Cervical cancer screening guidelines for adolescents

Geng,Bertie;Vash-Margita,Alla;

Cervical cancer is the fourth- most-common cancer in women, with an estimated 600,000 new cases each year around the world.¹ Approximately 14,100 women in the United States will receive new diagnoses of and
4280 will die from cervical cancer in 2022.²

Since the implementation of national screening guidelines for cervical cancer and development of vaccines against human papillomavirus (HPV), cervical cancer rates in the United States have decreased from 13.9 cases per 100,000 women in 1975 to 6.4 per 100,000 women in 2021.² This article will focus on cervical cancer screening in adolescent girls and women aged
13 to 21 years.

HPV and risk factors for cervical cancer

Cervical cancer develops largely because of persistent high-risk HPV (hrHPV) infection. HPV is one of the most common sexually transmitted diseases in the United States. HPV is transmitted via skin-to-skin contact, and infection rates are highest in women younger than
30 years and decrease with increased age.^3,4Prior to the widespread adaptation of HPV vaccines, the prevalence of HPV infection was estimated to be 27% in US women overall, 40% in sexually active adolescents aged
14 to 19 years, and 49% in sexually active women aged 20 to 24 years.⁴

There are more than 200 strains of HPV that can be classified as low risk (6, 11, 42, 43, 44) and high risk (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). Infections with hrHPV, particularly strains 16 and 18, are responsible for approximately 70% of cervical cancers.³

Approximately 83% of women aged 21 to 65 years are up to date with cervical cancer screening.

HPV infection is necessary but not sufficient for the development of cancer. HPV-16 and HPV-18 contain oncogenes E5, E6, and E7 that disrupt cell growth and differentiation pathways that over time drive normal cervical epithelium to uncontrolled proliferation.⁵

However, most HPV infections are transient and will be cleared by the cell-mediated immune system in 1 to 2 years, particularly in women younger than 21 years.³ Risk factors associated with persistent HPV infection and cervical cancer include cigarette smoking and immunocompromised status.³

History of screening guidelines in adolescents

Secondary prevention methods aim at detecting precursor lesions that are likely to progress if untreated. Because of widespread screening starting in the 1950s, the incidence of and mortality from cervical cancer decreased by approximately 50% from 1975 to 2022.²

George Papanicolaou published a landmark paper in 1943 showing that asymptomatic cancers can be detected using vaginal smear, or what is now referred to as the Papanicolaou (Pap) test, a form of cervical cytologic testing.⁶ The American Cancer Society (ACS) issued guidelines on cervical cancer screening in 1988 that were accepted by the National Cancer Institute, American College of Obstetricians and Gynecologists (ACOG), the American Medical Association, and several other national organizations.^7,8

These guidelines recommended annual Pap tests starting at age 18, or younger if patients were sexually active. After 3 consecutive normal screens, screening could be spaced.⁷This recommendation was based on the concern that because HPV is sexually transmitted, all sexually active women, including adolescents, were at risk of contracting HPV and developing cervical cancer.

In 2002, the ACS revised guidelines to recommend starting screening 3 years after onset of coitarche, or no later than age 21. The recommendation to begin screening 3 years after coitarche was based on the estimated length of time for cervical intraepithelial neoplasia 2 (CIN2) to progress to carcinoma in situ or invasive cancer in women younger than 25 years.8 These recommendations were supported by the US Preventive Services Task Force (USPSTF) and ACOG in 2003.^9,10

The American Society for Colposcopy and Cervical Pathology (ASCCP) along with the ACS held a consensus conference in 2009 that recommended beginning screening at age 21 regardless of first sexual activity.

Additionally, with increased evidence that most HPV infections and CIN1/2 lesions regress spontaneously in adolescents, the consensus recommended against HPV testing in adolescents.¹¹ ACOG also endorsed these recommendations in 2009.¹²

In 2012, the ACS, ASCCP, American Society for Clinical Pathology, and USPSTF again recommended against cervical cancer screening before age 21. For women aged 21 to 29 years, they recommended screening using cytology alone every 3 years.^13,14

In their latest guidelines, the ACS recommended starting screening at age 25 years for individuals at average risk.¹⁵ This recommendation was based on evidence that screening women aged 21 to 24 years does not reduce the incidence of cancer compared with starting at age ^25.16

Additionally, only 0.8% of new cervical cancer cases are in individuals aged 20 to 24 years, and only 0.5% of deaths are attributable to cervical cancer diagnosed in individuals aged 20 to 24 years. This is compared with 4% and
3% in women aged 25 to 29 years, respectively.¹⁵

These 2020 guidelines also recommended primary HPV-based testing every 5 years rather than cytology-based screening with either Pap test or liquid-based cytology. With a greater understanding of hrHPV as the cause of most cervical cancers, there are now HPV tests approved by the US Food and Drug Administration (FDA) that are sensitive and reliable enough for screening use.¹⁵

Although the incidence and mortality associated with cervical cancer have decreased since implementation of screening, there are significant disparities in these reductions. Overall, approximately 83% of women aged 21 to 65 years are up to date with cervical cancer screening. This is below the Healthy People 2020 goal of 93%.¹⁷

Moreover, women who are younger, have lower incomes, have lower educational attainment, have a shorter period of residence in the United States, or who are without insurance are more likely to have lower rates of screening.¹⁷Out of concern that raising the initial screening age to 25 years could exacerbate health inequities and worsen the adherence rate of cervical cancer screening in individuals younger than 30 years, ACOG, ASCCP, and the Society of Gynecologic Oncology continue to recommend starting screening at age 21 (Figure 1).¹⁸

However, just as many are underscreened for cervical cancer, many adolescents also undergo unindicated cervical cancer screening. A recent study performed in a large health care system found that from 2012 to 2018, 90% of cervical cancer screens performed on patients aged 13 to 20 years were unindicated. The same study found high-grade squamous intraepithelial lesion (HSIL) on 0.2% of Pap tests and no cases of cervical cancer, once again demonstrating the low risk of high-grade cervical dysplasia or cervical cancer in adolescents.¹⁹

Cervical cancer screening in special populations

Adolescents with HIV

Screening guidelines generally address patients at average risk. Given the role of the cell mediated immune system in clearing HPV infections, women with HIV (WWH), specifically those with low CD4 cell counts, are at higher risk of having persistent HPV infections, precancerous cervical dysplasia, and cervical cancer.²⁰

In 1995, the US Public Health Service and the Infectious Diseases Society of America recommended WWH be screened with Pap tests twice in the year they are first diagnosed. WWH with normal results should then be screened annually.²¹ The Centers for Disease Control and Prevention (CDC), National Institute of Health (NIH), and HIV Medicine Association of the Infectious Diseases Society of America (HIVMA) largely supported these guidelines in 2009.22 In 2011, the ASCCP recommended screening adolescents with HIV at the onset of vaginal intercourse.¹¹

In the latest practice bulletin in 2016, ACOG recommended starting screening WWH within 1 year of onset of sexual activity or at age 21. If WWH have consecutive normal cytology screenings for 3 years, then they can be screened every 3 years. Routine HPV cotesting is not recommended for WWH younger than age 30; however, WWH with atypical squamous cells of undetermined significance (ASC-US) with positive hrHPV should be referred for colposcopy. If hrHPV results are not available, repeat cytology is recommended in 6 to 12 months. WWH with repeat ASC-US results or worse should undergo colposcopy.³

Prior to 2021, guidelines generally supported screening WWH starting at a younger age than the general population. However, with advancements in combined antiretroviral therapy, the percentage of abnormal Pap tests in WWH has decreased from 38% in 1994 and 1995 to 16% in 2013 through 2015.²³

In 2021, the CDC, NIH, and HIVMA recommended screening WWH at the time of diagnosis only starting at age 21. WWH should then have another screening test in 12 months. With 2 normal results, individuals can be screened with Pap tests every 3 years. WWH younger than 30 years should not have HPV cotesting. Individuals with ASC-US and no reflex HPV testing should have repeat cytology in 6 to 12 months. Individuals with ASC-US and hrHPV or low-grade squamous intraepithelial lesion (LSIL), HSIL, or ASC-US cannot rule out HSIL and should be referred to colposcopy.²⁰

This recommendation was based largely on the HIV/AIDS Cancer Match Study that compared a population of 164,084 WWH with the general population. The rate of invasive cervical cancer in this population was 47.7 per
100,000, which is 3.4 times higher than in the general population. In 69,900 person-years of follow-up, there were no cases of invasive cervical cancer in WWH younger than 25 years. In comparison, there were 20 cases of invasive cervical cancer in WWH aged 25 to 29 years in 73,030 person-years of follow-up, which is a standardized incidence ratio of 5.34 compared with the general population.²⁴

In recommending starting cervical cancer screening at age 21 in WWH, the 2021 CDC/NIH/HIVMA guidelines purposefully provided a 4-year window to screen individuals prior to age 25, when the risk of cervical cancer in WWH exceeds that of the general population (Figure 2).²⁰

Other high-risk individuals

Immunosuppressed individuals and those with in utero exposure to diethylstilbestrol are also at higher risk of developing cervical cancer.^3,15,25 Higher-risk populations are generally screened annually or by using the same guidelines as for WWH.³

A panel of providers in 2019 recommended screening the following population using guidelines for WWH: individuals with solid organ or hematopoietic stem cell transplants, inflammatory bowel disease (IBD) on immunosuppressive drugs, systemic lupus erythematosus, or rheumatoid arthritis (RA) on immunosuppressive therapy. They recommended that women with IBD or RA not on immunosuppressive therapy or those with type 1 diabetes mellitus follow routine screening guidelines (Table).²⁵

Women with Müllerian anomalies

Individuals with uterovaginal aplasia such as Mayer-Rokitansky-Küster-Hauser syndrome do not need to undergo cervical cancer screening, even after the creation of a neovagina. In cases of duplicated uteri such as uterus didelphys, screening should occur from both cervices and be labeled as such (usually, right and left). There is limited evidence that women with congenital Müllerian anomalies may have a higher incidence of cervical cancer,^26d so timely screening is of paramount importance.

Adolescents with disabilities and sexual minorities

The existing evidence shows that women with disabilities are often underscreened for breast and cervical cancer.²⁷ Individuals with disabilities, regardless of type or severity, should undergo cervical cancer screening according to general guidelines. For providers caring for adolescents with disabilities, it may be helpful to discuss the purpose of screening with patients and/or caregivers starting at age 20 with plans to initiate screening at age 21.

Pap tests/pelvic exams under sedation can be offered if a patient is otherwise unable to tolerate screening. This exam can be coordinated in conjunction with any other procedures that require sedation, such as dental work or MRI imaging.

Females who identify as lesbian or transgender should undergo cervical cancer screening according to general guidelines. Apprehension of pelvic exams is common and can be alleviated with education, coaching, and the option of exams under sedation.

History of cervical dysplasia

For adolescents with previous screening results of ASC-US or LSIL, ASCCP recommends repeat cytology in 12 months without colposcopy or HPV testing. ASCCP recommends observation for CIN1 and CIN2 lesions and managing CIN3 lesions with cold knife cone or loop electrosurgical excision procedure.11 In individuals with a diagnosis of CIN2, CIN3, or cancer, ACOG recommends annual screenings for at least 20 years.¹²

Indications for HPV vaccine

ACOG and the CDC’s Advisory Committee on Immunization Practices recommend HPV vaccination for children starting at 9 to 12 years old and administering catch-up vaccination through age 26.^28,29 The first commercially available HPV vaccine, a 4-valent vaccine against HPV strains 16, 18, 6, and 11, was approved by the FDA in 2006. In 2009, a second bivalent HPV vaccine against strains 16 and 18 was approved. Finally, a 9-valent vaccine against HPV strains 16, 18, 6, 11, 31, 33, 45, 52, and 58 was approved in 2014 for use in males and females aged 9 to 45 years and is now the only vaccine available in the United States.^3,28

Despite proven benefit in terms of disease reduction, only 58.6% of adolescents aged 13 to 17 years received the HPV vaccine series in the US in 2020.³⁰ Obstetrician-gynecologist generalists are uniquely positioned to provide counseling and should make every effort to strongly recommend the HPV vaccine and engage patients and families in discussions about the potential to reduce the chance of cervical cancer.

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10.Melnikow J, Henderson JT, Burda BU, Senger CA, Durbin S, Weyrich MS Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the us preventive services task force. JAMA. 2018;320(7):687-705. doi:10.1001/jama.2018.10400

11.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(1):73-80. doi:10.1097/lgt.0b013e3181cec411

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18.Updated cervical cancer screening guidelines. April 2021. Accessed July 9, 2022. https://www.acog.org/en/clinical/clinical-guidance/practice-advisory/articles/2021/04/updated-cervical-cancer-screening-guidelines

19.Hosier H, Sheth SS, Oliveira CR, Perley LE, Vash-Margita A. Unindicated cervical cancer screening in adolescent females within a large healthcare system in the United States. Am J Obstet Gynecol. 2021;225(6):649.e1-649.e9. doi:10.1016/j.ajog.2021.07.005

20.What’s new in the guidelines. NIH. Updated April 12, 2022. Accessed July 9, 2022. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/whats-new

21.Kaplan JE, Masur H, Holmes KK, et al. USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: an overview. USPHS/IDSA Prevention of Opportunistic Infections Working Group. Clin Infect Dis. 1995;21(suppl 1):S12-S31. doi:10.1093/clinids/21.supplement_1.s12

22.Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58(RR-4):1-207; quiz CE1-4.

23.Massad LS, Xie X, Minkoff H, et al. Longitudinal assessment of abnormal Papanicolaou test rates among women with HIV. AIDS. 2020;34(1):73-80. doi:10.1097/QAD.0000000000002388

24.Stier EA, Engels E, Horner MJ, et al. Cervical cancer incidence stratified by age in women with HIV compared with the general population in the United States, 2002-2016. AIDS. 2021;35(11):1851-1856. doi:10.1097/QAD.0000000000002962

25.Moscicki AB, Flowers L, Huchko MJ, et al. Guidelines for cervical cancer screening in immunosuppressed women without HIV infection. J Low Genit Tract Dis. 2019;23(2):87-101. doi:10.1097/LGT.0000000000000468

26.Zong L, Wang W, He Y, Cheng N, Xiang Y. Carcinoma of the lower female genital tract in patients with genitourinary malformations: a clinicopathologic analysis of 36 cases. J Cancer. 2019;10(13):3054-3061. doi:10.7150/jca.30486

27.Horner-Johnson W, Dobbertin K, Andresen EM, Iezzoni LI. Breast and cervical cancer screening disparities associated with disability severity. Womens Health Issues. 2014;24(1):e147-e153. doi:10.1016/j.whi.2013.10.009

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29.American College of Obstetricians and Gynecologists’ Committee on Adolescent Health Care, American College of Obstetricians and Gynecologists’ Immunization, Infectious Disease, and Public Health Preparedness Expert Work Group. Human papillomavirus vaccination: ACOG committee opinion, number 809. Obstet Gynecol. 2020;136(2):e15-e21. doi:10.1097/AOG.0000000000004000

30.Pingali C, Yankey D, Elam-Evans LD, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years - United States, 2020. MMWR Morb Mortal Wkly Rep. 2021;70(35):1183-1190. doi:10.15585/mmwr.mm7035a1