By Rebecca B. Perkins, MD, MSc
Professor, Department of Obstetrics and Gynecology, Boston University School of Medicine/Boston Medical Center, Boston
This narrative review summarizes the steps of human papillomavirus (HPV)-mediated cervical carcinogenesis and uses this to explain current guidelines for HPV vaccination, cervical cancer screening, and management of abnormal results.
Perkins RB, Wentzensen N, Guido RS, Schiffman M. Cervical cancer screening: A review. JAMA 2023;330:547-558.
This review by Perkins et al evaluated the natural history steps through which human papillomavirus (HPV) infection causes cervical cancer and describes the national guidelines for vaccination, screening, and management that follow logically from this science.1 Each year in the United States, nearly 100,000 people are treated for cervical precancer, more than 14,000 people are diagnosed with cervical cancer, and more than 4,000 people die from cervical cancer. We have decades of evidence showing that nearly all cervical cancers worldwide are caused by persistent infections with one of 13 carcinogenic HPV genotypes.2
These genotypes can be divided into hierarchical categories from the most to least likely to cause cancer. HPV 16 is the most aggressive type, alone responsible for more than 50% of cervical cancers. HPV 18 and 45 are particularly associated with adenocarcinomas of the cervix and are responsible for approximately 20% of cancers. HPV 31, 33, 35, 52, and 58 are evolutionarily related to HPV 16 and each causes 2% to 4% of cancers. HPV 39, 59, 68, 51, and 56 are lower risk, each responsible for less than 2% of cancers.2
Currently available HPV vaccines prevent infection with the seven highest-risk genotypes and two low-risk strains that cause genital warts.3 Evidence indicates that vaccination provides greater than 90% protection against cervical cancer before age 30 years.4 Therefore, in the United States, HPV vaccination is routinely recommended at ages 9 to 12 years, with catch-up vaccination through age 26 years.3 Although HPV vaccination also is available for adults ages 27-45 years, most individuals have been exposed to HPV by this time; therefore, the public health benefits are limited.3 However, there may be benefit to vaccination of individuals following treatment for cervical precancer.5
For adults who are past the age of routine vaccination, screening for HPV infections and precancerous changes in cervical cells caused by HPV is critical for cancer prevention. Cervicovaginal HPV testing is 90% sensitive for detecting precancer and is the cornerstone of most screening guidelines. For the general population, the risk of precancer is less than 0.15% over five years following a negative HPV test. However, those with positive HPV screening tests require additional testing to determine the presence or absence of precancer.
HPV genotyping can provide valuable information, with those testing positive for HPV 16 or 18 having precancer risks high enough to warrant colposcopy. Cytology (Papanicolaou [Pap] testing) also provides important information on the risks of precancer and is recommended following a positive HPV test. A new test performed on cervical cells is p16Ki67 Dual Stain (CINtec plus). The cells are stained for markers of cell transformation and cell replication, which connote elevated precancer risk. This test is another option for determining whether colposcopy is indicated in the case of a positive HPV test.
The 2019 American Society for Colposcopy and Cervical Pathology (ASCCP) Risk-Based Management Consensus Guidelines were developed by a national consensus of 19 professional organizations, including the American College of Obstetrician Gynecologists, National Cancer Institute, American Cancer Society, and Centers for Disease Control and Prevention. These guidelines use the precisely estimated risk of precancer to guide management.
A current precancer risk of 4% is the threshold for recommending colposcopy. For individuals with current precancer risks less than 4%, repeat HPV testing is recommended in one, three, or five years, depending on the five-year precancer risk. Colposcopy is recommended for precancer risks of 4% to 24%, (e.g., positive HPV testing and low-grade Pap test results, such as atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion [LSIL], or a positive dual stain result).
When precancer risks are less than 25%, observation is preferred to treatment (e.g., in the case of CIN1 or histologic LSIL). When precancer risks exceed 25% (e.g., HPV-positive atypical squamous cells cannot rule out high-grade lesion or high-grade squamous intraepithelial lesion), the option exists for either performing colposcopy or proceeding directly to excisional treatment. Proceeding to treatment may benefit patients for whom attending repeat visits for colposcopy followed by treatment may be difficult or for post-menopausal patients in whom colposcopy may miss lesions because of regression of the transformation zone into the endocervical canal. Clinical decision support tools, such as the ASCCP app for smartphones or the patient-oriented website cervicalrisk.com, can facilitate correct management.
COMMENTARY
Cervical cancer is caused by one of 13 carcinogenic HPV genotypes. Most people are exposed to HPV, and the immune system usually controls infections in a few years. However, when HPV infection persists, the virus creates proteins that disrupt normal cell function, causing abnormal precancerous cells to build up. If this continues, the cells can invade and become cancer. HPV carcinogenesis has three steps: infection, precancer, and cancer. Using the tools currently available (HPV vaccination of adolescents and HPV testing for screening of adult women and individuals with a cervix), we have the possibility of nearly eliminating cervical cancer in our lifetimes.
The first step is preventing infection with vaccination. HPV vaccination at ages 9-12 years for both males and females likely will prevent 90% of cervical cancers in the future. Importantly, HPV vaccination prevents not only cervical cancer, but also cancers of the tongue and tonsils, anus, vagina, vulva, and penis.6
OB/GYNs play a critical role in secondary prevention of cervical cancer: detection and treatment of precancers. HPV testing is recommended for cervical cancer screening because it detects 90% of precancers. Cytology alone detects just 50% to 70%. An individual’s risk of cancer is based on their past history of HPV infection or precancer; this determines how often they need to be screened.
About 80% of people are considered “average” risk and can be screened with HPV testing every five years.7 About 20% of people require more frequent screening because of high-risk factors, such as a prior positive HPV test, treatment for precancer, or a weakened immune system.7 Managing patients based on their risk of precancer focuses testing and treatment on those who will benefit most while reducing testing and biopsies in those at low risk.8 Following new guidelines is both more effective and cost-effective for cervical cancer prevention.9
REFERENCES
- Perkins RB, Wentzensen N, Guido RS, Schiffman M. Cervical cancer screening: A review. JAMA 2023;330:547-558.
- Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and cervical cancer. Lancet 2007;370:890-907.
- Markowitz LE, Dunne EF, Saraiya M, et al. Human papillomavirus vaccination: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2014;63:1-30.
- Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med 2020;383:1340-1348.
- Michalczyk K, Misiek M, Chudecka-Głaz A. Can adjuvant HPV vaccination be helpful in the prevention of persistent/recurrent cervical dysplasia after surgical treatment? – A literature review. Cancers (Basel) 2022;14:4352.
- Jemal A, Simard EP, Dorell C, et al. Annual report to the nation on the status of cancer, 1975-2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst 2013;105:175-201.
- Lee YW, Morgan JR, Fiascone S, Perkins RB. Underscreening, overscreening, and guideline-adherent cervical cancer screening in a national cohort. Gynecol Oncol 2022; Sep 20. doi:10.1016/j.ygyno.2022.09.012. [Online ahead of print].
- 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.
- Munshi VN, Perkins RB, Sy S, Kim JJ. Cost-effectiveness analysis of the 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Am J Obstet Gynecol 2022;226:228.e1-228.e9.
