C e r v i c a l C a n c e r P re v e n t i o n Immunization and Screening 2015 Lauren Thaxton,

MD, MBA,

Alan G. Waxman,

MD, MPH*

KEYWORDS  Cervical cancer screening  Human papillomavirus  Cytology  HPV vaccine KEY POINTS  Immunization against 4 types of human papillomavirus (HPV) is now recommended for girls and boys aged 11 to 12, with catch-up vaccination up to age 26.  The 2012 screening guidelines recommend either cytology or cotesting with cytology plus a high-risk HPV test.  The negative predictive value of cotesting is high enough to extend the interval between screening tests to 5 years.

INTRODUCTION

Worldwide, approximately half a million new cases of cervical cancer are diagnosed per year, almost half of which are fatal. The burden of disease is highest in developing countries where cervical screening and immunization are not readily available. In the United States, where screening for cervical cancer has been routine for more than 50 years, cervical cancer is uncommon, with only 12,360 new cases and 4,020 deaths estimated for 2014.1 Approximately half of newly diagnosed cases of invasive cervical cancer are in women who have never been screened.2 It is now well established that human papillomavirus (HPV) is the necessary agent in the pathogenesis of cervical cancer. This virus is present in 99.7% of all cervical neoplasms,3 including essentially all squamous cell cancers and adenocarcinomas. Worldwide, HPV has also been associated with a significant proportion of cancer in sites beyond the cervix, including the anus (88%), vulva (43%), penis (50%), vagina (70%), and oropharynx (13%–56%).4 HPV is a double-stranded, encapsulated DNA virus. There are more than 100 types of HPV, at least 40 of which are known to infect the human genital tract and 15 are potentially oncogenic.5 Ninety percent of cervical cancers worldwide are caused by just 9 types with types 16 and 18 responsible for two-thirds to three-quarters of cases.6

Department of Obstetrics and Gynecology, 1 University of New Mexico, MSC 10 5580, Albuquerque, NM 87131, USA * Corresponding author. E-mail address: [email protected] Med Clin N Am 99 (2015) 469–477 http://dx.doi.org/10.1016/j.mcna.2015.01.003 medical.theclinics.com 0025-7125/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

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PRIMARY PREVENTION: THE HUMAN PAPILLOMAVIRUS VACCINES

In 2006, the Food and Drug Administration (FDA) approved the first vaccine against HPV, Gardasil. In premarketing studies, Gardasil showed a high level of protection against cervical, vulvar, and vaginal lesions caused by 4 HPV types: 6, 11, 16, and 18.7,8 In 2009, a bivalent vaccine, Cervarix, was approved by the FDA to target cervical intraepithelial neoplasia caused by HPV types 16 and 18.9 The efficacy of both these vaccines is very high if given before initial exposure to the virus.8,9 Gardasil has subsequently been approved for prevention of anal intraepithelial lesions in both male and female patients. The Advisory Committee on Immunization Practices (ACIP) and major professional organizations, including The American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics, recommend routine 3-dose vaccination at ages 11 to 12 (ie, before the onset of intercourse). Gardasil is approved for use in male and female patients, Cervarix for female patients only. Immunization may given to children as young as age 9 and those who have not completed the full 3 doses may be vaccinated up to age 26.10,11 In December 2014, the FDA approved Gardasil 9, a vaccine that protects against the four HPV types in Gardasil, plus types 31, 33, 45, 52, and 58. These five HPV types in addition to HPV types 16 and 18, are responsible for 90% of cervical cancers.6 At the time of this writing, the ACIP has not yet issued recommendations regarding this new vaccine. SCREENING FOR CERVICAL CANCER

In 1941, George Papanicolaou and Herbert Traut12 published a clinical trial demonstrating the value of the cytology test for cervical cancer.12 Over the next 2 decades, clinic-based and community-based demonstration projects of the Papanicolaou (Pap) test showed both a decline in invasive cancer and general acceptability of the test to the women to be screened.13 Since that time, screening recommendations regarding onset and frequency of screening have changed many times as our understanding of the pathogenesis of cervical cancer and the performance characteristics of available screening tests has expanded. Additionally, novel technologies, such as liquid-based cytology and HPV testing, have been developed. Why Add Human Papillomavirus Testing to the Papanicolaou Test?

Although the widespread use of cervical cytology in the United States has been accompanied by a marked decline in cervical cancer incidence, the sensitivity of a single Pap test to identify cervical intraepithelial neoplasia (CIN) grade 2 or worse is limited, and estimated in several studies between 51% and 55%.14–16 Moreover, the interreviewer reliability of the Pap test is low, on the order of 50% to 78%.17 In addition, cytology is poor at detecting adenocarcinoma.18 The Pap test has worked as well as it has despite the poor sensitivity of a single test because it is repeated periodically during the span of a woman’s lifetime. Studies have shown a cumulative risk of CIN3 or worse of 0.17% to 0.50% 3 years after a negative cytology without reference to previous screening.18–20 Testing for HPV is now readily available, and studies have consistently shown that testing for HPV has a higher sensitivity and a higher negative predictive value compared with cytology alone.21 Increased sensitivity, however, comes at a cost of lower specificity. Katki and colleagues18 analyzed the course of more than 300,000 women in the Kaiser Permanente Northern California (KPNC) system who were screened with cytology plus an HPV DNA test. In this study, abnormal cytology alone identified a cumulative incidence of CIN3 or worse of 4.7% over 5 years. The cumulative incidence

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among those testing positive for HPV regardless of cytology, on the other hand, was 7.6%. Of those whose cytology was negative at baseline but HPV test was positive for high-risk types, 5.9% developed CIN3 or worse by 5 years. Ronco and colleagues22 combined data from 4 European studies (Swedescreen, Population Based Screening Study Amsterdam [POBASCAM], A Randomised Trial of HPV Testing in Primary Cervical Screening [ARTISTIC], New Technologies for Cervical Cancer Screening [NTCC]) that included over 176,000 women randomized to cytology-based or HPV-based screening. The HPV group included both cotesting and screening with HPV alone. Although the rates of cervical cancer were comparable between the 2 groups over the first 2.5 years, there was 60% less cancer over the next 5.5 years in the group screened with HPV tests. Early diagnosis of precancer in the HPV-based test group allowed early treatment and prevention of invasion. Although the rates of squamous cell carcinoma of the cervix have declined in the United States, adenocarcinoma seems to be on the rise.23 Like squamous cell carcinoma, adenocarcinoma is an HPV-mediated disease. The offending type of HPV in squamous cancer is HPV 16 in 50% to 60% of cases and HPV 18 in only 10% to 20% of cases. In adenocarcinoma, this ratio is reversed with 30% attributable to HPV-16 and 40% to 60% to HPV-18.24 In an analysis of KPNC patients, HPV testing was found to be significantly more efficient at detecting adenocarcinoma in situ (AIS) and adenocarcinoma than was cytology. Whereas 60% of AIS lesions and 85% of adenocarcinomas were cytology negative, only 20% and 22%, respectively, tested negative for high-risk HPV.18 The increase in sensitivity provided by addition of HPV testing to cytology allows a longer interval to be safely permitted between screens. A joint European study comparing cytology with HPV testing alone in 24,000 women in 6 countries showed a risk of CIN3 or worse of 0.51% 3 years after a negative Pap test and 0.27% 6 years after a negative HPV test.20 The KPNC database showed a cumulative risk of CIN3 or worse of 0.26% and 0.08% 5 years after negative cytology alone and negative cotesting respectively.25 Hence, testing with both cytology and HPV at 5 year intervals gives greater protection than testing with cytology alone at 3 year intervals. In addition, it is more likely to diagnose adenocarcinoma and adenocarcinoma in situ. An important caveat is to use FDA-approved and clinically validated tests for high-risk HPV. The performance characteristics of these tests have been established based on large randomized clinical trials against defined endpoints such as CIN2, CIN3, and cancer. Other, laboratory-developed, tests may be analytically validated to insure internal validity for diagnosing HPV; however, management guidelines are based on established HPV load and established clinical endpoints. In addition, laboratory-developed tests are exempt from FDA oversight. Currently, there are 4 FDA-approved high-risk HPV assays: Hybrid Capture 2, Cervista, Cobas, and Aptima. Each tests for 13 or 14 high-risk HPV types at established clinically validated thresholds. These 4 HPV tests are all approved for clinical use in the United States for 2 indications: reflex testing with atypical squamous cells of undetermined significance (ASC-US) cytology and cotesting in women aged 30 and older. In April of 2014, the FDA approved extended indications for use of the Cobas HPV test, to include primary screening in women age 25 and older. The ATHENA trial showed a 12% risk of CIN3 or worse in women who were cytology negative but positive for HPV type 16 and 10% risk in women who were positive for 16 or 18.26 The FDA approval allows for direct referral to colposcopy if the Cobas test reveals a positive HPV-16 or positive HPV-18. Cytology triage is recommended for patients testing positive for 1 or more

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of 12 other high-risk HPV types. Use of this algorithm in women over the age of 25 compared favorably compared with the current recommendations for detecting CIN2 or worse and CIN3 or worse. The guidelines that follow are recommended by the US Preventive Services Task Force, American Cancer Society, ACOG, and other professional organizations.27–29 CURRENT SCREENING GUIDELINES When to Enter Screening

Cervical cancer screening should begin at age 21, regardless of age of sexual debut (Table 1). This recommendation is based on the natural history of HPV infection and dysplasia in adolescents and young women. In a study of female university students, the cumulative incidence of HPV infection over 24 months was 32.3%.30 Despite this exposure, the incidence of cervical cancer before age 20 is exceedingly low at 0.1 per 100,000,31 because most HPV infection in this age group spontaneously regresses. In a similar study of female university students, the cumulative incidence of HPV infection over 36 months was 43% and the median duration of infection was 8 months. By 12 months following diagnosis of infection, 70% of women were no longer infected and by 24 months only 9% continued to be infected.32 This is not to say that the female adolescent does not require well-woman care. ACOG continues to recommend regular visits in this age group to discuss safe sex practices, HPV vaccination, and contraception.29 This does not require invasive pelvic examination, and providers are encouraged to test for gonorrhea and chlamydia by urine samples rather than traditional cervical swabs. Screening Intervals

For women 21 to 29 years old, screening should be completed using cytology (Pap testing) alone every 3 years. This recommendation for triennial cytologic screenings is based on modeling studies showing that annual screening provides minimal benefit in cancer risk reduction while doubling the number of colposcopies Table 1 2012 Cervical cancer screening recommendations When to start screening

Age 21 regardless of age at coitarche

—

Screening interval

Ages 21–29

Cytology alone every 3 y (HPV testing for ASC-US triage age 25–29) Cotesting every 5 y or cytology alone every 3 ya

When to stop screening

Age 65 with 3 consecutive negative Paps or 2 consecutive negative HPV tests in prior 10 y and no history of CIN21 in the last 20 y or posthysterectomy with removal of the cervix with no history of CIN21 in 20 y

Ages 30–64

Screening recommendations by American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology, and the US Preventive Services Task Force. a Both options acceptable. ACS/ASCCP/ASCP preferred option is cotesting every 5 years. USPSTF preferred option is every 3 years. Adapted from Moyer VA. U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;156(12):880–91; and 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. J Low Genit Tract Dis 2012;16(3):175–204.

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performed.33 Cotesting with cytology and HPV testing is not recommended in this age group because of the high prevalence of high-risk HPV infection and rarity of progression of those infections to invasive cancer.34 As discussed above, the Cobas HPV test is FDA-approved after age 25 for primary screening. For women 30 to 64 years old, screening options include cytology every 3 years or cotesting with cytology plus HPV testing at 5-year intervals. The screening guidelines recommended by the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology recommend cotesting at 5-year intervals with triennial cytology as a fallback method if HPV testing is not available.28 Conversely, the US Preventive Services Task Force recommends cytology every 3 years as the default screening method with cotesting every 5 years reserved for those women wanting to extend the interval.27 When to Exit Screening

Women with adequate prior screening and no history if CIN2 or greater in the prior 20 years should exit screening at age 65. Adequate prior screening is defined as 3 consecutive negative Pap tests or 2 consecutive negative HPV tests within the 10 years before exiting, with most recent test within the last 5 years. Screening should not be resumed after it has been stopped even if the patient reports a new sexual partner.28 Women in this group are recommended to exit screening for many reasons. The prevalence of HPV declines with age leaving postmenopausal women less than half as likely as young women to acquire the infection.35,36 Additionally, natural history studies have shown that the progression from HPV to CIN3 to invasive disease occurs over a similarly long timeline regardless of age of viral infection.34,37 Therefore, even if exposed to HPV, older women are less likely to develop invasive cancer during the remainder of their lives. Low-grade cytologic abnormalities reported in this age group are more likely to be false-positive because of the decreased incidence of disease as well as atrophic changes that can be mistaken for atypia. Postmenopausal women with false-positive test results will, in turn, require expensive, potentially painful, and anxiety-provoking downstream workups with little risk reduction benefit.38 Special Considerations Total hysterectomy with no history of dysplasia

Women with a prior history of removal of the cervix for benign indications without a history of CIN2 or worse, do not merit further cervical cancer screening and should not resume screening at any point, even in the event of a new sexual partner. Hysterectomy is the second most common surgical procedure performed on women in the United States. It is important for the primary care physician to note that in some instances the cervix is left in situ, known as a supracervical hysterectomy. For this reason, discussion with the patient about the details of her surgical history, as well as examination, is important before discontinuation of screening. Cytology in this group is no longer a screening test for cervical cancer. Instead, it screens for primary vaginal cancer, a very rare disease with an estimated incidence of 0.7 per 100,000 women.39 In a retrospective cohort study of cytology from the vaginal cuff, the positive predictive value of cuff cytology for identification of vaginal cancer was zero.40 Continued screening after treatment of cervical intraepithelial neoplasia grade 2 or worse

The risk of cervical cancer after treatment of a precancerous lesion, although very low, remains elevated above the baseline population for 20 years after treatment.41

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Therefore, screening should continue for 20 years even if this requires screening past the age of 65. Screening of human immunodeficiency virus–positive women

Although screening guidelines for the general population have been revised, as outlined above, recommendations for human immunodeficiency virus (HIV)–positive women have not changed in the past decade. HIV-positive and other significantly immunocompromised women, such as solid organ transplant patients, should be screened twice in the year of diagnosis, then annually thereafter. Screening vaccinated women

Recommendations for screening should not be modified by history of HPV vaccination. This recommendation is based on relatively low vaccination rates among young women aged 13 to 17 years old; only 37.6% have completed the 3-shot series as of 2014.42 A large proportion of the screened population has not yet reached the age of recommended screening. Because the vaccines are approved for women up to 26 years old, many women have been vaccinated after exposure to the virus. The vaccines are prophylactic only. Therefore, women vaccinated after exposure can expect significantly less protection than those immunized before exposure; in most cases this means before the onset of sexual activity. FUTURE CONSIDERATIONS

In 2007, Australia instituted a free school-based HPV immunization program. Since then, 70% to 72% of girls aged 15 to 17 years have received all 3 doses of the vaccine. In 2013, the program was extended to boys. In the period after initiation of the immunization program, they have seen a 61% decrease in new cases of genital warts, caused by HPV types 6 and 11, covered by the Gardasil vaccine.43 They have seen an early decline in CIN2 and CIN3 as well.44 Vaccine coverage in the United States is opportunistic and is roughly half that of Australia. Reasons parents give for not vaccinating their daughters include safety concerns even though the HPV vaccines compare favorably with other vaccines in terms of rarity of severe adverse events.42 They also cite lack of knowledge about HPV, that their daughters do not need the vaccine, that they are not sexually active, and (most telling) that their health care providers did not recommend the vaccine.42 It is not known what level of coverage will provide the degree of herd immunity needed to change the screening guidelines to reflect an immunized population. Ongoing vaccine-related research, such as the efficacy of fewer than 3 doses and the effect of implementing the new vaccine for 9 high-risk HPV types,6 will undoubtedly contribute to the discussion of screening protocols in the postvaccine era. All that can be certainly predicted is that, just as screening recommendations have changed multiple times since the 1950s, they will surely be revised again in the near future. REFERENCES

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38. Sawaya GF, Grady D, Kerlikowske K, et al. The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/progestin Replacement Study (HERS). Ann Intern Med 2000;133:942–50. 39. Wu X, Matanoski G, Chen VW, et al. Descriptive epidemiology of vaginal cancer incidence and survival by race, ethnicity, and age in the United States. Cancer 2008;113(Suppl 10):2873–82. 40. Pearce KF, Haefner HK, Sarwar SF, et al. Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gynecologic disease. N Engl J Med 1996;335:1559–62. 41. Melnikow J, McGahan C, Sawaya GF, et al. Cervical intraepithelial neoplasia outcomes after treatment: long-term follow-up from the British Columbia Cohort Study. J Natl Cancer Inst 2009;101(10):721–8. 42. Stokley S, Jeyarajah J, Yankey D, et al. Human papillomavirus vaccination coverage among adolescents, 2007–2013 and postlicensure vaccine safety monitoring, 2006–2014—United States. MMWR Morb Mortal Wkly Rep 2014;63: 620–4. 43. Harrison C, Britt H, Garland S. Decreased management of genital warts in young women in Australian general practice post introduction of National HPV Vaccination Program: results from a nationally representative cross-sectional general practice study. PLoS One 2014;9(9):e105967. 44. Brotherton JM, Fridman M, May CL, et al. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet 2011;377(9783):2085–92.

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