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Objectives: The purpose of this article is to educate nurse practitioners about human papillomavirus (HPV) and cervical cancer screening. After reading this article, the nurse practitioner should be able to:
- Describe the virology and prevalence of HPV;
- Discuss the transformation zone of the cervix;
- Describe the transient nature of HPV and the role of persistence in malignant transformation;
- Describe methods of adjunctive HPV; and
- Discuss the current consensus guidelines for ASCUS.
Recent Advances Improve the Clinical Picture
Recent advances in cervical cancer screening include new cytologic collection techniques, revised reporting terminology and triage strategies that involve molecular testing. These improvements offer health care providers the most effective tools to date in the complex labyrinth of cervical cytology management.
The introduction of Pap screening in the 1950s allowed for the detection and treatment of pre-invasive disease and has decreased invasive cancer in the United States by 75%. In parts of the world where women remain unscreened, cervical cancer is second only to breast cancer in incidence and mortality. Cervical cancer is the major cause of death in women of reproductive age in those regions.1 Cervical cancer morbidity and mortality drop dramatically when women are screened.
Providers who perform cervical cancer screening and triage must be able to responsibly communicate the results to women. HPV DNA testing for oncogenic (high-risk) HPV types is now a recommended strategy for identifying women at higher risk for cervical intraepithelial neoplasia (CIN) after a borderline abnormal Pap (atypical squamous cells-unspecified, or ASC-US).2 The decision to triage women directly to colposcopy, accelerated repeat Pap or HPV DNA testing is associated with emotional, economic and safety issues. An understanding of the natural history of human papillomavirus and its role in the initiation of CIN and cancer is imperative.
As testing for HPV status becomes more widely used for both ASC-US Pap triage and primary screening of women older than 30, more NPs will be charged with making evidence-based decisions and providing accurate information to patients about the meaning of HPV DNA status. The role of HPV in the development of abnormal cells and cervical cancer should be discussed with all women at the outset of cervical screening. NPs who use and report this information must understand the significance of a positive HPV DNA test for oncogenic HPV, offering both caution and reassurance as appropriate. In particular, NPs must understand that infection by high-risk HPV is extremely common in young women and is usually cleared to undetectable levels by an immune response. Persistence of high-risk HPV is necessary for the development of significant pre-invasive and invasive disease.
HPV Types and Oncogenicity
Cervical cancer is generally considered a preventable disease due to its long pre-invasive stage. Experts now know that it is caused by the persistence of oncogenic human papillomavirus.3,4 Significant cellular changes with the potential for progression to cancer can be identified on the cervix and treated as a prevention strategy. More than 100 types of HPV have been identified, and approximately 25 play a role in infection of the anogenital tract. These types can be classified into three relative risk categories: low, intermediate and high. The low-risk viruses include HPV types 6, 11, 42, 43 and 44, which are rarely found in association with high-grade squamous intraepithelial lesions (SIL) or cancer. HPV 6 and 11 are the most common initiators of condylomata (genital warts). The intermediate risk types, including 31, 33, 35, 39, 51 and 52, can be associated with invasive cervical cancer, although this association occurs less frequently than with the high-risk types. The high-risk HPV types include 16, 18, 45 and 58. High-risk HPV types are found in women with high-grade lesions (high-grade SIL). They are also common on the cervices of women who will never develop SIL. HPV 16 is the most common cause of squamous cancer. HPV 18 is the most prevalent viral type in adenocarcinomas. Current testing methods for HPV generally combine intermediate and high-risk types into one group (Table 1).5 Currently, no management strategies are available for treating latent HPV infections. A woman who is high-risk HPV-positive on HPV DNA testing but does not have abnormal cells requires careful follow-up. She may develop a lesion or clear the virus over time.
Most high-risk HPV exposure does not lead to intraepithelial neoplasia or cancer. Long-term persistence of the virus is necessary for HPV-induced cancer to develop. Therefore, women at risk for significant disease and neoplastic progression are the minority (10% to 20%) who do not have an adequate immune response to HPV exposure.5 They do not clear high-risk HPV from their genital skin cells.6
High-risk HPV can interfere with the normal protective mechanisms of anti-oncogenes for control over normal cell growth. The ability to inspect cell reproduction for mistakes or mutations in replication can be lost. High-risk HPV causes a loss of apoptosis, the destruction of cells that occurs with a deviation in genetic structure. HPV E6 and E7 genes block the function of anti-oncogenes and cell growth arrest, and cell death does not occur.3,6
The progression of normal cells to severely neoplastic cells is a multi-step process. Integration of HPV into the host cellular DNA appears to be a final step in transformation of the host cell to an immortalized cancer cell capable of invasion. Viral integration appears to occur when loss of host-cellular control and persistence of high-risk HPV result from poorly understood viral, host and cofactor interactions.6 It is important to understand that HPV infection is extremely common, but that most infection is cleared. The development of cancer is rare and requires the confluence of many factors. Some cofactors in the progression of CIN are well-defined (Table 2).
Prevalence and Presentation
HPV is the most common sexually transmitted infection in the female genital tract. Infection with or detection of HPV DNA does not necessarily mean that disease expression will occur.7 Most infections are asymptomatic and most infected women are unaware they are infected. Approximately one-third of sexually active women harbor some form of clinically manifested HPV infection.8 One investigation of sexually active college women found a cumulative prevalence of anogenital HPV infection of 69%.5,9
HPV exposure occurs primarily through sexual intercourse. To become infected, the virus must gain access to basal cells of a squamous epithelial surface, either through minor traumas such as skin abrasion or during sexual intercourse.10 Inoculation of the epithelium of the entire lower genital tract occurs with infection.11
It is important to understand that a condyloma (genital wart) arises from a field of HPV infection. After treatment and resolution of one condyloma, a new occurrence does not represent new infection or re-infection, but active growth from a field of latent HPV infection. A patient's immune response determines her outcome after exposure. Immune dominance means no visible change or minimal disease expression and easy clearance. Women who develop extensive warts after exposure to HPV 6 or 11, or are refractory with new warts developing more than 9 months after initial appearance, have not demonstrated an adequate immune response.
When external HPV is present, infection of the vagina and cervix is presumed. There is a risk of associated cervical abnormality initiated by the same HPV type that caused the external disease or by a different type. Multiple HPV types can co-exist in genital skin cells. A woman with low-risk HPV 6 or 11 and external condylomata could develop a significant high-grade cervical lesion. She may have been exposed to multiple HPV types.
There is individual variation in response by local and systemic immune mechanisms that influence the course of clinical manifestations. In addition, viral type and individual cofactors determine outcome after exposure. Outcomes range from absence of disease expression to minimally expressed disease to the actively expressed changes of exophytic condylomas, dysplasias and cancers. The most common recognized visible clinical lesion is the condylomata accuminata or genital wart (Figures 1 and 2). The lesions are typically multiple, well-circumscribed, papillomatous growths that may involve the vaginal introitus, the vulva, the perineum, the anus and less commonly, the cervix.10 It is important to be able to recognize the difference between active condylomatous disease and the normal variants of micropapilliferous and microfillamentous change, which are of no clinical significance (Figure 3).
Most HPV infection is not visible to the naked eye and would be considered subclinical. An acetowhite reaction that occurs with application of vinegar to the vulva is presumptive-not definite-evidence of HPV infection. When this skin is biopsied, a histologic diagnosis of HPV change called koilocytosis is possible. This change does not cause symptoms and there is no rationale for treating it (Figure 4).
Cervical cytology is the most common way that changes of HPV infection are diagnosed. Mild effects include atypia and koilocytotic atypia, although koilocytosis is no longer considered pathonomonic for HPV. The more significant cellular abnormalities are graded in their degree of neoplastic progression from low-grade to high-grade. The nomenclature changed in 1988 from the older terms of mild, moderate and severe dysplasia to the current use of CIN 1, 2 or 3. Currently, CIN 1 is in a low-grade category called LSIL (low-grade squamous intraepithelial lesion) and CIN 2 and 3 are combined in the high-grade category as HSIL (high-grade squamous intraepithelial lesion).
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