Clinical significance of human papilloma virus infection in the cervical lesions

Abstract

Cervical lesions have been regarded as the common and frequently occurring diseases in China. Recently, the morbidity and youth tendency of cervical cancer have gradually increased. Cervical cancer, related with human papilloma virus (HPV) infection, has been one of the severest diseases threatening health and life of women, and is an infectious disease. The universality of HPV infection in the reproductive tract should not be ignored. The well-known risk factors of HPV infection in cervical lesions consist of high-risk sexual behaviors, immunosuppression, age, contraceptive methods, the concurrent infection of other sexually transmitted diseases, etc. The variation of cervical lesions induced by HPV infection is involved in the continuous pathological process, including the subclinical, latent, and persistent infection of high risk (HR)-HPV, chronic cervicitis with abnormal results of cytological examination, cervical intraepithelial neoplasia (CIN), and cervical cancer. The outcome of patients with HPV infection is influenced by many factors, such as HPV subtype dominance, persistent HPV infection, HPV loading dose, and multiple HPV infection. Controlling HR-HPV persistent infection should be an important strategy for reducing cervical lesions.

Keywords

cervical lesion / high risk-human papilloma virus / persistent infection / loading dose / cervical intraepithelial neoplasia / cervical cancer

Human papilloma virus (HPV) infection of the cervical lesions

HPV infection rate of the cervical lesions

It has been reported that at least 80% of sexually active adults have been infected by one or more HPV subtypes of genital duct in a certain period [1]. The cervix HPV infection rate (IR) of women with normal results of cytological examination is 10.2%-40.0% [2-4], HPV IR for patients with atypical squamous cell of undetermined significance (ASCUS) was 20.0%-65.1% and 64.4%-90.9% for low grade squamous intraepithelial lesion (LGSIL), respectively. The high-risk HPV infection rate (HR-HPV IR) of patients with high-grade squamous intraepithelial lesion (HGSIL) was 73.3%-100.0% [2,3,5] and 88.4%-99.7% for patients with cervical cancer [2,5]. The examinations, including colposcopy, cervical biopsy, and HPV DNA detection were further applied for 314 women with abnormal cell smear results by Infantolino et al. It was found that the cervical abnormal hyperplasia level, and the HR-HPV IR were strikingly increased. The HR-HPV IR was 40.0% in patients with negative histology inspection, 59.6% for ASCUS, 77.3% for HGSIL, and 86.9% for cervical intraepithelial neoplasia (CIN) III [6]. Thus, the universality of HPV infection in the reproductive tract should not be ignored.

HPV recessiveness, latency, and subclinical infection

HPV infection manifests as clinical, subclinical, and latent infection in three patterns. Incubation period of HPV infection largely varies, usually 3-6 months long, but it may also be as long as decades. The rate of HPV hiding infection in genital duct is high, and the main HPV subtypes are other types, excluding HPV-6, -11, -16, and -18. This infection is related with the low viral infection capability due to their low proliferative ability and affinity, and their pathogenicity is weak or absent.

Related factors of HPV infection

The overwhelming majority of women with HPV infection do not develop into cervical cancer, which indicates that the single factor of HPV infection may be not sufficient for carcinogenesis. The well-known risk factors of HPV infection in cervical lesions consist of high-risk sexual behaviors, immunosuppression, age, contraceptive methods, other concurrent infection of sexually transmitted diseases, etc.

High-risk sexual behaviors

HPV infection is closely related with high-risk sexual behaviors. It has been indicated by epidemiological surveys that HPV mainly spreads via sexual intercourse. The infection condition is directly concerned with the number of women’s sexual partners, sexual frequency, the number of sexual partners corresponding to their partners and sexual partner’s genital warts, and so on [7]. HPV IR could be increased by many factors, such as excessive sexual partners, too early sexual life, and sexual confusion [8].

Immunosuppression

The immune system plays an important role in determining the natural history of HPV infection and the outcome of related diseases caused by HPV infection. Immune dysfunction is a high-risk factor of HPV infection. The cellular and the humoral immunity can be induced by HPV infection. The cellular immunity is essential for the process of viral elimination and is considered more important than the humoral immunity. HPV infection, mainly restricted to the mucosal epithelial cell layer, leads to the decreased molecule expression of major histocompatibility complex (antigen) I (MHC I) on the cell surface and the weakened killing effects of the cytotoxicity T lymphocytes (CTLs), and, finally, it results in the clinical manifestations. Therefore, the local cellular immune deficiency (CID) exists in the patients with cervical lesions and HPV infection. The level of local mucosal CID is in coincidence with the severity of cervical lesions caused by HPV infection. The risk for the women with severe immune deficiency to be infected with HR-HPV is increased by 10 fold [9].

Age

At present, there are two viewpoints toward the relationship between HPV IR and age. In the first opinion, HPV infection is most common in young women with active sexual behaviors, and HPV IR gradually decreased, while the patients’ age rises. It has been reported by Bekkers et al. that the peak age range of HPV infection was 18-30 years, while the highest age range of HPV IR was 20-25 years. The peak age of new infection cases was 20-24 years every year [10]. According to statistical results, there was also similar tendency of HPV detection rate in women with different ages in the USA. HPV IR from the newborn to 10 years was 1%, 20%-40% for the adolescents, and 40% for 20-29 years, and then, it gradually decreased to plateau region up to 50 years of age; furthermore, it was 5% for people older than 50 years [11]. The HPV positive rate for women between 30-50 years was 24%-28% in Yangcheng county and Xianghuan county, Shanxi Province, China [12]. It can be seen that HPV IR is age dependent. Women with too early sexual life, sexual overfrequency, and sexual confusion are more likely to be infected with HPV. Moreover, the immune system of young women is not sensitized, and they are susceptible to HPV infection. Especially, the cytological paramorphia is likely to be resulted in for women with persistent HR-HPV infection. In the second opinion, there are two HPV infection peaks in young and elder women. It has been shown by Sellors et al. that the HPV IR was increased at the first peak in women between 20-24 years (24%) and decreased to 3.4% in women between 45-49 years; and another peak of HR-HPV infection of 10%-12% was in patients older than 60 years [13]. The reason why HPV IR is increased in women older than 60 years is unknown. It has been supposed that it is related to the virus revival in latency period caused by the evanescence of intrinsical immunity and the decrease of hormonal immunity.

Contraceptive methods

It is controversial whether the condom utilization of sexual partners reduces female HPV IR. It has been indicated that HPV IR of women whose sexual partners used condoms was lower (9.4%) [14]. However, no evidence was found that the condom utilization cut down HPV IR in other studies, and the contact of genital duct skins between sexual partners was not avoided because the condom is merely a kind of physical barrier [2]. The dispute of the impact of oral contraceptives on HPV IR is still great. It has been reported that oral contraceptives were obviously related with HPV infection. The risk of cervical HPV infection was increased in women using oral contraceptives in a long duration (more than five years). Furthermore, the risk of cervical cancer for the cervical HPV carriers was increased by 4 fold [15]. However, it has also been confirmed in other studies that there was no effect of oral contraceptives on HPV infection [2].

The concurrent infection of other sexually transmitted diseases (STDs)

The susceptibility of the reproductive tract to HPV infection can be increased by the STD pathogens, the main pathogen of the female reproductive tract infection in sexually active women [16]. The infection rate of mycoplasma urealytium (Uu) is highest in the HPV carriers with concurrent infection of other STD pathogens. The HR-HPV IR was also increased in patients with human immunodeficiency virus (HIV) infection (41%-74%), while HPV IR was 21%-41% in women with serum HIV(-) [9].

Cervical lesions caused by HPV infection

HPV infection and cervical condyloma acuminatum (CCA)

CCA is a cervical mucosal hyperplasia disease caused by HPV infection and the virus was inoculated to certain site via minor injury. According to the literature, HPV-6, -11, -16, -18, and -24 were associated with CCA among the HPV subtypes, especially HPV-6 [17]. CCA is often detected in patients with CIN and cervical cancer, and the phase of the transition tissue between CCA and cervical cancer has been found, which suggests that the continuity of biological behavior may exist between CCA and cervical cancer [9]. The host immune system may be damaged by some high-risk mutated subtypes; therefore, the virus persistently exists and eventually leads to malignant transformation.

HPV infection of patients with CIN and cervical cancer

The relationship between HPV genital infection and CIN and cervical lesions was first proposed by German virologist Zur Hausen [18] and has attracted more and more attention. It was reported that the detection rate of HPV infection in normal women, patients with CIN I, CIN II, CIN III, and cervical cancer was 4%, 30%, 55%, 65%, and 99.8%, respectively [19]. These results indicated that HPV infection was closely related with cervical cancer and precancerous lesions.

Most studies about the risk assessment of the exposure of HPV infection are consistent. In a prospective study of 1417 women with normal cervical cytology, the risks of occurrence of LGSIL and HGSIL in HPV DNA-positive women were 3.8 and 12.7 times of HPV DNA-negative women, respectively. As for HPV-16, the risks were increased by 5.8 and 63.9 times [20]. Twenty thousand women were tracked by Sherman et al. for more than 45 months, and the results showed that the accumulative incidence of CIN III or cervical cancer was 4.5% in HPV (+) women or women whose smears were ASCUS or more severe, whereas it was only 0.16% in women with HPV(-) or those whose smear was normal. The risks of CIN and cervical cancer in HPV (+) women were 24.96 and 24.03 times of those in HPV (-) women [21]. According to epidemiological studies and biological research, it has been confirmed that HPV infection plays an important role in the precancerous lesion and cervical cancer. (1) The relative risk (RR) between HPV and precancerous lesions or cervical cancer was 20-70 in most studies, and no other risk factors were stronger than HPV infection. (2) The correlation between HR-HPV and precancerous lesions was higher. (3) HPV DNA was mostly detected in patients with CIN, cervical squamous carcinoma, and adenocarcinoma. (4) Anti-HPV-16 antibody could be detected in patients with cervical squamous carcinoma. (5) Cervical carcinoma could be induced by continual exposure to HPV-16.

Main factors associated with the outcome of HPV infection

HPV subtype dominance

Distribution of HPV subtype dominance and pathogenicity

Up to date, more than 100 HPV subtypes with different oncogenic characteristics have been identified. Generally, all kinds of HPV genotypes can be divided into two categories according to their carcinogenicity. One is the low-risk group (noncarcinogenic), which includes HPV-6, -11, -42, -43, and some new types. The other is the high-risk group (carcinogenic), including HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, and -59 genotypes. Besides, HPV-66, -70, -72, -53, -67, and -83 may also be carcinogenic types [22]. It has been reported in many studies that the specific HPV subtype dominance is associated with several particular morphological alterations and cervical lesions. The low-risk HPV subtype infections are usually related with the high-risk sexual behaviors and result in chronic cervicitis, genital wart, CIN I, and partial CIN II, which are always naturally eliminated by themselves. Almost no patients infected by low-risk HPV subtype suffered with CIN III or cervical cancer [6,23]. The HR-HPV infections are often found in women older than 40 years and related with CIN III and invasive cervical cancer. This kind of pathological changes could not fade by themselves and hardly change.

Distribution of HPV subtype dominance in SIL

The high-risk HPV-16 and-18 are closely related with cervical pathological changes of HGSIL. Woodman et al. reported that the most important risk factor was HPV-16 (+) and then was HPV-18 (+) or HPV-33 (+) for HGSIL [24]. However, Yang et al. found that HPV-16 (+) had the highest OR (OR= 9.59) in risk factors associated with HGSIL, and the next to it were HPV-33 (+) and-31 (+) (OR= 2.99 and 2.52, respectively) [25]. It has been shown by Tang et al. that the top five of HPV subtypes were HPV-16, -58, -18, -33, and -31 in a descending order. HPV-18 infection rate is much higher in LGSIL than that in HGSIL [26].

Distribution of HPV subtype dominance in CIN

It has been reported by Tsai et al. that the progression of CIN was significantly promoted by HR-HPV. The incidence of cervical cancer in patients with the HR-HPV infection was about 1%, while it was only 0.1% in those with the low-risk HPV infection [27]. In patients with CIN, HPV-16 is the most common pathogenic subtype (about 47%), and the detection rate of HPV-31, -33, -35, -51, and -58 is about 23.8%, while low-risk HPV subtypes HPV-6, -11, -42, -43, and -44 are usually detected in patients with low-grade cervical lesions (20%).

Distribution of HPV subtype dominance in cervical cancer

It has been indicated by considerable epidemiological and molecular biological evidence that HPV infection is closely related with cervical cancer and precancerous changes, and HR-HPV subtypes are the major pathogenic agents of cervical cancer. The infection rate of HPV-16 and-18 inclines to be the highest in patients with cervical cancer [6]. The research about the cervical cancer tissue samples derived from the various regions worldwide showed that HPV-16 was the most common pathogenetic subtype in cervical cancer, by which about 60% was induced. The second prevalent subtype was HPV-18, accounting for 14% and 10.5% for HPV-31, -33, -35, -51, and -58. However, the detection rate of low-risk HPV-6, -11, -42, -43, and -44 in cervical cancer samples was nearly 0%. It has been reported by Schellekens et al. that 95.6% of HPV DNA was positive, and the most common types were HPV-16 (44%) and HPV-18 (39%), followed by HPV-52 (14%) and HPV-45 (6.8%) [28]. It has also been shown by another report that the detection rate of HPV-58, instead of HPV-18, was No. 2 of HPV subtypes in patients with cervical cancer [29].

HPV subtype dominance and pathological characteristics of cervical cancer

The pathologic types of cervical cancer with different HPV subtypes are distinct, which shows that HPV subtypes have different carcinogenicity, leading to different pathological characteristics even different prognoses of cervical cancer as well. It has been reported by Tsai et al. that squamous cancer accounted for 80%-85% in cervical cancer, adenocarcinoma for 10%, and adenosquamous carcinoma for 3%, and the rest are other minor types such as clear-cell carcinoma. HPV infection is an etiological factor of nearly all of squamous carcinoma (95%-100%) and most of adenocarcinoma (80%-92%); however, it has no relationship with other types of cervical cancer [27]. It has also been reported by Bulk et al. that HPV-16 was closely related with the development of squamous carcinoma, while HPV-18 was related with adenocarcinoma. Moreover, the prognosis of squamous carcinoma was both influenced by HPV-16 and-18. Patients with HPV DNA (+) had relatively poor prognosis [30]. According to the report of Altekruse et al., the detection rate of HPV-18 was both high in cervical adenocarcinoma and adenosquamous carcinoma [31], and HPV-18 ranked the second place in cervical cancer but not in HGSIL [2]. It is inferred that tumor patients with HPV-18 (+) may develop faster, and the recurrence rate is higher. The progression speed is faster than that in patients with other HR-HPV types, and the prognosis is worse than other genotypes in the same clinical stage [32].

Regional variations of HPV subtype dominance

HPV pathogenic subtypes vary in different geographical regions. For HR-HPV types, there are different subtypes in different regions, and the pathogenicity is also different. The detection rate of HPV-16 is high in Panama but very low in Israel. The detection rate of HPV-18 is higher in Southeast Asia, while HPV-45 infection rate is higher in Western Africa. HPV-19 and -59 infection was only confined in Central and South America [17]. In Latin American, the most common HPV subtypes in patients with cervical cancer are HPV-16, -18, and -31 [32]. It has been analyzed by Clifford et al. that HPV-52 and -58 were superior to HPV-45, -31, and -33 [33]. In China, HPV subtypes are diverse in different nationalities and areas due to the vast region. It has been reported that there were HPV-16, -18, -31, -33, -45, -48, and other genotypes. HPV-16 mainly exists in the northern area, and the detection rate of HPV-58 is increased and kept balance with HPV-16 in the middle and lower reaches of the Yangtze River.

Persistent HPV infection

It has been confirmed by most studies that the majority of HPV infection was temporary, and 96% of the cervical lesions in HPV infection patients were self limited. About 80% of HPV infection was temporary and removed in 6-8 months. Among the other 20% HPV infection cases, about 80% were also removed in three years. After the disappearance of HPV infection that was not treated, even for the patients with HR-HPV infection, they were seldom developed into cervical cancer [34]. Only the persistent HPV infection presented in a trifle of patients (about 4%) was not removed, resulting in persistent CIN and further cervical cancer [19,22,35].

It has been indicated that tpersistent HPV infection was related with the progression of cervical lesions. The persistent existence of HPV infection led to slight pathological changes in the first 1-2 years. About 15%-20% LGSIL lesions were transformed to HGSIL. It took about 9-10 years for HGSIL to develop into precancerous changes and 4-5 years for precancerous lesions to change to infiltrating carcinoma [2]. Persistent HPV infection is a vital factor for HGSIL. Compared with HPV (-) patients, the relative risk of HGSIL for patients with persistent carcinogenic HPV infection was 10-12 [36]. In 2001, the results of a prospective study of persistent HPV infection were reported by Schlecht et al., and 1611 women were followed up in this research. Compared with HPV DNA (-) patients, the relative risk of SIL for patients with persistent infection of HR-HPV was 10.19. Moreover, the relative risk of SIL for those persistently infected by HPV-16 or -18 was higher (11.6%), while it was only 8.68 in patients without persistent HPV infection [36]. In addition, the relative risk of CIN III for twomen with persistent HR-HPV infection was increased by 100-300 times [1]. It has been shown by the screening results of a Dutch population that the duration from CIN I to cervical cancer was 12.7 years. The persistent infection of HR-HPV types was the necessary process in this duration, and the interval from HR-HPV infection to cervical cancer was 15 years [38].

There are several related factors for persistent HPV infection: (1) HPV (+) women above 30 years old are easy to be persistently infected and involved in the severe cervical lesions [19,35], (2) HR-HPV infection, (3) HPV (+) or immunosuppression, (4) Years of education<12 years, (5) Drug abuse, and (6) Multiple HPV infection.

HPV loading dose and cervical lesions

The severity of cervical lesions and HPV loading dose

Compared with that in the normal cervix and cervicitis, the total distribution of HPV DNA loading is significantly different in cervical cancer and precancerous changes. The contents of HPV DNA are increased in different grades of cervical precancerous changes, from CIN I to CIN II and CIN III, which manifests that the content of HPV DNA may be related with the occurrence and development of cervical cancer. The progress from cervicitis to cervical precancerous changes (CIN I, II, and III), finally, to cervical cancer is gradually promoted by the high levels of HPV DNA [38]. The results of Sun et al. indicated that the relative risk of SIL for cervical cancer patients with high HPV loading dose was significantly higher (OR= 18.0) than that of low HPV loading dose, and HPV loading dose was relevant to the degree and range of cervical lesions [39,40].

HR-HPV loading dose

It has been reported that HR-HPV infection with high loading dose is the most powerful crucial factor for the occurrence of cervical cancer. Several prospective research data indicated that the HR-HPV loading dose was closely related to CIN progress, and it might be a biological index for predicting the progress of cervical precancerous changes [41,42]. As for the research about the relationship between persistent and high HPV-16 loading dose and the occurrence of cervical carcinoma in situ, it has been reported by Josefsson et al. that the OR of cervical carcinoma in situ was gradually increased from low to high HPV-16 loading dose groups in comparison to that of HPV-16 (-) group [43]. Similarly, in 2005, Moberg et al. reported that HPV-16 infection with high dose was not only related to CIN progress but also strongly indicated that the risk of invasive cervical cancer was increased [44]. Therefore, the standards and detective method of HPV loading dose should be further formulated. Whether or not the high HPV DNA loading dose should be regarded as an index to predict the risk of cervical lesion degrees depends on further research of HPV loading dose in the pathogenic mechanism of cervical lesions.

Persistent HR-HPV loading dose

It has been manifested that persistent HR-HPV infection is a prerequisite for the occurrence of cervical cancer [18,36,42]. Moreover, the viewpoint of the significant dose-effective relationship between HPV loading dose and cervical cancer has been accepted by most scholars. Persistent HR-HPV infection depends on its characteristic of high loading dose and virus replication and the high viral copies, and the influence of persistent HR-HPV infection on CIN progress is mostly exerted by the copy number. It was found by Ho et al. that persistent HPV infection was related with the persistent existence of SIL (OR= 3.91) and OR= 4.97 for the persistent and high HPV loading dose. Compared with that of HR-HPV (-) women, the relative rate of abnormal cytological examination for patients with low-median and high HPV loading dose was 1.65 and 8.66, respectively [46]. Therefore, HR-HPV loading dose is possibly related with the degree and range of cervical lesions.

Multiple HPV infection

HPV infection has the characteristics of mixed infection of multiple subtypes, and the carcinogenicity of multiple HPV infection is inconsistent in literatures. In 2003, Munoz et al. summarized the results of a case-control study including 1918 cervical cancer patients and 1928 controls in nine countries from 1985 to 1997. It has been considered that there was no significant difference in the incidence of cervical cancer between patients with multiple HPV infection and simple infection (OR= 0.7) [17]. However, in 2003, a review by Eileen considered that multiple HPV infection of different HPV types (39%) existed in the HPV infection patients with cervical lesions, and multiple HPV infection was related with the severity degrees of cervical lesions. Multiple HPV infection was found in women with 11.8% of normal cytology results and ASUCS and 35.4% of low-median atypical hyperplasia. Moreover, at least one subtype was HR-HPV [47]. It has been found by Lee et al. that seven cases suffered from multiple HPV infection in 77 cases of cervical cancer (9.1%), and only three cases in the control group (0.5%, 592 women with normal cytology results). It was indicated that the risk of cervical cancer was increased by 31.8 times due to multiple HPV infection and 19.9 times for the simple infection [48].

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