Fifty years ago, cervical cancer was the primary cause of cancer deaths for American women (Spitzer, 2007). The introduction of the Papanicolaou (Pap) smear for cancer screening in 1945 and cervical cancer screening programs in the United States have reduced cervical cancer mortality by 70% (Datta, Koutshky, Ratelle, Unger, Shlay, McClain, et al., 2008; Spitzer, 2007). Despite this progress, in the United States 12,280 women were diagnosed with the disease in 2007 and 4027 died (U.S. Cancer Statistics Working Group, 2010). Worldwide, cervical cancer is still the most common type for women, especially in sub-Saharan Africa (Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). Recent research and scientific advances have identified human papillomavirus (HPV) as the causal infective agent in cervical cancer (Datta, Koutshky, Ratelle, Unger, Shlay, McClain, et al., 2008; Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). Despite the significant improvement in cervical cancer death rates, there is still confusion about appropriate cancer screening recommendations across the life span (Datta, Koutshky, Ratelle, Unger, Shlay, McClain, et al., 2008). This article summarizes the current science regarding the most recent guidelines for cervical screening and the research that supports these recommendations. The focus will be on the incidence, progression, regression, and persistence of HPV DNA to enable nurse practitioners (NPs) to provide appropriate high-quality, cost-effective care.
During the 1970s and 1980s, researchers determined that an infectious, sexually transmitted disease known as HPV was the cause of cervical cancer (Stanley, 2010). In the 1990s, researchers identified many different strains of HPV and noted histologic changes in cervical squamous cells resulting from exposure to certain high-risk HPV types (Stanley, 2010; Widdice & Moscicki, 2008). Persistent cervical infection with these oncogenic HPV types was associated with the development of cervical cancer (Stanley, 2010; Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010; Widdice & Moscicki, 2008). Current estimates are that at least 50%–80% of young, sexually active women will contract HPV infection within 24–36 months of coitarche (Datta, Koutshky, Ratelle, Unger, Shlay, McClain, et al., 2008; Moscicki, 2007). The HPV Sentinel Surveillance project determined that 35% of young women aged 14–19 and 29% of those aged 20–29 have high-risk HPV (Datta, Koutshky, Ratelle, Unger, Shlay, McClain, et al., 2008; Moscicki, 2007).
The risk of developing an HPV cervical infection is about 80% in a lifetime (Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). The U.S. prevalence rate of HPV in sexually active women is 40% for those 14–19 years old and 49.3% in those 20–24 years old (Widdice & Moscicki, 2008). However, major longitudinal studies have demonstrated that young women were found to clear HPV over time, without progression to invasive cancer (Moore, Fetterman, Cox, Poitras, Lorey, Kinney, et al., 2010). Of those infected with HPV, studies have shown that 90% clear within 2 years and that HPV persistence affects only a small group (Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). While young women are four times more likely to acquire HPV infections than older women, those aged 15–19 have only a 0.1/100,000 incidence rate of cervical cancer (Moscicki & Cox, 2010).
Adolescent cervical anatomy
Young women's cervixes have unique anatomical features that make them more vulnerable to HPV (Moscicki & Cox, 2010; Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). Where the adult cervix contains protective squamous epithelium, the immature cervix contains columnar epithelium, which undergoes the process of metaplasia during the adolescent period (Moscicki & Cox, 2010). Metaplasia allows HPV easier access to the basal cell layer, which is the site of rapid replication and differentiation (Moscicki, 2007; Moscicki & Cox, 2010). Microabrasion caused by tampons or intercourse allows HPV to infect the basal cell level (Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). This active metaplasia in the epithelium facilitates the squamous intraepithelial lesion development (Moscicki, 2010). As a result of these changes, the large metaplastic transformation zone is vulnerable and susceptible to HPV in the adolescent, and this area is where cervical cancer develops (Moscicki, 2007; Moscicki & Cox, 2010; Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). Despite these anatomical features in young women and their high prevalence of HPV, research has demonstrated that young women have the ability to clear HPV with minimal risk of cervical cancer (Moore, Fetterman, Cox, Poitras, Lorey, Kinney, et al., 2010; Moscicki, 2007, 2010; Moscicki & Cox, 2010).
Risk factors for acquisition of HPV
Several risk factors have been studied that relate to the progression and regression of HPV, including the immunosuppressive effect of smoking (Moscicki, Ma, Wibbelsman, Powers, Darragh, Nozzari, et al., 2008; Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). Smoking may also enhance metaplasia (Moscicki, 2010). The lack of a protective effect from condoms against HPV development in women has been reported in multiple studies, but the reliability of the data has been questioned (Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). Additional research is needed to understand why the use of oral contraceptives is associated with increased HPV risk. Oral contraceptives have the biologic effect of increased cervical ectopy, which may facilitate HPV uptake (Moscicki, Ma, Wibbelsman, Powers, Darragh, Nozzari, et al., 2008; Veldhuijzen, Snijders, Reiss, Meijer, & van de Wijgert, 2010). Estrogen increases the acidity of the vaginal canal, which then stimulates the process of squamous metaplasia (Moscicki, 2010). Researchers suspect that oral contraceptive use may increase the risk of having multiple partners, and each new partner results in a 10-fold increase in incident HPV (Moscicki, 2010). Immunosuppression and HIV are the two most significant risk factors for the development of high-grade lesions and increased risk for cervical cancer (Massad, Seaberg, Wright, Darragh, Lee, Colie, et al., 2008). All women should be assessed for HIV risk factors and screened appropriately (Massad, Seaberg, Wright, Darragh, Lee, Colie, et al., 2008). If a woman is found to be HIV positive, Pap smears should be ordered more frequently as a result of the increased risk for persistent HPV infections, multiple HPV-type infections, and increased risk for HPV genital cancers (Massad, Seaberg, Wright, Darragh, Lee, Colie, et al., 2008; Moscicki, 2010). Age of first intercourse prior to age 24 is an additional risk factor (Moscicki, 2010). Early intercourse has been shown to increase the risk for cervical cancer, due possibly to HPV persistence in the vulnerable cells of the transformation zone (Moscicki, 2010).
Cervical cancer screening guidelines
Many providers have found cervical cancer screening to be a confusing process as a result of the number of organizations that issue guidelines and the frequency of recent revisions (Moscicki, 2010). The American Cancer Society (ACS), the United States Preventive Services Task Force (USPSTF), and the American College of Obstetricians and Gynecologists (ACOG), have developed guidelines for providers who care for women of all ages (Datta, Koutshky, Ratelle, Unger, Shlay, McClain, et al., 2008; Wright, Massad, Dunton, Spitzer, Wilkinson, & Solomon, 2007). While there is overlap among the guidelines, subtle differences have led to confusion among clinicians (Moscicki, 2010). The guidelines for these three national organizations are summarized in Table 1 and reflect alternative screening options that clinicians can adopt.
Adding to the confusion regarding cervical screening have been recent changes in Pap smear methods, classification, and reporting of results. The 1988 Bethesda System nomenclature of reporting Pap smears was revised in 1991 and again in 2001 (Datta, Koutshky, Ratelle, Unger, Shlay, McClain, et al., 2008; Wright, Massad, Dunton, Spitzer, Wilkinson, & Solomon, 2007). There is a choice in cervical screening methods now that includes the use of liquid-based or conventional cytology (ACOG, 2009). The liquid-based cytology is more expensive, has a decreased specificity, but is able to test for HPV, chlamydia, and gonorrhea from the same sample (ACOG, 2009). Liquid-based cytology is easier for cytotechnologists to read (ACOG, 2009).
Historical development of Pap smear guidelines
For many years, including the 2001 cervical cancer screening guidelines, it was recommended that all women be screened with a Pap smear at coitarche (Moscicki, 2010). However, given the high HPV incidence rates in young women, this annual screening found many cervical abnormalities (Moscicki & Cox, 2010). This led to unnecessary treatments of low-grade cervical intraepithelial neoplasia (CIN) deemed necessary by otherwise unneeded colposcopies and biopsies (Moscicki & Cox, 2010). Young women were subsequently found to clear HPV over time, without progression to invasive cancer, according to the Atypical Squamous Cells of Undetermined significance/Low-Grade Squamous Intraepithelial Lesions (LGSILs) triage study group (ALTS) in 2000 and 2003 (Moore, Fetterman, Cox, Poitras, Lorey, Kinney, et al., 2010; Moscicki & Cox, 2010). The additional cervical procedures that followed abnormal Pap smears resulted in more invasive procedures. These led to complications such as incompetent cervix, cervical stenosis, premature deliveries as a result of cervical harm, and psychological trauma (Moscicki, 2007). Consequently, it was determined that Pap smears were unnecessary in these young women under 21 (Moscicki & Cox, 2010).
With the advent of new Pap smear technology, liquid-based cytology, and HPV DNA testing, screening ability improved, bringing a better predictive value in who should proceed to a more invasive evaluation (Spitzer, 2007). The improvement in understanding of epidemiology and virology regarding HPV and cancer screening techniques led to the 2006 revision of the 2001 U.S. cervical screening guidelines (Moscicki, 2010). The 2006 revisions affected how providers screened women for cervical cancer and were specific about when to begin screening adolescents and young women (Spitzer, 2007; Wright, Massad, Dunton, Spitzer, Wilkinson, & Solomon, 2007). The landmark ALTS Study group research findings, literature reviews, and experts in these associations formulated the 2006 guidelines to begin Pap smears at 3 years after coitarche or age 21 (Moscicki & Cox, 2010; Wright, Massad, Dunton, Spitzer, Wilkinson, & Solomon, 2007).
When to begin cervical cancer screening?
Many sexually active adolescents have abnormal Pap smears caused by HPV infection, but research has demonstrated a low prevalence of cervical cancer in the group aged 15–20. Table 2 provides a summary of research for women under age 21. Earlier recommendations for screening young women led to additional visits for colposcopies, biopsies, and invasive treatments that resulted in increased risk for incompetent cervix and cervical stenosis. While the incidence of an abnormal Pap is high in this age group, given time, it frequently resolves on its own. Studies have shown that low-grade changes will resolve within 36 months and that progression to high-grade lesions is rare in this age group (Moscicki & Cox, 2010). There are no studies of CIN 2 progressing to CIN 3 because researchers are obligated to intercede, but it is known that this age group has a low rate of invasive cervical cancer (Moscicki, Ma, Wibbelsman, Powers, Darragh, Nozzari, et al., 2008). It is unclear how long HPV must persist for the development of high-grade squamous intraepithelial lesion (HGSIL), but studies indicate that the increased risk is significant when HPV is detected in the group over 30 years old, not the adolescent woman (Moscicki, Ma, Wibbelsman, Powers, Darragh, Nozzari, et al., 2008). Any woman who has had a biopsy CIN 2 or greater should be followed annually for at least 20 years as a result of a low risk of persistent HPV that can pass in and out of detection (Sycuro, Xi, Hughes, Feng, Winer, Lee, et al., 2008). It should be noted that a Pap smear is not recommended for the adolescent with genital warts, as these wart types are not oncogenic (Moscicki & Cox, 2010). Pap smears are imperative for any woman with HIV, immunosuppression, or diethylstilbestrol exposure (Massad, Seaberg, Wright, Darragh, Lee, Colie, et al., 2008; Moscicki & Cox, 2010).
How often to screen?
Under the 2009 ACOG guidelines, health visits will involve cervical cancer screening on women aged 21–29 every 2 years (ACOG, 2009). Less frequent screening of immunocompetent women with normal Pap smears is based on the longitudinal studies that show if they do contract HPV, the HPV will clear in the course of 6–36 months, and no significant high-grade lesions or invasive cancers are diagnosed when women receive regular care (Moore, Fetterman, Cox, Poitras, Lorey, Kinney, et al., 2010; Moscicki, 2010; Rodriguez & Fadare, 2007). Any women who test positive for atypical cells of undetermined significance (ASCUS) with high-risk HPV, LGSIL, or HGSIL are referred for colposcopy (ACOG, 2009). In the age group of adolescent and young women, the progression rate from LGSIL to HGSIL is low, and generally this is biopsied as CIN 2, which shows a 60% regression rate within 3 years (Moscicki, Ma, Wibbelsman, Powers, Darragh, Nozzari, et al., 2008). CIN 3 is rare in the under-25 age group (Moscicki, Ma, Wibbelsman, Powers, Darragh, Nozzari, et al, 2008). The incidence of cervical cancer in the 20–24 age group reported by the National Cancer Institute's Surveillance Epidemiology and End Results is 1.7 cases per 100,000 (Moore, Fetterman, Cox, Poitras, Lorey, Kinney, et al., 2010). Moore, Fetterman, Cox, Poitras, Lorey, Kinney, et al. (2010) found it to be zero when databases from Northern California Kaiser Permanente Medical Care Program were reviewed over 5 years for 1620 women aged 21–24 who were diagnosed with ASCUS-HPV positive and LGSIL (Moore, Fetterman, Cox, Poitras, Lorey, Kinney, et al., 2010).
It is apparent from the longitudinal studies shown in Table 3 that cervical cancer is rare in the college-age population despite a high prevalence of HPV infection (Moscicki & Cox, 2010). Performing Pap smears yearly in this age group may not be beneficial and may in fact lead to unnecessary visits, testing, adverse outcomes, and costs (Moscicki & Cox, 2010). The low risk for persistent HPV in the 21–29 age range can be addressed individually with closer follow-up for those specific women at increased risk. Research indicates that women aged 20–24 with a diagnosis of CIN 2,3 have a 50% likelihood of regressing without intervention (Moscicki & Cox, 2010). The adoption of guidelines into practice improves quality care and outcomes for young women (Moscicki & Cox, 2010).
When to use HPV cotesting?
For women aged 30 and over, there is the option of HPV cotesting and screening intervals of 3 years if the Pap history has been negative (ACS, 2002; ACOG, 2009). See Table 4 for these studies. Sycuro, Xi, Hughes, Feng, Winer, Lee, et al. (2008) contacted women who were known HPV positive during college and repeated testing 3–12 years later to determine the epidemiology of HPV persistence, shown in Table 3 (Sycuro, Xi, Hughes, Feng, Winer, Lee, et al., 2008). In these 147 women in this study known to be positive for HPV on cervical screening, it was found that HPV can have periods of negativity where the viral levels are below detection threshold (Sycuro et al., 2008). Sixteen percent of these women had persistent infection of the same type (Sycuro, Xi, Hughes, Feng, Winer, Lee, et al., 2008). In Yoost's (2009) retrospective analysis of women followed 2 years with LGSIL diagnosis and primary outcomes of persistence, regression, or progression by age at initial diagnosis, there was a 31% progression to a higher grade lesion for women 30 or over, which put them at increased risk (Yoost, Goetzl, Hoda, Soper, & Barry, 2009). Moscicki (2007) reports that this reflects persistent HPV in the older woman with an increased risk for HGSIL (Moscicki, 2007). As a result of the increased risk for persistence and progression in this age group, continuing Pap smears yearly for 20 years is appropriate in women with past diagnosis of CIN 2 or greater. The research studies had certain limitations regarding persistent HPV. Sycuro, Xi, Hughes, Feng, Winer, Lee, et al. (2008) noted that their low statistical power may have been a limitation and recommended larger sample sizes and the incorporation of shorter sampling frequency as a means to look more carefully at persistence of HPV (Sycuro, Xi, Hughes, Feng, Winer, Lee, et al., 2008). Studies have also shown that HPV DNA testing may be more accurate than cervical cytology at detecting risk for CIN 3 (Arbyn, Ronco, Cuzick, Wentzensen, & Castle, 2009; Kinney, Fetterman, Cox, Lorey, Flanagan, & Castle, 2011). HPV cotesting may identify women earlier who are at risk for CIN 3 and carcinoma in situ (Kinney, Fetterman, Cox, Lorey, Flanagan, & Castle, 2011). Retrospective record review noted a 5% risk over 10 years of developing CIN 3 or cancer in women over 30 who had negative Pap smears but positive HPV (Kinney, Fetterman, Cox, Lorey, Flanagan, & Castle, 2011). This suggests that cervical cytology detects squamous cell carcinomas but may miss certain adenocarcinomas (Kinney, Fetterman, Cox, Lorey, Flanagan, & Castle, 2011). HPV DNA testing has greater sensitivity than cytology for detecting CIN 3 and cancer (Kinney, Fetterman, Cox, Lorey, Flanagan, & Castle, 2011).
When to stop screening?
The ACS recommends discontinuing cervical screening in women aged 70 or over who have had at least three recent consecutive negative Pap smears and no history of abnormal screenings in the last 10 years (Smith, Cokkinides, Brooks, Saslow, Shah, & Brawley, 2011). The 2009 ACOG recommendations stop screening at age 65–70 with three consecutive normal Pap smears and no abnormal tests in the last 10 years (ACOG, 2009). ACOG recommends continued screening of sexually active women of any age who have multiple partners (ACOG, 2009). Most studies have shown that women with abnormal Pap smears or no Pap smears in the past are at higher risk of developing cervical cancer than women who have been screened regularly (Albert & Clark, 2008). Decisions to stop screening should be based on risk factors, past screening history, overall health, and life expectancy (Albert & Clark, 2008).
This review on the state of the science of Pap smears supports evidence-based guidelines related to prevalence, progression, regression, and persistence of cervical abnormality. NPs may express concerns about implementing the new guidelines in young women who are known to have high incidences of HPV. Historically, providers have been taught to perform annual Pap smears as a means to detect cervical abnormalities in order to prevent cervical cancer deaths. Many textbooks have not been updated to the current Pap smear screening guidelines. In many health centers, the standard protocol required a Pap smear before the birth control pill could be prescribed, and refills were contingent on a yearly Pap smear. Many young women request a Pap smear without understanding what is being evaluated, and some women ask for the Pap smear as part of screening for a sexually transmitted infection. Although the HPV vaccine was not a focus of this literature review, discussing it at visits and providing this vaccine for young women is important considering that HPV 16 is responsible for many of the infections in this age group (Moscicki & Cox, 2010). Moscicki and Cox (2010) report that evidence-based studies suggest HPV vaccination should be targeted to adolescents prior to sexual activity, as research data reveal increased efficacy in the sexually naïve. Despite HPV vaccination status, current recommendations include regular cervical cancer screening (Moscicki & Cox, 2010). The following summary of our findings points to an urgent need to incorporate the evidence-based science found in these national clinical guidelines into our practices:
- Literature reveals that educating providers about the evidence related to a change in practice guidelines is one intervention that may result in increased implementation of the guidelines (Moscicki & Cox, 2010).
- NPs may use the woman's health exam as an opportunity to focus on educating a woman about her body, smoking risks associated with persistent HPV infection, substance use implications, contraception, and prevention of sexually transmitted infections such as chlamydia, gonorrhea, HPV, HSV, and HIV.
- The literature reflects that HPV may be associated with other genital infections and that early screening, detection, treatment, and prevention of sexually transmitted infections is important in women under 25 (Widdice & Moscicki, 2008).
- It is known that there is an association between HIV and infection with multiple HPV types in immunosuppressed women, which has important implications for women's health exams (Massad, Seaberg, Wright, Darragh, Lee, Colie, et al., 2009).
- The focus of cervical cancer prevention in the adolescent age group should be HPV vaccination rather than cervical cytology (Moscicki & Cox, 2010).
NPs with knowledge about the science behind cervical screening can educate their patients about the indications for screening. All three guidelines are scientifically based recommendations, and each provider should feel confident implementing any of these guidelines into practice. Science has allowed health providers to go from a test for cancer, to testing for the specific type of HPV that can be a precursor to that cellular cervical change. The evidence regarding cervical cancer screening guidelines is clear. NPs are in an important position to play a significant role in promoting the education and science around cervical cancer screening for women.
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