By Rebecca B. Perkins, MD, MSc
Associate Professor, Department of Obstetrics and Gynecology, Boston University School of Medicine/Boston Medical Center, Boston, MA
SYNOPSIS: In this registry-based screening study of women in Catalonia, Spain, a negative human papillomavirus (HPV) and cytology co-test at baseline was associated with a cumulative incidence of cervical precancer of 0.4% at five years and 1.3% at nine years, compared to 27% among women with abnormal HPV testing at baseline.
SOURCE: Ibáñez R, Roura E, Monfil L, et al. Long-term protection of HPV test in women at risk of cervical cancer. PLoS One 2020;15:e0237988.
Cervical cancer screening is considered one of the most effective cancer prevention tests. The screening guidelines released in 2018 by the U.S. Preventive Services Task Force (USPSTF) allow screening with either cervical cytology (Pap tests) alone, cervical cytology with oncogenic human papillomavirus (HPV) co-testing, or HPV testing alone.1 However, guidelines released in July 2020 by the American Cancer Society favor HPV testing over co-testing or Pap testing alone.2 In addition, revised 2020 guidelines for follow-up after abnormal screening test results also favor HPV testing, with or without a Pap test, because of higher sensitivity for detection of precancer.3 Both USPSTF and the American College of Obstetricians and Gynecologists (ACOG) allow choice at the practice, provider, and patient levels among screening modalities; therefore, understanding the relative risks and benefits is paramount.1,4
In this study, a cohort of underscreened women enrolled in the public health system in Catalonia, Spain, were followed for nine years after a baseline HPV and Pap co-test. A total of 1,831 underscreened women were identified in 2007 and followed through 2016. Women were screened with co-testing at baseline, then followed with cytology every three years through age 65 years if results were negative or followed with repeat testing or colposcopy if tests were abnormal, as recommended by national guidelines. Overall, 92.4% of women had negative HPV and Pap results, 1.3% had abnormal results on both tests, 6.7% were HPV-positive, and 2.2% had an abnormal Pap test. During the nine-year follow-up period, 23 women were diagnosed with cervical intraepithelial neoplasia grade 2 or higher (CIN2+), including nine cases of CIN3 and CIN4 cancers. A single positive HPV test detected 83% of all lesions, while the Pap test alone detected 35%. All cancers were positive on both HPV and Pap testing. No CIN3 or cancers were detected within five years of a negative HPV test, regardless of the cytology result. Among HPV-negative women, the cumulative incidence was 0.3% at nine years. Adherence to continued screening was low, consistent with the population of women who were underscreened at baseline. Within the nine-year follow-up period, only 60.2% of women with negative screening results on both tests obtained follow-up. Adherence was higher after an abnormal result: 74.5% within three years and 83.7% within nine years underwent follow-up testing.
This study adds important evidence to help providers and patients choose between screening options. In this population of underscreened women aged 40 years and older, HPV testing clearly is superior to Pap testing alone. HPV testing missed only one case of CIN3+, while Pap testing missed six cases. As noted in other settings, Pap testing added little to HPV testing alone.5 Women with negative HPV test results had a low risk for precancer that remained low up to nine years after the initial screen, regardless of Pap test results. In addition, no women with a negative HPV test and abnormal Pap test developed precancer. The finding that a negative HPV test provides long-term reassurance against the development of precancer and cancer, and that the addition of a Pap test adds relatively little risk stratification, also is supported by other large randomized controlled studies from the United States and Europe.6-8 Overall, these findings support the most recent recommendations for cervical cancer screening, made by the American Cancer Society, the European Society of Gynaecologic Oncology, and the European Federation of Colposcopy, which favor HPV testing as the first-line screening test over co-testing or cytology alone.2,9
Another important finding from this study is relatively low rates of subsequent adherence to screening after negative results. Educating patients on the importance of returning for screening over extended intervals, as well as the establishment of reminder or recall systems that can track patients over five-year intervals, is critical.10
Obstetrician-gynecologists often are the primary source of information on cervical cancer screening for our patients, our colleagues, and our communities. This study and others indicate that including HPV testing in screening detects more precancer than Pap testing alone, and can lead to a decrease in cervical cancer mortality within eight years of instituting HPV screening.5-8,11 Co-testing with Pap and HPV testing together is used widely in the United States, and also has been associated with extremely low cancer rates.12 HPV testing alone has the advantages of lower costs and fewer false-positive results than co-testing, and superior precancer detection compared to Pap testing alone. HPV testing also may be used for self-collected samples, which currently are pending Food and Drug Administration approval in the United States. Self-sampling, when available, may be helpful to extend screening to populations who currently do not have screening access or for whom pelvic exams are difficult, painful, or traumatic.9,13,14
- US Preventive Services Task Force; Curry SJ, Krist AH, Owens DK, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA 2018;320:674-686.
- Fontham ET, Wolf AM, Church TR, et al. Cervical Cancer Screening for Individuals at Average Risk: 2020 Guideline Update from the American Cancer Society. CA Cancer J Clin 2020;70:321-346.
- Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low Genit Tract Dis 2020;24:102-131.
- The American College of Obstetricians and Gynecologists. Cervical cancer screening (update). August 2018. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2018/08/cervical-cancer-screening-update
- Schiffman M, Kinney WK, Cheung LC, et al. Relative performance of HPV and cytology components of cotesting in cervical screening. J Natl Cancer Inst 2018;110:501-508.
- Elfstrom KM, Smelov V, Johansson AL, et al. Long term duration of protective effect for HPV negative women: Follow-up of primary HPV screening randomised controlled trial. BMJ 2014;348:g130.
- Wright TC, Stoler MH, Behrens CM, et al. 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;136:189-197.
- Dijkstra MG, van Zummeren M, Rozendaal L, et al. Safety of extending screening intervals beyond five years in cervical screening programmes with testing for high risk human papillomavirus: 14 year follow-up of population based randomised cohort in the Netherlands. BMJ 2016;355:i4924.
- Kyrgiou M, Arbyn M, Bergeron C, et al. Cervical screening: ESGO-EFC position paper of the European Society of Gynaecologic Oncology (ESGO) and the European Federation of Colposcopy (EFC). Br J Cancer 2020;123:510-517.
- Tsoa E, Kone Pefoyo AJ, Tsiplova K, Kupets R. Evaluation of recall and reminder letters on retention rates in an organized cervical screening program. J Obstet Gynaecol Can 2017;39:845-853.
- Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical cancer in rural India. N Engl J Med 2009;360:1385-1394.
- Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: An observational cohort study. Ann Intern Med 2018;168:20-29.
- Goldstein Z, Martinson T, Ramachandran S, et al. Improved rates of cervical cancer screening among transmasculine patients through self-collected swabs for high-risk human papillomavirus DNA testing. Transgend Health 2020;5:10-17.
- Arbyn M, Smith SB, Temin S, et al. Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: Updated meta-analyses. BMJ 2018;363:k4823.