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Clinical Controversies in Cervical Cancer Screening

BUS-KWOFIE, AMA MD; CHAN, CATHERINE MD; KAHN, RYAN MD; HOLCOMB, KEVIN MD

Clinical Obstetrics and Gynecology: December 2019 - Volume 62 - Issue 4 - p 644–655
doi: 10.1097/GRF.0000000000000478
Clinical Dilemmas and Unresolved Issues in Gynecology
Free

Through the implementation of systematic cervical cancer screening in the mid-20th century, the United States and other developed countries have seen death rates from cervical cancer decreased by ≥70%.The purpose of this article is to address several of the most controversial issues associated with cervical cancer screening recommendations in light of historical and evolving data. In this article, we will explore the controversies around the age at which to initiate and exit screening, human papilloma virus testing alone as a primary screening approach, and the impact of human papilloma virus vaccination on cervical cancer rates.

Department of Obstetrics and Gynecology, Weill-Cornell Medicine, New York, New York

The authors declare that they have nothing to disclose.

Correspondence: Kevin Holcomb, MD, 525 East 68th Street, Suite J130, New York, NY. E-mail: keh2004@med.cornell.edu

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Introduction

Through the implementation of systematic cervical cancer screening in the mid-20th century, the United States and other developed countries have seen death rates from cervical cancer decreased by ≥70%.1 However, with the advent of new screening modalities, emerging data from several randomized trials and an increasing focus on the costs of maintaining high-quality health care, what once started out as a simple annual pap smear for every women has now turned into a progressively complicated algorithm outlining who to screen, how to screen, when to screen, and how frequently to screen. In 2012, the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) reviewed and updated the 2002 screening guidelines for prevention and early detection of cervical cancer to incorporate these new and emerging data. The new screening recommendations addressed age-appropriate screening strategies, the incorporation of human papilloma virus (HPV) testing into the screening, and screening recommendations for women who received the prophylactic HPV vaccine.2 The purpose of this article is to address several of the most controversial issues associated with cervical cancer screening recommendations in light of historical and evolving data. In this article, we will explore the controversies around the age at which to initiate and exit screening, HPV testing alone as a primary screening approach, and the impact of HPV vaccination on cervical cancer rates.

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Age to Initiate Cervical Cancer Screening

The ultimate goal of cervical cancer screening is to reduce the morbidity and mortality from cervical cancer while simultaneously avoiding detection and unnecessary treatment of transient HPV infections and associated benign lesions that are of doubtful clinical significance. Beginning in 2009, and confirmed in the 2012 guidelines, the recommended age for initiation of cervical cancer screening was changed to no sooner than 21 years of age regardless of the age of first sexual encounter.3,4 This marked a significant change from the prior guidelines, which suggested beginning cervical cancer screening following the initiation of sexual activity.5 The impetus for this change was on the basis of increasing data showing exceedingly low cancer rates among adolescents,6 higher rates of regression for dysplastic lesions,7 and increased potential for harm related to the intervention.8

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Evidence for Delaying Screening to Age 21

Using combined data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program, Benard and colleagues found that between 1999 and 2008, only 1% of invasive cervical cancers were found in women under the age of 20 years. During this time period, an average of 3063 cases annually were identified, with an average of 14 carcinomas per year (rate of 0.15/100,000 female individuals) among those aged 15 to 19 years and 125 carcinomas per year (rate of 1.4/100,000 female individuals) among those aged 20 to 24 years.6 This number has remained unchanged since the early 1970s, suggesting that the screening of this population has detected relatively few cancers while potentially exposing them to harm with increased follow-up and interventions.

It has also been suggested that the decreased efficacy for screening in the adolescent population may be because of biological differences that render these cancers and precursor lesions less detectable by traditional screening methods, more aggressive clinically, and more likely to arise during screening intervals.9,10 Invasive cervical cancers in this age group are less likely to be carcinomas that would have been detected through screening and more likely to be rare tumors such as embryonal rhabdomyosarcoma.6

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Controversies Surrounding Initiation of Screening at Age 21

COST OF NONADHERENCE TO GUIDELINE RECOMMENDATIONS

Despite widespread acceptance and agreement by national organizations to delay initiation of cervical cancer screening to age 21, screening continues to be performed in the adolescent population. Using the National Ambulatory Medical Care Survey (NAMCS), Vash-Margita et al11 found a nonsignificant decrease in rates of cervical cancer screening among adolescents following the 2009 ACOG recommendation [5.0% (2005 to 2008) vs. 4.4% (2009 to 2012); P=0.41]. In addition, in 2010, 52.2% of women aged 18 to 21 years reported they had been screened for cervical cancer (compared with 73.7% in 2000) and 41.5% reported screening in the past 12 months (compared with 65% in 2000).12 Although compliance with recommendations is improving, significant over screening in this population persists. Cost calculations have shown an estimated cost of screening of ~$11,646,800 per cancer case in the youngest age group (15 to 19 y) and $3,285,200 per cancer case for women aged 20 to 24 years.6

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Management of Abnormal Screening Results for Women Aged <21 Years

Given the evidence that a large proportion of women will be screened before the age of 21, management of abnormal results in this young population often presents a clinical dilemma. Regression rates of both low- and high-grade cytologic lesions are high among teens and young women. Moscicki et al7 demonstrated regression rates of low-grade squamous intraepithelial lesions (LSIL) of over 60% at 12 months and 91% at 36 months for teens and young girls. In addition, for high-grade squamous intraepithelial lesions as well as biopsy-proven cervical intraepithelial neoplasia (CIN)2, 50% of these young women will regress in 2 years and 75% in 3 years, with only 8% progressing to CIN3.13

Overtreatment in this population results not only in the immediate emotional impact a teenager has to a newly diagnosed sexually transmitted infection with malignant potential but also the potential increased risk of preterm delivery and decreased birth weights if an excisional procedure is performed.4 Therefore, it is recommended that a result of atypical squamous cells of undetermined significance or LSIL in an adolescent be managed expectantly with repeat cytology in 12 months. If the repeat cytology reveals high-grade squamous intraepithelial lesions or greater, colposcopy is indicated. If repeat cytology is atypical squamous cells of undetermined significance or LSIL, cytology should be repeated again in 12 months, and any cytologic abnormality at the second visit should prompt colposcopic evaluation.3 This conservative approach will result in less harmful intervention while still actively managing the detected abnormality.

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AGE TO EXIT CERVICAL CANCER SCREENING

According to both the United States Preventative Services Task Force (USPSTF) and the ACS-ASCCP-ASCP 2012 guidelines, women over 65 years of age with evidence of adequate negative prior screening and no history of high-grade dysplasia within the last 20 years should not be screened for cervical cancer with any modality2,14 However, despite agreement on the overall recommendation, the organizations differ in their opinion of the strength and quality of the evidence supporting the recommendation. The USPSTF has given this recommendation a grade D, indicating that “there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.” However, the ACS-ASCCP-ASCP classified this recommendation as “weak” given the age at which to discontinue screening is on the basis of expert opinion and was chosen to “balance the benefits and harms of screening older women.”

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Controversies for Exiting Women Out of Screening

QUALITY OF EVIDENCE FOR EXITING SCREENING AT AGE 65

When looking at screening trials, women older than 65 years were often not included, thus direct evidence for or against the recommendation for exiting screening at age 65 is not available. The decision of when to discontinue screening is based primarily on decision modeling and expert opinion, which has concluded that the rate of high-grade dysplasia diagnosed by cytology is “low” in older women who have had adequate prior screening. However, there is no clearly predefined or agreed upon threshold for the incidence of cervical cancer, which is considered acceptably low. Dinkelspiel et al15 in 2012 reported an annual risk of invasive cervical cancer incidence of 4.2 per 100,000 in women aged 65 and older within the Kaiser Permanente Northern California population, which potentially results in a cumulative incidence of 60 per 100,000 in women by age 80. Is this acceptably low? According to the National Cancer Institute SEER database, the reported annual incidence in 2015 for women aged 65 to 74 years is 10.0 per 100,000 (which is an increase from 8.4/100,000 in 2014) versus 5.3 per 100,000 for women older than 75 years.16 The incidence in the age group 65 to 74 years is very similar to the incidence of invasive cervical carcinoma seen in women aged 55 to 64 years (11.6/100,000) and higher than the age group 20 to 49 years (9.0/100,000), both groups in which screening is still considered appropriate. These numbers suggest that there is still what some may consider sufficient risk of invasive cervical cancer over the age of 65 to continue screening. We do not have the data currently to capture the absolute risk of invasive cervical cancer in the greater than 65-year-old population following the exit of screening. With the relatively recent implementation of co-testing and primary HPV testing, the stratification of risk on the basis of these data will take years to mature.

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ADJUSTMENT FOR HYSTERECTOMY PREVALENCE INCREASES INCIDENCE OF CERVICAL CANCER AMONG OLDER WOMEN

According to national survey data, many women in this country have undergone a benign hysterectomy, however, national cervical cancer incidence rates have not been adjusted to remove these women from the population risk denominator.17 Consequently, multiple studies have shown that when these corrections are made, the age-associated incidence of invasive cervical cancer increases among older women. Rositch and colleagues found that after correcting for hysterectomy data, there is a steady increase in the incidence of cervical cancer up to ages 65 to 69. In fact, they noted that the highest corrected incidence was observed among the age 65 to 69 cohort with a rate of 27.4 cases per 100,000 women as opposed to the highest uncorrected rate of 15.6 cases per 100,000 women noted in the 40- to 44-year-old cohort.18 In addition, they noted that hysterectomy-adjusted age-specific incidence varied significantly by race, with a corrected incidence among white women aged 65 to 69 years of 24.7 per 100,000 versus 53.0 per 100,000 for black women. Thus, by not removing women who have had a hysterectomy from the population risk denominator, there has been a gross underestimation of the risk of cervical cancer overall and especially in older women. These data suggest a shift in peak incidence to older women and an increase in disparity among black and white women in this older age group. These data must be taken into consideration when evaluating the recommendation for the cessation of routine screening at age 65.

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HPV as a Primary Screening Tool for Cervical Cancer

Various methods for cervical cancer screening have been developed as the introduction of the Papanicolaou smear in 1941. This includes high-risk human papilloma virus (hrHPV) testing and hrHPV genotyping. As new technologies are developed and continue to evolve, so do the recommendations for when and how to use them, and how to manage the results. According to the ACS-ASCCP-ASCP guidelines, recommended screening for women aged 21 to 29 years is with cytology alone every 3 years. However, for women 30 to 65 years, the preferred method of screening is with HPV and cytology “co-testing” every 5 years. Alternatively, cytology alone every 3 years is considered acceptable.3

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EVIDENCE FOR HPV TESTING AS PRIMARY SCREENING

Greater than 90% of cervical cancers are because of cellular changes related to persistent infection with high-risk types of HPV.19,20 HPV types 16 and 18 are the most oncogenic and are identified in the majority of these cases.21 Thus, an argument has been made for using hrHPV testing as a primary screening tool for cervical cancer. In 2008, a large US-based trial titled Addressing the Need for Advanced HPV Diagnostics (ATHENA) evaluated the Roche cobas HPV Test as the primary screen for cervical cancer in women aged 25 years and older. The Roche cobas HPV Test is the only Food and Drug Administration (FDA)-approved first-line screening for cervical cancer in women aged 25 years and older. In this study, Wright and colleagues demonstrated the superiority of primary HPV testing in identifying patients at risk of cervical dysplasia. Primary HPV testing identified 64.2% more high-grade cervical neoplasia (CIN3+) than cytology alone, and 22.5% more when compared with co-testing (n=47,208). Comparable results were demonstrated for the CIN2+ endpoint.22 They concluded that HPV primary screening is more sensitive in detecting high-grade cervical dysplasia than co-testing or cytology alone in women of 25 years and older age.

Following this, in 2015, the ASCCP and Society of Gynecologic Oncology published interim guidance on the use of HPV testing alone as a primary screening tool. Previously, primary screening with hrHPV was explicitly not recommended given the lack of data regarding efficacy and interpretation of results. In contrast, this interim report stated that primary hrHPV testing can be considered as an alternative method to cervical cancer screening given its relative superior effectiveness.23 Moreover, they provided an algorithm for hrHPV primary screening (Fig. 1).

FIGURE 1

FIGURE 1

Since the publication of the interim guidance, various trials have been conducted to assess the clinical applicability of primary hrHPV screening in cervical cancer prevention. In 2017, Cochrane performed a systematic literature review to determine the diagnostic accuracy of HPV testing in women undergoing primary screening. Approximately 40 total studies were reviewed comprising >140,000 women between the ages of 20 and 70 years. Findings consistently demonstrated the increased sensitivity of HPV tests in detecting precancerous cervical dysplasia (CIN2+ and CIN3+) compared with cytology alone.24 Simply stated, a negative HPV test is more reassuring than a negative cytologic test. They concluded that although primary hrHPV testing has the potential to further reduce morbidity and mortality related to cervical cancer, more investigation should be conducted to evaluate the feasibility and cost-effectiveness of primary hrHPV testing.

There continues to be consistent evidence to suggest that primary hrHPV screening will detect higher rates of high-risk cervical dysplasia when compared with conventional screening methods. Follow-up data from the ATHENA trial demonstrated a cumulative incidence of CIN3+ of <1% over the course of 3 years. As a result, they concluded that screening should not occur at intervals <3 years. In addition, the HPV FOCAL trial, which was designed to directly compare the incidence of CIN3+ detected following the screening with primary hrHPV testing versus cytology alone, found similar results. Detection of CIN3+ was higher at an initial screening in the hrHPV group and lower at the 4-year screen when compared with cytology alone. Women who were hrHPV negative at baseline were significantly less likely to have high-risk cervical dysplasia at 48 months compared with women who were cytology negative. This again demonstrates the sensitivity of hrHPV primary screen to capture patients with premalignant lesions.25–28 Consequently, in 2018, the USPSTF published an update on recommendations for cervical cancer screening. For women aged 30 to 65 years, the USPSTF now recommends screening every 5 years with hrHPV testing alone, every 5 years with co-testing, or every 3 years with cytology alone.14

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Controversies Surrounding Primary HPV Screening

COST-EFFECTIVENESS

In a follow-up study looking at the financial impact of primary HPV screening, Wright and colleagues cited a 19% reduction in cost compared with current recommendations of cytology every 3 years or co-testing without genotyping every 5 years. Of the strategies modeled, HPV primary screening and co-testing with genotyping every 3 years demonstrated the lowest incidence of cervical cancer per year. However, the cost of HPV primary screening was lower when compared with co-testing with genotyping every 3 years.29 Following this, a micro-simulation modeling study comparing primary hrHPV screen, co-testing, and cytology alone estimated that primary hrHPV screening may represent a reasonable balance of harms and benefits when performed every 5 years. Harms were defined as colposcopies and benefits as life-years. Currently, the most efficient harms-to-benefit ratio is found in switching from cytology to hrHPV testing at 30 years of age.30 This suggests that primary HPV screening is a cost-effective method for early detection of cervical cancer.

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Psychological Effects Related to Primary HPV Screening

An increase in the detection of high-risk cervical dysplasia associated with primary hrHPV screening will result in an increase in the number of colposcopy referrals. Overall, screening with hrHPV was associated with more false-positive results, higher rates of colposcopy, and potentially psychological harm related to unnecessary procedures.31 The question remains—how can we balance the benefits of early detection with the potential adverse effects related to a false-positive screen? Andreassen and colleagues studied the psychological effects of primary hrHPV screening compared with cytology alone. Women aged 34 to 69 years were randomly assigned to hrHPV testing every 5 years (followed by cytology if hrHPV positive) or cytology every 3 years. Follow-up questionnaires, including Patient Health Questionnaire-4 (PHQ-4), were used to assess psychological responses. Comparing anxiety and depression scores at 4 to 24 months after screening, Andreassen and colleagues reported no differences between the primary hrHPV group and the cytology group. They concluded that primary hrHPV screening would not adversely affect patients’ psychological response compared with conventional screening methods.32

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Capturing the Unscreened and Inadequate Screened

Cervical cancer primarily affects unscreened or inadequately screened women. Effective outreach strategies can potentially decrease the incidence and mortality related to cervical cancer by way of increased participation in screening. Self-collection of hrHPV may be one of these methods. Unlike cytology, samples for hrHPV testing have the potential to be collected by the patient and mailed to health programs for analysis, thus increasing screening in those populations with limited access to care. Several systematic reviews have demonstrated a significant improvement in screening participation when HPV self-collection was used.33 Moreover, trials comparing the clinical accuracy of self-sampled material with controls (clinician-sampled material) demonstrate similar rates in CIN2+ detection between the 2 groups.33 As a result, primary hrHPV screening is an accessible, clinically accurate, and cost-effective strategy to enhance detection of high-risk cervical dysplasia.

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Impact of HPV Vaccination on Cervical Cancer Rates

THE HPV VACCINE

In 2006, the US FDA approved the first HPV vaccine Gardasil (types 6, 11, 16, 18), developed by Merck & Co.34 By early 2007, GlaxoSmithKline developed a similar preventive HPV vaccine, Cervarix (types 16, 18).35 In 2014, Merck & Co. then released Gardasil 9 which protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.36 This vaccine offers more coverage than Gardasil or Cervarix for the prevention of anogenital cancers and dysplastic lesions of the cervix, vulva, vagina, and anus.37

The HPV vaccine was initially approved for female individuals between the ages of 9 and 26 years. The approval was then extended to male individuals within the same age range for protection against both genital warts and anal cancer.38 On October 5, 2018, the FDA approved Gardasil 9 for use in individuals aged 9 through 45 years.39 The recommended dosing schedule for individuals 9 through 14 years is either a 2-dose regimen at 0, 6 to 12 months or a 3-dose regimen at 0, 2, and 6 months. Individuals 15 through 45 years are recommended for the 3-dose regimen.40

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Uptake of the HPV Vaccine

Major medical societies have implemented widespread HPV vaccination recommendations and the Patient Protection and Affordable Care Act now requires that all insurance plans cover the HPV vaccine.41–43 In addition, the Vaccines for Children Program provides HPV vaccination for uninsured individuals younger than 19 years at no cost.44 However, the rate of HPV vaccination has remained suboptimal. A 2013 report by the Center for Disease Control and Prevention (CDC) demonstrated that 57.3% of girls of 13 to 17 years of age underwent vaccination and only 37.6% went on to complete the series.45 The uptake of the HPV vaccine is significantly lower than other adolescent 3-dose vaccines such as tetanus, diphtheria, and pertussis and hepatitis B vaccines with 92.8% and 84.6% rates of coverage, respectively.46 The reasons for low levels of uptake are complex and have been attributed to inadequate knowledge about HPV, limited physician recommendations, parental concerns about safety, mistrust, and religious or philosophical beliefs.41,47

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Improvement in Cervical Cancer Rates

As of 2018, there have been >100 million doses of the HPV vaccine distributed in the United States.48 The CDC estimates that HPV vaccination has the potential to prevent >90% of HPV-associated cancers or roughly 31,200 cases per year in the United States.48

Powell and colleagues analyzed 1900 women aged 18 to 31 years and found that CIN grades 2, 3, and adenocarcinoma in situ (CIN2+) were significantly lower among women who initiated vaccination >24 months before their abnormal Pap (adjusted prevalence ratio 0.67; 95% confidence interval, 0.48-0.94).49 Guo and colleagues found that the 4-year average annual cervical cancer incidence rates among female individuals between the ages 15 and 24 years in 2011 to 2014 were 29% lower than before the introduction of the HPV vaccine in 2003 to 2006 (95% confidence interval, 0.64-0.80). However, there was no significant decrease found in cervical cancer incidence among female individuals aged 25 to 34 years after 2006.50 Hariri et al51 found similar results showing that incidence rates of CIN2+ significantly decreased among 18- to 29-year-old cohort, however, rates did not differ in the 30- to 39-year-old cohort.

The reduced incidence of cervical cancer among young female individuals in these studies may reflect the early effects of the HPV vaccine. However, demonstrating vaccine efficacy is exceedingly difficult given incomplete reporting of vaccination history, deficient state-based or national immunization registries, and evolving cervical cancer screening guidelines.51 Because most vaccine data are on the basis of ecologic studies, causal results cannot be interpreted. In addition, HPV DNA typing information has not been included in most large national databases.50 To assess the direct impact of the HPV vaccine on cervical cancer rates, more studies are needed with an emphasis on HPV types and improved population-based registries.

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Controversies Surrounding the HPV Vaccine

RELIGIOUS AND PHILOSOPHICAL OPPOSITION

Worldwide, HPV is the most common sexually transmitted infection.52 Despite recommendations regarding the importance of vaccination from major medical societies, there has been public debate from religious and parental organizations over issues of adolescent sexuality. Some have expressed concern that receipt of the HPV vaccination may promote risky sexual behavior or early sexual debut. Opposition on the basis of fear of sexual disinhibition has been attributed to one of the main barriers of HPV vaccination program uptake.53,54 However, there has been no evidence to support these claims.55 Smith et al56 analyzed a Canadian population-based cohort of 128,712 girls (mean age 13) and found that vaccination status had no effect on indicators of sexual behavior (pregnancy and non-HPV related sexually transmitted infections). This suggests that concerns regarding sexual behavior should not deter from HPV vaccination at a young age. Therefore, further efforts are needed to address these system-level barriers; such as improving communication between physicians, patients, and parents to reinforce the importance of vaccinating adolescents before they become sexually active.54

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ADVERSE EFFECTS

Another barrier to HPV vaccination uptake has been concern regarding safety and adverse effects. The CDC identifies all of the HPV vaccines as both safe and effective at preventing HPV.57 Gardasil and Gardasil 9 were studied in clinical trials with >29,000 and 15,000 participants, respectively, before licensure and continue to be monitored. The most common adverse events reported following HPV vaccination are injection site reactions (pain, swelling, redness), dizziness, nausea, headache, fever, and syncope.57 Slade et al58 reviewed the Vaccine Adverse Event Report System (VAERS) following receipt of the quadrivalent HPV vaccine between 2006 and 2008. This study found a total of 12,424 adverse events following immunization, a rate of 53.9 reports per 100,000 doses distributed. Adverse events following immunization were not greater than background rates compared with other vaccines, with the exception of an increased reported rate of syncope and venous thromboembolism (VTE) following HPV vaccination.58 Gee et al59 examined a total of 600,588 quadrivalent HPV doses and found no significant increased risk for any of the outcomes studied. This study noted a nonstatistically significant risk of VTE following vaccination, however, all 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity, or prolonged hospitalization).59 There has yet to be an established cause-and-effect relationship between HPV vaccination and adverse events.

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Conclusions

Systemic cervical cancer screening has resulted in dramatic decreases in overall incidence and mortality associated with invasive cervical cancer within the United States. There are strong data to support the initiation of cervical cancer no sooner than age 21. However, the decision of when to exit screening is more complicated and will require continued re-evaluation in light of new and emerging data.

Primary hrHPV co-testing has consistently demonstrated increased detection of CIN3+ by as much as 2 to 3 times when compared with cytology. On the basis of the data that we have, primary hrHPV testing seems to be cost-effective. There is limited evidence to suggest that compared with abnormal cytology results, hrHPV positivity may be associated with greater short-term psychological harm but this may be balanced with the increased sensitivity associated with this method.

Overall, evidence has shown that the HPV vaccine is safe and effective at preventing HPV infection on a population-based level. The reduced incidence of cervical cancer among young female individuals seen in some studies may reflect the early benefits of vaccination. However, there have been inconclusive results in older populations and the study designs make it difficult to interpret the direct impact that the vaccination has had. Although there has been no clinical evidence to support certain barriers to HPV vaccination, many continue to believe these factors to be true, ultimately limiting HPV vaccine uptake. Continued efforts are necessary to address population-based interventions to improve HPV vaccination rates. In addition, more studies are needed in the future with an increased emphasis on HPV type and improved vaccination registries.

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Keywords:

cervical cancer; screening; dilemmas

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