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Cervical cancer screening: evidence behind the guidelines Brittany F. Lees, MD; Britt K. Erickson, MD; Warner K. Huh, MD

Cervical cancer screening involves a complex process of cytology, human papillomavirus (HPV) testing, colposcopy, and a multitude of algorithms for the identification of preinvasive disease and prevention of invasive disease. High-risk HPV is a prerequisite for the development of almost all types of cervical cancer; therefore, a test for high-risk HPV has become an integral part of new screening strategies. Major changes to screening guidelines in the last decade include initiation of screening at age 21 years, conservative management of young women with abnormal cytology, extended screening intervals for women age
30 years, and cessation of screening in low-risk women at age 65 years. This review will focus on the evidence that has led to the current evidence-based guidelines. Evidence regarding primary HPV testing as well as postvaccine-based screening strategies will also be reviewed. Key words: cervical cancer screening, colposcopy, cytology, human papillomavirus testing, human papillomavirus vaccine

C

ervical cancer screening was once a simple annual Pap smear. This has since evolved into a more sophisticated, albeit complex, process of cytology, high-risk human papillomavirus (hrHPV) testing, colposcopy, and a multitude of algorithms for the prevention of cervical cancer. As new evidence emerges regarding the natural history of human papillomavirus (HPV) and the optimal screening strategies, primary care providers as well as obstetriciangynecologists have had to continually adapt to the ever-changing guidelines from the American Cancer Society From the Department of Obstetrics and Gynecology (Dr Lees), Division of Gynecologic Oncology (Dr Huh), University of Alabama at Birmingham, Birmingham, AL; and Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN (Dr Erickson). Received Aug. 11, 2015; revised Oct. 17, 2015; accepted Oct. 22, 2015. Disclosure: Dr Huh is a consultant for Merck and THEVAX. Corresponding author: Brittany F. Lees, MD. [email protected] 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2015.10.147

(ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), and US Preventive Services Task Force (USPSTF). The objective of this review is to discuss the evidence behind the major changes in current cervical cancer screening guidelines including initiation of screening at age 21 years, conservative management of young women with abnormal cytology, extended screening intervals for women age
30 years, and cessation of screening in low-risk women at age 65 years (Table 1). Evidence regarding primary HPV testing as well as postvaccination screening strategies will also be reviewed.

HPV and cervical cancer Cervical cancer develops from hrHPVinfected cells that typically originate in the squamocolumnar junction, an area of high cell turnover. Through viral proteins E6 and E7, HPV causes reduced cell apoptosis and unregulated cell growth.1,2 The causal link between HPV infection and the development of cervical cancer was first identified in 1984 by Dr Harald zur Hausen, who won the Nobel Prize for isolating HPV types 16 and 18.3 Further study has identified 14

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hrHPV types. HPV 16 and 18 remain the most prevalent types, and are associated with approximately 70% of all cervical cancers.4 Not every woman who becomes infected with HPV develops a precancerous lesion or cancer. The majority of young women are able to clear the HPV virus. As evidenced by negative follow-up hrHPV DNA testing, approximately 90% of HPV infections are cleared within 1-2 years.5-7 Although it is possible that the HPV virus could remain dormant at undetectable levels,8 it is most likely that women make anti-HPV antibodies that confer long-term protection against subtype-specific infection. HPV infections that persist are at much greater risk of progression to a precancerous lesion or cervical cancer. When these lesions are detected, cervical excisional procedures are highly efficacious (90-95%) in eliminating preinvasive disease.9

History of cervical cancer screening In the 1920s, Dr George Papanicolaou began work on the cervicovaginal smear at Weill Medical College in New York City, which was first published with his partner Dr Herbert Traut in 1941. This test would later become known as the “Pap smear.”10,11 No large randomized control trials have confirmed its efficacy and as such, cervical cytology was never formally evaluated before being implemented as a screening test. However, global epidemiologic studies have convincingly demonstrated its efficacy as a cancer prevention strategy. In areas where cervical cytology was implemented, the mortality and morbidity from cervical cancer has been greatly reduced.12-14 In the United States, rates declined from 36.3 per 100,000 women in the 1930s to 7.2 per 100,000 women in the 1990s. The greatest decline was

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Expert Reviews

TABLE

Review of recent cervical screening guidelines Important references

Recommendation

Rationale

Initiate screening at age 21 y

- Low incidence of invasive cervical cancer - Higher rates of HPVþ, but lower rates of HPV persistence - Minimize no. of colposcopies performed

9,23,24

Screening ends at age 65 y in low-risk women

- Smaller transformation zone decreases rate of transmission - Modeling studies show rates of cervical cancer deaths minimally affected by prolongation of screening - Minimizes no. of colposcopies

5,42

Cytology every 3 y at age 21-29 y

- Modeling studies demonstrate similar cervical cancer death rate compared to screening every 2 y - Minimizes no. of colposcopies

5,26,27,29

Cotesting every 5 y at age
30 y

- Addition of hrHPV testing increases sensitivity - A negative result indicates 5-y cumulative CIN3þ incidence rate low

5,29,37,38

Repeat cytology at 12 mo with ASCUS/HPVþ or LSIL age 21-25 y

- Lower risk of progression to CIN3þ compared to >30 y - Minimizes no. of colposcopies

5,31

Primary HPV testing age
25 y

- Increases sensitivity of CIN3þ - Minimizes no. of screening tests performed

20,22

ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; hrHPV, high-risk human papillomavirus; LSIL, low-grade squamous intraepithelial lesion. Lees. Cervical screening reviewed. Am J Obstet Gynecol 2016.

from 1950 through 1970, with a decline of 3% per year, which correlates with the adoption of routine cervical cancer screening programs in the United States (Figure 1).15 Traditional cytology has been shown to have a sensitivity of only 51% (30-87%) and specificity of 98% (86-100%).16 Additionally, due to the subjective nature of the screening test, there is significant interobserver variability in the interpretation of cytology, which further contributes to its variable sensitivity and specificity rates.17 Annual screening has been able to overcome this low sensitivity (ie, false-negative rate) of cervical cytology. A metaanalysis by Spence et al18 sought to understand how women develop cervical cancer despite availability of widespread screening programs. In this study, which examined 42 studies from 1950 through 2007, the authors concluded that an estimated 29% (95% confidence interval, 21e40%) of failures to prevent invasive cervical cancer can be attributed to falsenegative cytology. Given the inherent deficiencies of cytology screening, hrHPV testing developed initially as an adjunct to

traditional screening. Approved by the Food and Drug Administration (FDA) in 1999, hrHPV testing was first recommended for reflex testing of atypical squamous cells of undetermined significance (ASCUS) cytology to triage

patients to colposcopy.19 In 2004, the National Institute of Health National Cancer Institute, ASCCP, and ACS convened and agreed on interim guidelines to expand the use of hrHPV to cotesting women age
30 years given

FIGURE

Cervical cancer screening timeline

Brief overview of screening practice changes and related discoveries. FDA, Food and Drug Administration; HPV, human papillomavirus. Lees. Cervical screening reviewed. Am J Obstet Gynecol 2016.

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data that demonstrated high sensitivity and specificity in this age group.20,21 Many clinical trials have now been performed that have increased our understanding of the performance of hrHPV testing. The data have consistently shown HPV testing to have a higher sensitivity and reproducibility with increased negative predictive values compared to cytology, thus leading to a scientific and clinical interest in primary HPV testing as a method for cervical cancer screening.22

Delayed screening start until age 21 years In 2009, experts convened and reviewed the available literature and recommended screening start at age 21 years.23 The rationale for this decision is based on the following primary concept: although the rates of HPV infection in the age group is high, the incidence of cervical cancer in this age group is exceedingly low. The Surveillance, Epidemiology, and End Results (SEER) data from 1998 through 2003 (and again in 2007 through 2011) estimated there was an average of 14 invasive cervical cancers diagnosed in US females <20 years old, with an incidence of 0.1 per 100,000 women.24 To prevent 1 case of cervical cancer, 1 million young women would need to be screened. This would lead to thousands of unnecessary colposcopies, biopsies, and excisional procedures. The costs and morbidities associated with this far outweigh the benefits in this population. To further emphasize the ineffectiveness of screening in this age group, an expert group compared SEER data from the 1970s to data from the present era, and noted that since the initiation of widespread screening programs in the United States, the incidence rate of invasive disease is largely unchanged in this age group9 indicating that screening in this population has had no effect on incidence. Although the incidence of cervical cancer in young women is very low, many young women harbor both low-risk HPV and hrHPV infections. According to the 2003 through 2006

National Health and Nutrition Examination Survey, the US HPV prevalence in those <20 years of age is estimated at 32.9% with hrHPV prevalence estimated at 28.3%. Women age 20-24 years have slightly higher rates of hrHPV infection at 43.4%.25 From these new screening guidelines, one should not assume that women age <21 years do not acquire a persistent HPV infection or go on to develop a high-grade preinvasive lesion. Instead, because time to progression from preinvasive to invasive disease is long (years to decades), screening at age >21 years can still prevent the development of invasive disease.

Screening in the 20s and conservative management of low-grade cytology Once screening has been initiated, one goal is to detect the majority of precancerous lesions while limiting morbidity associated with detection and treatment. The appropriate screening intervals and treatment guidelines in young women age 21-29 years slowly evolved throughout the early 2000s. Initially, the ACS, USPSTF, and American Congress of Obstetricians and Gynecologists (ACOG) wrote separate opinions throughout this time period with varying recommendations. In 2012, the ACS/ ASCCP/ACS, USPSTF, and ACOG all aligned their recommendations to change the cytology screening interval to every 3 years.5,26,27 This increase in the screening interval was based on concepts similar to those that guided initiation of screening at age 21 years. Although this age group has a high rate of HPV infection (46.8-53.8%),25 rates of cervical cancer remain exceedingly low, at 1.2-1.4 per 100,000 in women age 21-24 years and 5.1 per 100,000 in women age 25-29 years.24,28 The appropriate screening interval should be set long enough to minimize harms, while still maximizing detection of abnormal lesions prior to progression. It should be noted that there is limited prospective data evaluating the appropriate screening interval in this young age group. A decision analysis by Kulasingam et al29 showed that the predicted death rate from cervical cancer with screening every 3 years

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was 0.05 per 1000 women. When this was compared to screening every 2 years, the predicted death rate was equivocal, but there was a 40% increase in the number of colposcopies performed.5 As to whether to extend the interval >3 years, a large Scandinavian study reviewed the screening history of women with cervical intraepithelial neoplasia (CIN)3. This study found that women with
3 years since their last negative cervical cytology screen were at an increased risk of having CIN3 compared to women who had screening intervals <3 years with an age-adjusted incidence rate of 12.2 vs 1.5 and a relative risk of 1.3 (95% confidence interval, 0.6e3.2).30 Overall, the current 3-year guideline is based on limited data that are not specific to this age group, but to most providers, a 3-year interval appears to align with current acceptable risk-benefit parameters. The most recent ASCCP guidelines recommend women age 21-24 years with ASCUS/HPVþ or low-grade squamous intraepithelial lesion (LSIL) cytology results have repeat cytology at 12 months instead of colposcopy, which has been a past recommendation.9 The rationale for these changes is based primarily on the ASCUS-LSIL Triage Study indicating similar low risk of progression to cervical cancer with either LSIL or ASCUS/ HPVþ cytology in young women.31 Women age
30 years with LSIL cytology have a 5-year cumulative risk of CIN3þ of 5.2%, which is high enough to necessitate colposcopy examination.32 However, in women age <25 years, the risk is substantially lower at 3.0%.33 Although HPV prevalence is high in this age group, HPV clearance is also high and therefore delaying colposcopy until a woman has proven HPV persistence (with consecutive abnormal cytology) can be considered in younger women. However, given the possibility of persistence, these individuals should have closer follow-up to ensure clearance.5,34-36

Extended screening interval in the 30s According to SEER data from 2007 through 2011, compared to young

ajog.org women age <30 years, cervical cancer incidence is significantly higher in women ages 30-39 years at 24.0 per 100,000 women.24 The increased incidence necessitates a screening program that has a high sensitivity for early detection in this age group. It is also important to minimize testing of women at low risk of developing CIN3þ. Compared to younger women, women age
30 years are less likely to clear a new HPV infection and more likely to have HPV persistence. Therefore, the focus of screening is to detect persistent HPV infections and extend the screening interval testing for those who are HPV negative (and thus low risk). In the most recent guidelines, women age
30 years can continue with cytology alone every 3 years.5 Notably, simply adding hrHPV cotesting to a 3year screening interval would increase the detection rate of HPV, but would simultaneously lead to an increase in colposcopy examinations. As demonstrated in the model by Kulasingam et al,29 this would translate to an increase from 3-15 incremental colposcopies per life-year. However, studies have shown the safety and costeffectiveness of extending the screening interval in this age group to every 5 years with a negative HPV cotest. A European study of 330,000 women demonstrated that women with negative cytology had a risk of CIN3þ of 0.17% at 3 years. When women were HPV negative, either via primary HPV test or with a cotest, the rate of CIN3þ at 5 years was similar at 0.17% and 0.16%, respectively, indicating comparable risk to screening with cytology every 3 years.37 Katki et al38 used the large database of HPV cotests collected by Kaiser Permanente Northern California to demonstrate that the 5-year cumulative incidence rate of CIN3þ in women age
30 years with negative cytology screening is 7.1 per 100,000, but with a concurrent negative HPV cotest that rate was reduced by >50% to 3.2 per 100,000. Thus, given acceptable reductions in risk with minimal impact on the harms, the ACS/ASCCP/ASCP Consensus guidelines recommended cytology with HPV cotesting for women

Gynecology age
30 years at 5-year intervals.5 As Kinney et al39 recently argued, the safety of extension to a 5-year interval was based on comparison to 3-year screening intervals and not to annual screening cytology. This indicates a potentially higher risk of a subsequent cervical cancer diagnosis long-term compared to the gold standard of annual cytology. Moving forward, the risk of cervical cancer and potential death (not just CIN3) should be considered in future modeling studies. Another important benefit of HPV cotesting is the diagnosis of cervical adenocarcinoma and adenocarcinoma in situ. Due to its endocervical location, traditional cytology often fails to diagnose these lesions. In a large pooled analysis of almost 200,000 women enrolling in various HPV screening trials, HPV testing (compared to traditional cytology) showed improved detection of adenocarcinoma compared to squamous cell carcinoma.40 Adenocarcinoma incidence is increasing and accounts for 15-25% of invasive cervical cancers,41 further supporting the addition of HPV testing in screening algorithms.

Why stop at age 65 years? To determine the appropriate age to stop cervical cancer screening, guidelines must take into account a combination of screening history, known pathophysiology of HPV in the older age groups, and the potential risk of developing clinically significant disease. The ASCCP guidelines recommend cessation at age 65 years only in women with previous adequate negative screening. The ASCCP defines adequate negative screening as 3 consecutive negative cervical cytology results or 2 consecutive negative HPV tests within the past 10 years prior to screening cessation with the most recent screen not <5 years ago. Women with a history of CIN2þ should continue screening until 20 years following their diagnosis of CIN2þ given their increased risk of developing preinvasive or invasive disease.42 Alternatively, women in this age group with a negative screening history are at very low risk of developing persistent HPV

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infection that will become cervical cancer. Women age >65 years have a smaller and less accessible transformation zone, which makes the acquisition and progression of HPV infections less likely.5 While there are no clinical trials to confirm the exact incidence of invasive cervical cancer in this age group, mathematical models demonstrated that continuing screening until age 90 years only prevented 0.5 cervical cancer deaths per 1000 women, but at the cost of 127 additional colposcopies.29 The decision to exit cervical screening requires knowledge of the patient’s cytology screening history and appropriate counseling about potential risks.

Primary HPV screening HPV is found in the vast majority of cervical cancers.4 HPV’s role in cervical cancer carcinogenesis as well the low sensitivity and poor reproducibility of cervical cytology has led to investigations regarding HPV testing as a primary screening strategy. Multiple studies have demonstrated that HPV testing increases the sensitivity for detecting new CIN2þ lesions, but at the cost of decreased specificity and therefore increased cost.22,40,43-47 For these reasons, the FDA initially approved its use in the setting of cotesting in women age
30 years. However, there are now data that clearly show the efficacy of hrHPV testing alone as a primary screening strategy. The Addressing the Need for Advanced HPV Diagnostics Trial was the first US-based prospective cohort study to evaluate hrHPV testing as an upfront screening trial. Over 40,000 women age
25 years were enrolled and had both cervical cytology and HPV testing. Abnormal testing was referred for colposcopy and subsequent follow-up as appropriate. All women had repeat colposcopy with biopsy at a 3-year follow-up. The objective of this study was to evaluate various screening strategies. Endpoints included detection of CIN2þ, number of screening tests required, and number of colposcopies required.48 Cytology alone (with HPV testing only for ASCUS triage) had the

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lowest sensitivity for detecting CIN2þ. Primary HPV testing with triage to colposcopy based on HPV typing (that is, immediate colposcopy if HPV 16þ or 18þ and follow-up HPV testing if other hrHPVþ) had the highest sensitivity to CIN2þ detection (80%) but required more colposcopy exams. Cotesting with both upfront cytology and hrHPV testing had similar sensitivity, but required many more screening tests.49 These data support a potential primary HPV screening (with colposcopy triage based on HPV subtype analysis) for women age >25 years.22

Post-HPV vaccination screening There are currently 3 FDA-approved HPV vaccines: a bivalent (Cervarix, GlaxoSmithKline, Brentford, England), a quadrivalent (Gardasil, Merck & Co., Inc., Kenilworth, New Jersey), and the new 9-valent (Gardasil 9, Merck & Co., Inc). Prior to starting vaccination programs, there were concerns regarding their potential impact on screening methods. The positive predictive value (PPV) of any screening test is highly dependent on the prevalence of the disease (in this case CIN2þ). The intention of the vaccine is to greatly decrease the prevalence of HPV, and consequently CIN2þ and cancer, in the vaccinated population. Following the introduction of Cervarix, the prevalence of HPV 16 or 18 in women age 16-24 years decreased from 19.1-6.5% in one study in England.50 Additional data released from Gertig et al51 following the school- and community-based vaccination program in Australia demonstrated a significant reduction in high-grade cytology in the vaccinated women compared to unvaccinated women (15.3 vs 11.9/1000 person-years). Although these results are encouraging, a decrease in overall incidence of HPV infection will further lower the PPV of current screening tests. One mathematical model shows a decrease in the PPV of cytology from the current 50-70% to 10-20% in a vaccinated cohort will lead to more false-positive results and unnecessary interventions.52 Thus, primary HPV testing may be a better screening test as its higher sensitivity would allow it to

maintain a higher PPV despite a decreasing prevalence. The additional challenge in the post-HPV vaccination era is whether we can make specific screening recommendations in women who have been previously vaccinated. Given the low rate of HPV vaccination in the United States, it is unclear whether this will be possible in the near future.

Conclusion Despite the profound impact of cervical cancer screening programs, in 2015 an estimated 12,900 women will be diagnosed with cervical cancer with 4199 women dying from the disease.53 While many of these women may never have been screened (or were underscreened), it is still imperative that the cervical cancer screening algorithms be effective at detecting precancerous changes while minimizing harm. The initial screening algorithm of annual cytology proved to be effective in decreasing the incidence of cervical cancer. However, with a clearer understanding of disease pathogenesis and natural history with an emphasis on cost-effective screening strategies and a reduction on morbidity, screening algorithms have undergone substantial changes. Unfortunately, the complexity of cervical screening guidelines has been challenging for many health care professionals, which in some cases has caused delay in adoption of new guidelines. With a better understanding of the data behind these evidence-based guidelines, practitioners can ensure that they are screening their patients appropriately while minimizing unnecessary harms. REFERENCES 1. Thomas M, Pim D, Banks L. The role of the E6-p53 interaction in the molecular pathogenesis of HPV. Oncogene 1999;18:7690-700. 2. Boyer SN, Wazer DE, Band V. E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitinproteasome pathway. Cancer Res 1996;56: 4620-4. 3. Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W, zur Hausen H. A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J 1984;3:1151-7. 4. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary

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cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-9. 5. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol 2012;137:516-42. 6. Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM; ALTS Group. A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis 2007;195:1582-9. 7. Rodriguez AC, Schiffman M, Herrero R, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008;100:513-7. 8. Shew ML, Ermel AC, Tong Y, Tu W, Qadadri B, Brown DR. Episodic detection of human papillomavirus within a longitudinal cohort of young women. J Med Virol 2015;87: 2122-9. 9. Massad LS, Einstein MH, Huh WK, et al. 2012 Updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013;17:S1-27. 10. Papanicolaou GN, Traut HF. The diagnostic value of vaginal smears in carcinoma of the uterus. 1941. Arch Pathol Lab Med 1997;121: 211-24. 11. Shepard EM. George Papanicolaou: development of the Pap smear. Medical Center Archives of New York-Presbyterian/Weill Cornell. 29 June 2011. Available at: http://weill.cornell. edu/archives. Accessed May 8, 2015. 12. van der Aa MA, Pukkala E, Coebergh JW, Anttila A, Siesling S. Mass screening programs and trends in cervical cancer in Finland and the Netherlands. Int J Cancer 2008;122: 1854-8. 13. Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix in England: evaluation based on routinely collected statistics. BMJ 1999;318: 904-8. 14. Sasieni P, Adams J. Effect of screening on cervical cancer mortality in England and Wales: analysis of trends with an age period cohort model. BMJ 1999;318:1244-5. 15. Wingo PA, Cardinez CJ, Landis SH, et al. Long-term trends in cancer mortality in the United States, 1930-1998. Cancer 2003;97: 3133-275. 16. Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000;132:810-9. 17. Stoler MH, Schiffman M; Atypical Squamous Cells of Undetermined Significance-Lowgrade Squamous Intraepithelial Lesion Triage Study Group. Interobserver reproducibility of

ajog.org cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 2001;285:1500-5. 18. Spence AR, Goggin P, Franco EL. Process of care failures in invasive cervical cancer: systematic review and meta-analysis. Prev Med 2007;45:93-106. 19. Solomon D, Schiffman M, Tarone R; ALTS Study Group. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293-9. 20. Wright TC Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103:304-9. 21. Schiffman M, Herrero R, Hildesheim A, et al. HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica. JAMA 2000;283:87-93. 22. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol 2015;125: 330-7. 23. Moscicki AB, Cox JT. Practice improvement in cervical screening and management (PICSM): symposium on management of cervical abnormalities in adolescents and young women. J Low Genit Tract Dis 2010;14:73-80. 24. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 19752012, National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/csr/1975_ 2012/. Accessed February 16, 2016. 25. Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital human papillomavirus among females in the United States, the National Health and Nutrition Examination Survey, 20032006. J Infect Dis 2011;204:566-73. 26. Moyer VA; US Preventive Services Task Force. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med 2012;156:880-91. W312. 27. Committee on Practice Bulletinse Gynecology. Screening for cervical cancer. ACOG Practice bulletin no. 131. Obstet Gynecol 2012;120:1222-38. 28. Benard VB, Watson M, Castle PE, Saraiya M. Cervical carcinoma rates among young females in the United States. Obstet Gynecol 2012;120:1117-23. 29. Kulasingam SL, Havrilesky L, Ghebre R, Myers ER. Screening for Cervical Cancer: A Decision Analysis for the U.S. Preventive Services Task Force. AHRQ Publication

Gynecology No. 11-05157-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; May 2011. 30. Gram IT, Macaluso M, Stalsberg H. Incidence of cervical intraepithelial neoplasia grade III, and cancer of the cervix uteri following a negative Pap-smear in an opportunistic screening. Acta Obstet Gynecol Scand 1998;77:228-32. 31. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188:1383-92. 32. Katki HA, Schiffman M, Castle PE, et al. Benchmarking CIN 3þ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines. J Low Genit Tract Dis 2013;17:S28-35. 33. Katki HA, Schiffman M, Castle PE, et al. Five-year risk of CIN 3þ to guide the management of women aged 21 to 24 years. J Low Genit Tract Dis 2013;17:S64-8. 34. Moore K, Cofer A, Elliot L, Lanneau G, Walker J, Gold MA. Adolescent cervical dysplasia: histologic evaluation, treatment, and outcomes. Am J Obstet Gynecol 2007;197:141.e1-6. 35. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001;357:1831-6. 36. Castle PE, Schiffman M, Wheeler CM, Solomon D. Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol 2009;113:18-25. 37. Dillner J, Rebolj M, Birembaut P, et al. Longterm predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ 2008;337:a1754. 38. Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 2011;12: 663-72. 39. Kinney W, Wright TC, Dinkelspiel HE, DeFrancesco M, Thomas Cox J, Huh W. Increased cervical cancer risk associated with screening at longer intervals. Obstet Gynecol 2015;125:311-5. 40. Ronco G, Dillner J, Elfstrom KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomized controlled trials. Lancet 2014;383:524-32. 41. Silverberg SG, Ioffe OB. Pathology of cervical cancer. Cancer J 2003;9:335-47. 42. Melnikow J, McGahan C, Sawaya GF, Ehlen T, Coldman A. Cervical intraepithelial

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neoplasia outcomes after treatment: longterm follow-up from the British Columbia Cohort Study. J Natl Cancer Inst 2009;101: 721-8. 43. Rijkaart DC, Berkhof J, van Kemenade FJ, et al. HPV DNA testing in population-based cervical screening (VUSA-Screen study): results and implications. Br J Cancer 2012;106: 975-81. 44. Leinonen MK, Nieminen P, Lonnberg S, et al. Detection rates of precancerous and cancerous cervical lesions within one screening round of primary human papillomavirus DNA testing: prospective randomized trial in Finland. BMJ 2012;345:e7789. 45. Malila N, Leinonen M, Kotaniemi-Talonen L, Laurila P, Tarkkanen J, Hakama M. The HPV test has similar sensitivity but more overdiagnosis than the Pap testea randomized health services study on cervical cancer screening in Finland. Int J Cancer 2013;132:2141-7. 46. Gyllensten U, Gustavsson I, Lindell M, Wilander E. Primary high-risk HPV screening for cervical cancer in post-menopausal women. Gynecol Oncol 2012;125:343-5. 47. Ogilvie GS, Krajden M, van Niekerk DJ, et al. Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomized controlled trialethe HPV FOCAL Study. Br J Cancer 2012;107:1917-24. 48. Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol 2012;206:46.e1-11. 49. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol 2015;136:189-97. 50. Mesher D, Soldan K, Howell-Jones R, et al. Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunization in England. Vaccine 2013;32:26-32. 51. Gertig DM, Brotherton JM, Budd AC, Drennan K, Chappell G, Saville AM. Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study. BMC Med 2013;11:227. 52. Franco EL CJ, Hildesheim A, de Sanjose S. Chapter 20: Issues in planning cervical cancer screening in the era of HPV vaccination. Vaccine 2006;24:171-7. 53. American Cancer Society. Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society; 2015.

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