Adolescent Biological Vulnerability

Young age at first intercourse has long been associated with risk for invasive cancer. The risk of invasive cancer increases twofold in women who initiate sexual intercourse under the age of 18 years as compared with those initiating sexual intercourse after 19 years when controlling the number of lifetime sex partners (23). This finding suggests that there is a certain biological vulnerability of the cervix of young women to HPV infection. The adolescent cervix is structurally different from the cervix of adult women (6). It frequently has a mosaic appearance with different cellular components including relatively large areas of columnar and metaplastic squamous epithelium. Although, the adult cervix also contains these components, the predominant cell type in adults is the mature squamous cell. Both columnar and metaplastic squamous cells are vulnerable to HPV probably for a variety of reasons of which thinness of the epithelium may be one factor.

Once sexual activity is initiated, active immature squamous metaplasia occurs. This process is characterized by replacement of the columnar epithelium by rapidly proliferating immature squamous epithelium. This rapidly proliferating cellular population is presumably vulnerable to HPV infection resulting not only in replication of the virus, but also accompanying viral induced genetic alterations in the host metaplastic squamous epithelium, which if infection persists can lead to HSIL. Cervical maturity, in which immature metaplastic epithelium is transformed to mature glycogenated epithelium in adolescent populations is directly correlated with the number of sexual partners (24,25). Although, the mature squamous epithelium provides more protective barrier to HPV than the thin columnar epithelium, the process of transformation creates a fertile environment for HPV infection and development of SIL.

Understanding the life cycle of HPV clarifies the role of cervical immaturity in viral acquisition, persistence, and development of SIL. It is believed that HPV gains access to basal cells in the squamous epithelium as a result of small tears in the superficial layers of the squamous epithelium during sexual intercourse or through inflammatory processes. HPV replication and patterns of transcription are highly dependent on the differentiation program of keratinocytes in the cervical squamous epithelium with transcription of HPV proteins E6 and E7 occurring shortly after infection (26). HPV E6 and E7 are important oncoproteins with well-described transformation properties (27). As cells go through differentiation, the infected cell expresses E1, E2, and E4 viral proteins. It is not until the cell has undergone terminal differentiation that HPV expresses large amounts of its cap-sid proteins, L1 and L2, for the final formation of infectious virions. Immature metaplas-tic squamous epithelium in adolescents supports viral replication because of the rapid cellular proliferation and differentiation of the metaplastic cells. The expression of E6, E7, and E4 proteins results in basal cell proliferation, nuclear enlargement, and abnormal mitotic figures, similar to features of SIL (28). A study of adolescent women showed that those with evidence of active metaplasia based on colpoposcopy were more likely to develop LSIL if infected with HPV than adolescents with a relatively quiescent cervix (29). In a longitudinal study of HPV infection in adolescents 50% acquired HPV and more than one-quarter of those developed LSIL, underscoring the common manifestation of productive HPV infection as LSIL in this age group (19).

Factors that influence or induce squamous metaplasia are not well defined. Because of the active immature squamous metaplasia during adolescence compared with childhood, the influence of estrogen is believed to be important. However, other factors including local trauma and infection have also been shown to induce metaplasia. Several decades ago, Singer et al. (24) showed that adolescents who had initiated intercourse, and reported several sexual partners were more likely to have mature cervixes covered predominantly by squamous epithelium in comparison with virginal adolescents whose cervixes were predominantly covered by columnar epithelium. In a recent study of high-risk adolescents using colpophotographical descriptions, the more the number of sexual partners the more likely these women had a mature cervix (25). These studies suggest that factors associated with sexual intercourse (i.e., sperm, STIs) may be capable of inducing metaplasia and increase the risk of HPV and LSIL. Schachter et al. (30) showed that Chlamydia trachomatis was associated with metaplasia on histology, suggesting that inflammation and repair can induce the process of squamous metaplasia. In a longitudinal study of adolescents, having HSV antibodies was an independent risk factor for acquiring HPV (19).

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