Understanding the viral replication cycle is essential to understanding the clinical implications of HPV DNA and disease detection in adolescents. The target cell for HPV infection is the epithelial basal cell. The virus life cycle is dependent on the ability of these cells to divide, differentiate, and move toward the epithelial surface.1
In the basal layer, the early proteins (termed E6 and E7) facilitate replication and maintenance of the viral genome and cause cellular proliferation as well. As the cell matures, different HPV proteins are expressed that continue to maintain viral genomic replication. Expression of the late proteins, which create the essential outer capsid, occurs in the upper layer of the epithelium. This is followed by packaging of the DNA into the capsid and eventual release of infectious virions from the normally desquamated epithelial cell.
Without cell differentiation, the virus cannot replicate. The period between basal cell infection and release of virus is thought to be somewhere between 3 weeks and 3 months.
Viral replication and its associated protein expression induce the development of the low-grade squamous intraepithelial lesion (LSIL), which is characterized by mild basal cell proliferation and nuclear enlargement. These changes are in part due to the expression of the oncogenes E6 and E7 and perinuclear halos secondary to E4 expression, which interferes with cytoskeletal structure. As the intraepithelial lesions advance in grade, expression of products important in cell transformation, such as E6 and E7, predominate resulting in chromosomal abnormalities and the aneuploidy characteristic of the higher-grade squamous intraepithelial lesions (HSIL). Hallmarks of cancer development include viral integration and interference with telomerase activity.2
As a point of clarification, the cytological diagnoses of LSIL and HSIL correspond to the histologic diagnoses of cervical intraepithelial neoplasia (CIN) 1 and CIN 2 or 3, respectively.3
Because the virus is nonlytic, the inflammatory response to HPV is much more subtle than other infections such as C. trachomatis
. During early HPV infection, the host remains somewhat immunologically unaware of the virus because the virions are released in the outer epithelial layer, away from the submucosa, the primary site of immune surveillance. It appears that an initial HPV infection triggers an innate immune response4
through activation of Toll-like receptors (TLRs), which recognize genetically imprinted pathogen-associated membrane proteins or through activation of natural killer cells.5
Innate immune responses are thought to be responsible for rapid clearance—those seen within weeks to a few months.
Chronic HPV infections are likely cleared by the development of adaptive immune responses,6,7
dependent on presentation of viral antigens to antigen-presenting cells (APCs), such as Langerhans and dendritic cells.8
Successful adaptive immune responses may take months to years to develop and oncogenic HPV types, specifically HPV 16, are able to downregulate both the innate and the adaptive immune response through numerous mechanisms.4
Because HPV infections are localized to the epithelium, it is believe that the majority of both innate and adaptive immune responses are mucosal. These immune parameters are important to remember when we review the efficacy of preventive vaccines.
Epidemiology and the Natural History of HPV and SIL in Adolescents
Anogenital HPV infections are extremely common in the sexually active adolescent, with over 50% having a positive HPV DNA test over a 3-year period.9–12
Numerous studies have shown that a recent new sex partner is the strongest risk for acquiring HPV.10,12–14
Other risks include having a sexually transmitted infection, which may reflect partner risk or inflammation resulting in a break in the epithelial barrier. Fortunately, in adolescents 50% of HPV infections are cleared within 6 months and 90% within 2–3 years.15–18
Since LSIL is a reflection of viral replication and HPV is most common in the adolescent age group, it is not surprising that LSIL is also most common in adolescents with a prevalence ranging from 2–14%.19
In parallel with HPV DNA clearance rates, over 90% of LSIL diagnosed in adolescents or young women also resolve spontaneously.
HSIL is far less common than LSIL, but adolescents and young women have a prevalence equivalent to older women with rates around 0.7%. The greatest single risk for HSIL development is HPV persistence. However, in one study, 7% of adolescents developed a HSIL shortly after HPV acquisition, suggesting some women develop HSIL without lengthy persistence.20
Other risk factors include smoking cigarettes21
and prolonged oral contraceptive use.22
Since nicotine can be measured directly in cervical mucous, proposed mechanism for cigarette use includes local immune suppression and/or local carcinogenic affect. The role for oral contraceptives is more elusive, but estrogen has been shown to induce cellular proliferation as well as enhance HPV oncogene transcription.23,24
Reinfection with numerous HPV types is common in adolescents contributing to the high prevalence rate observed in young women. This vulnerability is thought to be due in part to a naïve immune response since the rate of HPV declines with age, even when controlling for sexual activity.9,11,25–27
Clearance of infection appears to protect women from repeat infections with that genotype. This was well illustrated in the HPV vaccine trials where women seropositive for HPV 16 but HPV DNA 16 negative at baseline (ie, evidence of previously cleared infection) had low rates of HPV 16 infection during the trial although they were in the placebo arm.28–30
Adolescents and Biological Vulnerabilities to HPV, SIL and Cancer
Several studies, including a recent collaborative study of over 45 000 women have shown age of first intercourse to be an important risk for the future development of cervical cancer.31–34
In that study, an increase in the risk for the development of cervical cancer was noted in women initiating intercourse before 24 years of age, with risk increasing with each declining year until age 17.34
Some speculate that the risk of cancer increases because there is a longer time allowed for HPV persistence. Biologically, adolescence reflects a period of dramatic changes in an area of the cervix referred to as the transformation (T) zone where squamous cell cancers develop.35
Most neonates are born with an abrupt squamo-columnar junction visible on the ectocervix. This junction remains quiescent until puberty when estrogen and increased acidity of the vagina induces uncommitted basal cells of the columnar epithelium to become squamous cells through a process referred to squamous metaplasia. Consequently, the cervix in the adolescent is predominantly made up of columnar and metaplastic cells, whereas adults are predominantly squamous epithelium. Theoretically, the former epithelium may be more vulnerable to wounds induced by intercourse, douching or tampons leading to breeches in the epithelium and easy access for HPV. No study to date has shown that ectopy (eg, the presence of the columnar and metaplastic epithelium on the exocervix) is a risk for HPV acquisition. However, Castle et al36
found that infections with HPV types including 16, 31, 33, 35, 52, 58, and 67 were more common in women with large areas of ectopy, but not common in women with mature cervixes. This observation might be related to age and immunologic memory which goes hand in hand with cervical maturation.
More important than the presence of columnar epithelium is likely the presence of active metaplastic epithelium. Cells that are rapidly undergoing differentiation and replication are “fuel for the fire” for SIL development.37
A recent study showed that both oral contraceptive and smoking enhance metaplasia in young women.38
This is quite interesting in light of both of these being risks for cervical cancer.
Cervical Cancer Rates and Screening
Despite the age of sexual debut decreasing and cervical cancer screening increasing in adolescents, cervical cancer rates have basically remained unchanged in the 15- 19-year-old group. From 1990–2006, Surveillance Epidemiology and End Results statistics show that an average of 14 cervical cancers occurred annually in girls age 15–19 years, reflecting an incidence rate of 0.1 per 100 000.39
This rate is unchanged from that reported in 1973–1977 when screening was initiated.40
In a recent study in England where there are active screening programs, Sasieni et al41
found that screening women aged 20–24 years had no detectable impact on reducing cervical cancer rates in women under the age of 30 years. In comparison, there was a dramatic reduction noted for women 30 years and above. In another study, Gustoffson et al42
compared rates of cervical cancer before and after screening programs were in place using data from several different countries including the United States. They showed that cervical cancer was significantly reduced among women between the ages of 35 and 55 years. No differences were found for women 25–35 years of age and those older than 70 years. Barnholtz-Sloan et al43
reported that U.S. incidence cervical cancer rates showed significant decreases in incidence between 1995–1999 and 2000–2004 for all age groups and race/ethnicities except for Hispanic/all races women aged 15–24 years and non-Hispanic/other women aged 15–24 years. Changes in white and black women aged 15–24 years decreased but only marginally. These data support the notion that cervical cancer screening by cytology does not effectively prevent the rare cervical cancer case in the adolescent.
Risk Factors that Influence Clearance of HPV and SIL and Progression to CIN3
It has been shown that the longer HPV persists, the more likely it will not be cleared.44
HPV persistence is key in the development of cervical cancers. However, how long persistence is required remains unknown. Persistence is likely necessary but not sufficient and other important carcinogenic events are needed before cancer develops.
Currently, CIN3 is considered a true precancer since regression is unlikely and progression to cervical cancer is estimated to be around 15% if left untreated. CIN1 is considered benign because of high rates of regression and rare progression. The diagnosis of CIN2 is clinically challenging and reproducibility being quite poor. Histologic readings are often either downgraded or upgraded on repeat analysis.45
Recent studies also show that CIN2 appears to regress in ~60% of young women.46,47
In the ALTS trial, depending on their study arm, some women with CIN2 were treated with excisional therapy at the end of the study.48
Many of these women no longer had evidence of CIN2. One of the protective factors associated with progression to CIN3 included young age at biopsy. Women aged 18–21 years of age had a 52% reduced risk of having CIN3 on follow-up compared with women aged 22–23 years.48
Another reason that CIN2 may commonly appear to regress is the low reproducibility of CIN2 lesions.49
Castle et al48
demonstrated that when CIN2 lesions were downgraded to CIN 1 by another review, the lesion was less likely to progress to CIN3 than those lesions that remained a CIN2 by the second review.
Although CIN3 does occur in adolescents, it is uncommon and the risk for CIN3 in this age group has not been well studied. Although there have been rare cases of spontaneous CIN3 shortly after HPV acquisition, the risk factors are likely similar to those in older women.50
The lower progression rates from HPV or LSIL to CIN3 seen in adolescents is probably due to the fact that adolescents have not had enough time for progression to occur. However, better elucidation of the natural history of CIN3 among adolescents is unlikely to be garnered since it is considered unethical to leave potentially cancerous lesions untreated.
Cervical Cancer Screening
As discussed above, since cervical cancer screening has not changed cervical cancer rates over the last 3 decades in 15- to 19-year-olds or 20- to 24-year-olds and screening young women does not influence rates of cancer diagnosed under the 30 years of age,41
screening recommendations have been revised. A recent statement from a conference headed by the American Society for Colposcopy and Cervical Pathology and Centers for Disease Control and Prevention with 22 other organizations attending recommended that in the United States, cervical screening should start at the age of 21 years with no caveats related to the age of onset of sexual activity.51
This recommendation has been made an official guideline of the American College of Obstetrics and Gynecology and several other groups are moving to adopt this recommendation. The previous guideline recommending that screening begin at 21 years old or by 3 years after sexual debut (whichever comes first) has been difficult to follow, had poor adherence, and raised concern about causing more harm than good.52