Published Dec 2022
Authors: Rebecca S Gold, MD1; Heather Wainstein, MD2; Meagan Williams, MD3
Section Editor: Adelaide McClintock, MD4
Executive Editor: Yilin Zhang, MD5
1Resident, Department of Medicine, University of Washington
2Assistant Professor, Department of General Internal Medicine, UT Southwestern Medical Center
3Clinical Instructor, Department of General Internal Medicine, University of Washington
4Assistant Professor, Department of General Internal Medicine, University of Washington
5Assistant Professor, Department of General Internal Medicine, University of Washington – Valley Medical Center
Objective(s)
- Describe HPV virology and its role in the natural history of cervical cancer.
- Choose appropriate screening tests and intervals for patients at average risk for cervical cancer.
- Identify high-risk populations and apply alternate screening guidelines.
- Apply risk-based guidelines to manage abnormal results in average and high-risk individuals.
Teaching Instructions
Plan to spend at least 30-60 minutes preparing for this talk by reading through the Facilitator Guide and clicking through the Interactive Board to familiarize yourself with the animations. All clickable elements will be denoted as a rounded, shaded rectangle and/or a mouse cursor.
The anticipated time to give this talk is 20 min without cases and 30 min with cases.
Print out copies of the Learner’s Handout so they may follow along during the presentation and take notes as you expand on the charts and screening timelines and apply it through the practice cases. Begin with reviewing the objectives for the session.
- The ectocervix is lined with squamous epithelium, while the endocervix is lined by columnar epithelium. Where the ectocervix and endocervix meet is called the squamocolumnar junction.
- The transformation zone is a small region of squamous metaplasia (where columnar epithelium is replaced by squamous epithelium) located at the squamocolumnar junction. The HPV virus appears to preferentially infect squamous epithelial cells at the transformation zone beginning with basal layer cells then spreading vertically. HPV inserts its DNA into epithelial cells, leading to increased replication and production of oncoproteins that inhibit tumor suppressor genes leading to uncontrolled replication and resistance to apoptosis. Greater than 90% of cervical cancers develop at the transformation zone,5 so it is vital to sample this region during screening.
- Given the distinct cellular linings of the cervix, malignancy arising from the ectocervix is squamous cell carcinoma, while malignancy arising from the endocervix is adenocarcinoma (much less common).
Objective 2: Choose appropriate screening tests and intervals for patients at average risk for cervical cancer (Screening, Average Risk)
Ask your learners about the role of screening for cervical cancer.
Cervical cancer screening seeks to detect treatable changes and precancers likely to progress to invasive cancer. Over the last century, screening has been highly effective in reducing the incidence, morbidity, and mortality from cervical cancer.6
Screening tests – What are the different available technologies or tests that can be used for cervical cancer screening? Click on “screening tests” to reveal the answer.
There are three available tests for cervical cancer screening:
- Cytology: also known as Pap test or Pap smear
- Primary HPV test (high-risk HPV testing only): HPV testing detects the DNA of high-risk types of HPV in a sample taken from the cervix. Most HPV tests genotype the sample to identify if HPV-16, -18, or other high-risk genotypes are present.
- Co-test (cytology and HPV test administered together)
When a sample from a primary HPV test is positive for HPV, regardless of genotype, this sample should have additional reflex cytology testing performed.
Note that the term “HPV-based testing” is often used in guidelines and can represent Primary HPV testing or co-testing.
Who do we screen? – What cervical cancer screening guidelines are available for average risk individuals?
Screening recommendations have greatly evolved over time, largely due to our improved understanding of the natural history of cervical cancer, the causal role of hrHPV infection, and changing technologies. We are going to review two currently recommended guidelines, USPSTF 2018 and ACS 2020. Either is an acceptable method for screening average-risk individuals.
- US Preventive Services Task Force (USPSTF):7
Age range | Recommendation | Notes |
21-29 years | Cytology (Pap smear) alone every 3 years | No HPV-based testing in those <30 because of high prevalence of transient HPV in this age group. |
30-65 years | Cytology (Pap smear) every 3 years – OR – HPV-based testing (primary HPV testing OR co-testing) every 5 years | Cytology (Pap smear) alone has lower sensitivity for precancer and cancer (especially adenocarcinoma) than HPV-based testing. HPV-based testing every 5 years is an effective screening strategy due to higher sensitivity and the long preclinical phase from hrHPV infection to development of precancerous lesions and then cervical cancer. |
- 2020 American Cancer Society (ACS):6
Age range | Recommendation | Notes |
25-65 years | Primary HPV testing every 5 years is preferred Acceptable alternatives (given access to primary HPV testing may be limited as there are currently only two FDA approved primary HPV tests):
| Start at age 25 because cervical cancer incidence and mortality is low in women <25.
Primary HPV testing is more sensitive than cytology (Pap smear) alone and is more efficient than co-testing.
|
- Both groups agree on:6
- When to stop: Click on “when do we stop?” to reveal the answer.
- Over age 65 if at average risk for cervical cancer with no history of CIN 2+ (CIN2 or worse) in the past 25 years and with adequate prior screening:
- 3 consecutive negative cytologies in last 10 years (most recent within 3 years)
- 2 consecutive negative HPV-based tests in last 10 years (most recent within 5 years)
- Over age 65 if at average risk for cervical cancer with no history of CIN 2+ (CIN2 or worse) in the past 25 years and with adequate prior screening:
- History of hysterectomy: Click on “what if they are post-hysterectomy?”.
- Screening can stop if patients have a total hysterectomy (with removal of the cervix) for benign indications with no history of CIN 2+ in the past 25 years
- Follow age-specific screening recommendations regardless of HPV-vaccination status.
- When to stop: Click on “when do we stop?” to reveal the answer.
| Age range | Recommendation | Notes |
| <30 years | Cytology (Pap smear) at baseline, then annually for 3 years.
– OR – If three consecutive Pap smears are normal, then Pap smears every 3 years (until age 30) |
Screening should begin at time of diagnosis but not before the age of 21. Cytology (Pap smear) only is recommended. Co-testing is not recommended due to high HPV prevalence in this age group. |
| ≥30 years | Cytology (Pap smear) only:
– OR – Co-testing: every 3 years |
Cytology or Co-testing is acceptable. Primary HPV testing with reflex cytology is not recommended in this population. Screening should continue throughout a patient’s lifetime (and not, as in the general population, end at 65 years of age), considering the patient’s life expectancy. |
Post-hysterectomy: Unlike average risk patients, patients with HIV who have undergone total hysterectomy for benign causes still require annual screening with cytology and co-testing in the following situations:
- Progression of HIV disease
- Inadequate viral suppression with ART
Non-HIV immunosuppressed patients: Recommendations remain limited due to lack of quality evidence. A panel of health care professionals involved in cervical cancer research and care proposed that screening guidelines for patients who are immunocompromised but do not have HIV follow either: 9
- Current Centers for Disease Control and Prevention (CDC) guidelines for patients infected with HIV – this can be followed by patients with solid organ transplant, hematopoietic stem cell transplant, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) on immunosuppression, or rheumatoid arthritis (RA) on immunosuppression.
- Guidelines for the general population – this can be followed by patients with IBD or RA not on immunosuppressive therapy or patients with type 1 diabetes mellitus.
Objective 4: Apply risk-based guidelines to manage abnormal results in average and high-risk individuals. (Management)
Management (Average Risk)
If your patient is at average risk for developing cervical cancer, use the American Society of Colposcopy and Cervical Pathology (ASCCP) 2019 risk-based management guidelines10 to interpret HPV and/or cytology (Pap smear) results and colposcopic biopsy results and decide on appropriate next steps. These guidelines have been officially endorsed by the American College of Obstetricians and Gynecologists (ACOG). ASCCP has created a management guidelines application online (free, https://app.asccp.org) and for smartphones (for purchase).
These guidelines are based on the principal of “equal management for equal risk” and therefore follow a risk-based rather than a results-based approach to determine management. Specifically, management decisions are based on the clinical question: is the immediate risk of CIN3+ (CIN3, AIS, or cancer) greater than 4%?
Based on data from a prospective longitudinal cohort of 1.5 million patients from Kaiser Permanente Northern California, the tool estimates a patient's risk using their current screening test results and prior screening test and biopsy results (if known), while considering personal factors such as age and immunosuppression. For example: the longer a hrHPV infection has been present, the higher the risk of CIN 3+. Additionally, HPV type (-16 or -18 versus other) impacts risk.
- If immediate risk is <4%, then the tool looks at the 5-year risk of CIN3+ and finds the correct surveillance interval: Click on “Determine surveillance interval” to reveal surveillance.
- >0.55% 5-yr risk → return in 1 year
- 15–0.54% → return in 3 years
- <0.15% → return in 5 years
- If the tool determines immediate risk of CIN3+ is >4%, then the level of risk determines the correct further management: Click on “Further management” to reveal next steps.
- 4-24% → Colposcopy (e.g., to confirm if CIN3+ is present prior to treatment)
- 25-59% → expedited treatment or colposcopy (e.g., depending on if a patient desires future pregnancy)
- 60-100% → expedited treatment (60–100% immediate risk) such as excision or cervical ablation
- Treatment options include:
- Excision – cold knife conization, loop electrosurgical excision procedure [LEEP], laser cone. Generally preferred to ablative treatment, particularly for histologic HSIL (CIN2 or CIN3) and AIS because tissue and pathology can be obtained.
- Cervical ablation – cryotherapy, CO2 laser ablation, thermal ablation
- Hysterectomy
BONUS: Pap smear vs. Colposcopy
Click on “colposcopy” to further teach more about the differences between Pap smear and colposcopy. Ask your learners to explain the difference between a Pap smear and colposcopy? What results you might receive with each test?
- Pap smear (Cytology) – the sample collected during a Pap smear is reviewed by a pathologist and a cytology report is generated. Cytology refers to the examination of exfoliated cervical cells under a microscope to check for the presence of abnormal cells or changes suggestive of acute HPV infection, precancer or cancer.6
- Cytologic findings: Possible cytology results include (roughly in order of increasing prevalence of abnormal cells):
- Negative for intraepithelial lesion or malignancy (NILM)
- Atypical squamous cells of undetermined significance (ASC-US)
- Low-grade intraepithelial lesion (LSIL)
- Atypical squamous cells, cannot rule out high-grade squamous intra-epithelial lesion (ASC-H)
- Atypical glandular cells (AGC)
- High-grade intraepithelial lesion (HSIL)
- If a patient’s cytology and/or HPV result and history suggest their risk of CIN3+ is elevated, the next step may be to undergo colposcopy.
- Cytologic findings: Possible cytology results include (roughly in order of increasing prevalence of abnormal cells):
- Colposcopy – colposcopy is an in-office procedure, during which the cervix is examined using a high-power microscope (colposcope) with the addition of acetic acid to help identify any abnormal appearing areas requiring biopsy to rule out precancerous or cancerous changes.11 When a biopsy is performed, this sample is reviewed by a pathologist and a histology report is generated. Histology refers to the examination of tissue architecture for vertical extension of abnormal cells and staining for p16 (a tissue marker of HPV oncogene overexpression) to determine histologic grade. Histologic grade is often reported using a hybrid grading system.
- Histologic findings: Possible results include (roughly in order of increasing prevalence of abnormal cells):
- No carcinoma in-situ or no cervical intraepithelial neoplasia (CIN)
- Histologic LSIL or CIN 1
- Histologic HSIL or CIN 2-3 or unspecified
- Adenocarcinoma in situ (AIS)
- Histologic findings: Possible results include (roughly in order of increasing prevalence of abnormal cells):
Management (High Risk)
Immunosuppressed patients:
- Refer to ASCCP web or mobile app “Special situation” → “Immunosuppressed” for quick reference10
- Colposcopy for:
- ASC-US, HPV-positive
- LSIL or more concerning cytology, regardless of HPV test results (if done)
Previous history of high-grade cervical dysplasia (CIN 2+):10 patients with a history of high-grade dysplasia require increased short term and long-term surveillance.
- Short-term follow-up after treatment
- If still has a cervix: HPV-based testing at 6 months (not necessary if treated with total hysterectomy), followed by
- Three consecutive annual HPV-based tests (regardless of treatment)
- Long-term surveillance
- HPV-based testing at 3-year intervals for a minimum of 25 years (even if >65 years old)
- Use shared decision making to decide about continuing q3 year screening beyond 65 years if 25-year surveillance period is complete
- Long-term population studies suggest persistent twofold increase in cervical cancer risk after treatment of histologic HSIL, which continues for at least 25 years and seems to be increased for patients older than 50
- As cervical cancer risk seems to remain above general population levels, continued screening is acceptable, as long as the patient remains in good health
- Discontinuation of screening is recommended if a patient has a limited life expectancy
- Use shared decision making to decide about continuing q3 year screening beyond 65 years if 25-year surveillance period is complete
- HPV-based testing at 3-year intervals for a minimum of 25 years (even if >65 years old)
Take Home Points
- Persistent infection with oncologic subtypes of HPV cause nearly all cases of cervical cancer.
- Routine screening for average risk individuals can be done with cytology alone, HPV with reflex cytology, or co-testing (both). USPSTF and ACS slightly differ in their recommendations but agree that screening can stop at age 65.
- Management of abnormal results and interval of routine screening is based on immediate risk of CIN3+, as calculated by the ASCCP application.
- Patients with immunocompromise or immunosuppression are at higher risk of HPV-related cervical cancer and have unique screening and management protocols.
References
- Schiffman M, Doorbar J, Wentzensen N, et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers. 2016;2(1):16086. doi:10.1038/nrdp.2016.86
- Mcquillan G, Kruszon-Moran D, Markowitz LE, Unger ER, Paulose-Ram R. Prevalence of HPV in Adults Aged 18–69: United States, 2011–2014. Published online 2011:2011-2014. https://www.cdc.gov/nchs/data/
databriefs/db280_table.pdf#1. - Bekos C, Schwameis R, Heinze G, et al. Influence of age on histologic outcome of cervical intraepithelial neoplasia during observational management: Results from large cohort, systematic review, meta-analysis. Sci Rep. 2018;8(1). doi:10.1038/s41598-018-24882-2
- Veldhuijzen NJ, Snijders PJF, Reiss P, Meijer CJLM, van de Wijgert JHHM. Factors affecting transmission of mucosal human papillomavirus. Lancet Infect Dis. 2010;10(12):862-874. doi:10.1016/S1473-3099(10)
70190-0 - Deng H, Hillpot E, Mondal S, Khurana KK, Woodworth CD. HPV16-Immortalized Cells from Human Transformation Zone and Endocervix are More Dysplastic than Ectocervical Cells in Organotypic Culture. Sci Rep. 2018;8(1):15402. doi:10.1038/s41598-018-33865-2
- Fontham ETH, Wolf AMD, 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(5):321-346. doi:10.3322/caac.21628
- Curry SJ, Krist AH, Owens DK, et al. Screening for Cervical Cancer: US Preventive Services Task Force Recommendation Statement. JAMA – Journal of the American Medical Association. 2018;320(7):674-686. doi:10.1001/jama.2018.10897
- National Institutes of Health C for DC and PHMA and IDS of A. Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Accessed August 1, 2022. ttps://clinicalinfo.hiv.gov/
en/guidelines/adult-and- adolescent-opportunistic- infection - 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). https://journals.lww.com/
jlgtd/Fulltext/2019/04000/ Guidelines_for_Cervical_ Cancer_Screening_in.1.aspx - 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(2):102-131. doi:10.1097/LGT.
0000000000000525 - Pierce JG, Bright S. Performance of a colposcopic examination, a loop electrosurgical procedure, and cryotherapy of the cervix. Obstet Gynecol Clin North Am. 2013;40(4):731-757. doi:10.1016/j.ogc.2013.08.008
