPV-16 and HPV-18 are the most oncogenic, and these two types are responsible for about 70% of cervical squamous cell carcinomas worldwide. In Japan, HPV-16/HPV-18 were detected in 24% of CIN1, 36% of CIN2/3, and 67% of invasive cervical cancer [5]. More importantly, the detection rate of HPV-16/HPV-18 in invasive cervical cancers varies according to the age and is the highest in patients aged 20–29 years (90.0%) [5]. The next most frequently detected HPV types in cervical cancer are HPV31, HPV-33, HPV-35, HPV-45, HPV-52, and HPV-58. HPV infection with these high-risk types is necessary for the development of cervical cancer, but other factors, such as smoking, immune suppression, and long-term oral contraceptive use, may increase the risk.

Invasive cervical cancer results from the progression of precancerous lesions named CIN or squamous intraepithelial lesion (SIL). CIN is histologically graded into CIN1, CIN2, and CIN3, although most CIN1 and some CIN2 regress. The results of a PAP test are presented according to the Bethesda system, based on cytologic findings: atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL) show transient HPV infection (CIN1), while high-grade squamous intraepithelial lesions (HSIL) show persistent HPV infection with cellular atypia (CIN2–3) (Fig. 5.1). In fact, over 70% of ASC-US or CIN1 lesions regress, while 10–30% CIN3 lesions progress to invasive cancer. After screening using cytology, women with abnormal results (ASC-US, LSIL, HSIL, AGC, or more) need colposcopy and biopsy to determine the histological diagnosis and subsequent management/treatment.

Usually, invasive cancer develops from CIN slowly over some years or longer. This long natural history from HPV infection to the development of cervical cancer provides the opportunity for screening to detect this process in precancerous stages and allows the treatment of preinvasive lesions before they become cancerous, which could prevent invasive cancer effectively.

Historically, cervical cancer screening was conducted using the PAP test (cytology) alone until HPV testing became available. Programs since the 1960s using annual screening with Papanicolaou-stained cervical cytology smears have been successful, and actually, it has contributed to a significant decrease in the mortality rate due to cervical cancer. However, it is now difficult to more effectively reduce the number of deaths from cervical cancer only through this screening measure, mainly due to its relatively lower sensitivity (the percentage of “true-positive” cases that are detected by the screening test). Previous studies showed that the sensitivity for detecting high-grade lesions on a single conventional PAP test is approximately 55–80% [6], and failures to prevent invasive cervical cancer can be attributed to false-negative Pap smears as well as to poor follow-up of abnormal results [7]. False-negative results occasionally occur, especially in pregnant women or in patients with glandular abnormality or precancerous/cancerous lesions of adenocarcinoma. Additionally, in Japan, the proportion of those undergoing such examinations is only 30–40% of targeted women >20 years old, which is lower than those in Western countries, at approximately 70–80%. Recently, the liquid-based cytology technique was developed to improve the sensitivity of screening. Up to now, there has been no evidence that liquid-based cytology significantly reduces the number of deaths compared with the conventional Pap smear test, although there is actually one advantage that the HPV test can be simultaneously conducted on the same preparation for the examination of liquid-based cytology.

In consideration of the limitations of cytology, efforts have focused on enhancing the sensitivity of screening to reduce false-negative results and developing new molecular/virological tests to detect high-risk HPV as well as to reduce unnecessary colposcopic examinations. Since 2000, various HPV-DNA tests have been developed, and now some are commercially available for the detection of HPV in cervical specimens [8]. Most of these tests generate a pooled result (“high-risk HPV-positive” or “high-risk HPV-negative”) to detect nucleic acids of the 12 HPV types altogether (HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, and HPV-59; some tests also detect HPV-66 and HPV-68). In contrast, HPV genotyping tests that distinguish individual HPV types are also available. HPV infections are particularly common in young women, and the majority clear their infection within 2 years; therefore, the challenge of incorporating HPV testing into cervical screening programs is to balance increasing sensitivity to detect CIN2/3 and minimizing overdiagnosis/treatment of women with transient HPV infections and cervical abnormality that may regress.

Actually, previous studies demonstrated that, compared with cytology, HPV-DNA testing was more sensitive for identifying women who have CIN2/3, with sensitivities of 84–97%, and that the combination of HPV testing and cytology led to an almost 100% sensitivity. In contrast, it has been noted that HPV-DNA testing generally has a lower specificity compared with cytology. Among women ≥30 years old, cytology had a specificity of 97% compared with 94% for HPV testing. The specificity of HPV-DNA testing is likely be lower among women younger than 30 years old, who have more transient HPV infection.

Now, HPV testing has been approved for use in the following: (1) as a second test (triage) following a cytology result of ASC-US; (2) for primary screening combined with the PAP test for women aged 30 years or older or primary screening by the HPV test alone may be considered; and (3) HPV genotyping tests that distinguish highly oncogenic HPV types, especially HPV-16 and HPV-18, for the further triage of women with a positive pooled result or for risk stratification in patients with CIN1/2.

A recent major clinical trial, “ATHENA HPV Study,” demonstrated that incorporating screening with HPV and triage of HPV-positive women by a combination of genotyping for HPV-16/HPV-18 and cytology provided a good balance between maximizing sensitivity (benefit) and specificity by limiting the number of colposcopies (potential harm) [9]. Furthermore, the study showed that primary HPV screening in women ≥25 years is as effective as a hybrid screening strategy that uses cytology if 25–29 years and cotesting if ≥30 years [10]. Further analysis of HPV genotyping from the ATHENA trial supported the identification of HPV-16 in primary screening for all women and demonstrated that the identification of HPV-18 is also warranted with a significant contribution to adenocarcinoma in situ (AIS) and cancer [11].

Table 5.1 demonstrates the current cervical cancer screening guidelines in the USA [8, 12]. All normal-risk women should begin cervical cancer screening at age 21. Between the ages of 21 and 29 years, women should be screened using cytology every 3 years. HPV testing is used following an abnormal cytology result. Primary HPV testing can be considered starting at age 25 every 3 years. For women aged 30–65 years, screening can be done using cytology alone every 3 years or HPV cotesting (cytology plus simultaneous HPV test) every 5 years. The guidelines support the discontinuation of screening in women older than 65 years who have three consecutive normal cytology results or two consecutive negative cotest results within the previous 10 years, with the most recent test performed within the past 5 years.

In Japan, the screening system using cytology in combination with the HPV test has not yet been established and is still under investigation by clinical trials. At this time, the guideline proposed by the Japan Association of Obstetricians and Gynecologists in 2012 (Fig. 5.2) is applied for cancer screening targeting women aged 30 years or older in some local areas or cities. According to this guideline, women who are both cytology-negative and HPV-negative can be screened 3 years later. Women who are cytology-negative, but HPV-positive, are recommended to undergo cotesting again 6–12 months later. Women with cytology of ASC-US and HPV-positive or cytology of LSIL or more should undergo colposcopy and biopsy. Such studies are expected to establish the appropriate screening system in Japan.

Two prophylactic vaccines are currently available in many countries worldwide for the primary prevention of cervical cancer and other HPV-related diseases [4, 13]. Both bivalent and quadrivalent vaccines are developed against two main oncogenic HPV genotypes, HPV-16 and HPV-18, responsible for 65–70% of invasive cervical cancer cases. The quadrivalent vaccine is also directed against low-oncogenic types, HPV-6 and HPV-11, that cause anogenital warts (condyloma). The quadrivalent vaccine was first licensed in 2006, followed by licensing of the bivalent vaccine in 2007. It is recommended that HPV vaccine should be administered before the onset of sexual activity (before the first exposure to HPV infection). Both vaccines are prepared from virus like particles that resemble HPV type-specific L1 protein, which contains no viral DNA and, therefore, is noninfectious. Immunologically, HPV vaccine can protect against HPV infecting cervical epithelial cells through humoral immunity mediated by neutralizing antibodies against HPV-16/HPV-18.