- Cancer of the uterine cervix
- Major histologic types:
- Squamous cell carcinoma: approximately 80% of cervical cancers
- Adenocarcinoma: 15%
- Adenosquamous carcinoma: 3%–5%
- Associated with human papillomavirus (HPV):
- Detected in 99.7% of cervical cancers
- Subtypes HPV 16 and 18 found in > 70% of cervical cancers
- Among gynecologic cancers, cervical cancer is:
- The 3rd most common cancer diagnosis
- The 3rd most common cause of death
- More than 80% of new cases worldwide are from less developed countries.
- In the United States:
- 14,000 new cases of invasive cervical cancer are diagnosed annually.
- Mean age at diagnosis: 50 years
- Early onset of sexual activity
- Multiple sexual partners
- Multiparity and early age at 1st birth
- History of vulvar or vaginal squamous intraepithelial neoplasia or cancer
- Human immunodeficiency virus (HIV) infection
- Co-infection with Chlamydia trachomatis or herpes simplex virus
- Non-HPV related:
- Low socioeconomic status
- African American race
- Use of oral contraceptives
- Cigarette smoking (associated with squamous cell carcinoma)
- Family history
- Negative risk factor: circumcised male partners
- Screening is recommended because:
- Women 21‒65 years of age are at risk for cervical cancer due to potential exposure to high-risk human papillomavirus (hrHPV) through sexual intercourse.
- A 75% decline in the incidence and mortality of cervical cancer occurred in the past 50 years due to screening.
- Most cases of cervical cancer are found in women who have not been adequately screened.
- Cervical cancer usually does not cause symptoms.
- Screening is not recommended earlier than age 21 because:
- Cancerous and precancerous lesions are rare before the age of 21.
- Prolonged progression from hrHPV infection, development of precancerous lesions, to cervical cancer
- Many precancerous lesions and HPV infections will regress.
- May lead to more harm from psychological distress and unnecessary procedures
Strategies for Screening
Screening strategies can be done independently or concurrently (co-testing).
- Cervical cytology:
- Ectocervical and endocervical cells are collected to evaluate the transformation zone (area at risk for cervical cancer).
- The procedure is performed with an endocervical brush and ectocervical spatula.
- Preparation methods:
- Conventional Papanicolaou (Pap) smear: Ectocervical spatula is smeared and the brush rolled onto a slide, with fixative applied immediately
- Liquid-based thin layer cytology: Collection device is placed and swirled in the liquid fixative solution, which is then processed by the laboratory.
- HPV testing:
- Identifies hrHPV subtypes
- Samples are collected from the endocervix.
- If liquid-based cytology is performed, the same cytology specimen can be used.
Cervical Cancer Screening for Average-Risk Individuals
The following recommendations are for average-risk individuals.
- United States Preventive Services Task Force (USPSTF) recommendations:
- Routine cytology screening every 3 years starting at the age of 21, regardless of sexual history
- For ages 21‒29: cytology alone every 3 years
- For ages 30‒65, options are:
- Cervical cytology alone every 3 years
- hrHPV every 5 years
- Cytology with hrHPV co-testing every 5 years
- Screening ends at the age of 65 if the patient has adequate negative screening.
- Updated American Cancer Society recommendations (2020):
- Initiate screening at the age of 25, regardless of sexual history, with primary HPV testing (approved testing that is adequate for screening by itself) every 5 years
- If primary HPV testing cannot be done:
- Co-testing with HPV and Pap smear every 5 years
- Pap smear alone every 3 years
- Screening ends at age 65 with adequate negative screening.
- Rationale for the above:
- Low incidence of cervical cancer in those < 24 years of age
- HPV testing is more specific.
- About 70% of adolescents have received at least 1 dose of the HPV vaccine.
- Adequate negative prior screening is defined as 1 of the following:
- 3 consecutive negative cytology results, with the last result within the past 3 years
- 2 consecutive negative co-test results within the past 10 years, with the most recent test within the past 5 years
- 2 consecutive negative primary HPV test results within the past 10 years, with the most recent test within the past 5 years
Cervical Cancer Screening for Special Populations
Certain conditions have a high risk for cervical cancer, so screening must be individualized and more frequent:
- HIV infection: Screening may start < 21 years of age, regardless of sexual history.
- Immunocompromised: Screening may start < 21 years of age, regardless of sexual history.
- In utero exposure to diethylstilbestrol (last used in the 1970s, so most relevant in women born after 1980)
- Previous treatment of a high-grade precancerous lesion or cervical cancer
- Screening is still recommended in women:
- With history of subtotal hysterectomy (cervix intact)
- With history of cervical intraepithelial neoplasia (CIN), even after hysterectomy
- No screening is recommended in women:
- With history of hysterectomy with removal of the cervix for a benign disease
- Without history of a high-grade precancerous lesion (CIN grade 2 or 3) or cervical cancer
Individuals > 65 years of age
- Screening may be indicated in older women with inadequate screening.
- Those at risk for inadequate screening:
- Patients with limited access to care
- Women from racial or ethnic minority groups
- Immigrant women from countries where screening is not available
- Duration of screening is based on:
- A life expectancy of ≥ 10 years
- An informed decision-making discussion with the patient
- Those at risk for inadequate screening:
- Continued screening is recommended for at least 20 years after a precancerous lesion regresses or is treated, even if screening goes past the age of 65.
Results (Bethesda system)
A standardized reporting of results, which includes the specimen adequacy, general categorization of findings, and results:
- Negative for intraepithelial lesion or malignancy
- Epithelial cell abnormalities:
- Squamous cell:
- Atypical squamous cells (ASC) of undetermined significance (ASC-US)
- ASC cannot exclude high-grade squamous intraepithelial lesion (ASC-H).
- Low-grade squamous intraepithelial lesion (LSIL)
- High-grade squamous intraepithelial lesion (HSIL)
- Squamous cell carcinoma
- Glandular cell (specify endocervical, endometrial, or not otherwise specified):
- Atypical endocervical, endometrial, or glandular cells (AGC)
- Atypical endocervical or glandular cells, favor neoplastic
- Endocervical adenocarcinoma in situ (AIS)
- Squamous cell:
- Trichomonas vaginalis
- Fungal elements (consistent with Candida)
- Cellular changes consistent with herpes simplex virus or cytomegalovirus
- Bacterial vaginosis
- Bacteria consistent with Actinomyces
- Other non-neoplastic findings may be included:
- Reactive cellular changes
- Glandular cells status post-hysterectomy
Interpretation of results
- Negative for intraepithelial lesion or malignancy: no cellular evidence of neoplasia
- Some cells seen are not normal, but do not meet the requirements to be precancerous.
- May be precancerous or associated with infection, irritation, or intercourse
- ASC-US (abnormal cells, but no squamous intraepithelial lesions)
- ASC-H (equivocal findings, but may be a sign of HSIL)
- Squamous intraepithelial lesion (SIL):
- Premalignant findings for invasive squamous cell carcinoma
- Low-grade dysplasia corresponding to cervical intraepithelial neoplasia (CIN 1)
- Early, mild changes in the size or shape of cells
- May regress on its own
- Moderate or high-grade dysplasia (CIN 2, CIN 3/carcinoma in situ)
- Increased risk of progression to invasive carcinoma (compared with LSIL changes)
- Glandular cell abnormalities:
- AGC: endometrial or cervical cell changes are abnormal and must be evaluated more closely.
- AGC, favor neoplastic: show features that suggest, but are not sufficient for, a diagnosis of adenocarcinoma
- AIS: premalignant lesion of invasive adenocarcinoma
Follow-up of abnormal results
Note: Colposcopy is a procedure in which a colposcope (magnifying device) is used to enhance visualization of the cervix, identify macroscopic abnormal areas, and guide biopsy.
- Unsatisfactory for evaluation:
- May be due to scant cellularity or obscured cells
- If HPV positive: Repeat cytology in 2‒4 months or colposcopy.
- If HPV negative: Repeat cytology in 2‒4 months.
- Abnormal HPV, normal cytology (≥ 30 years of age):
- If HPV 16 or 18: colposcopy
- Repeat co-testing in 1 year; If still positive, perform colposcopy.
- Age 21–24 years: Repeat cytology in 12 months.
- Age ≥ 25 years: Obtain HPV testing.
- If negative, check co-testing in 3 years.
- If positive, proceed with colposcopy.
- ASC-H: colposcopy
- Age 21–24 years: follow-up cytology at 12-month intervals
- Age ≥ 25 years: colposcopy
- Pregnant women: colposcopy (immediately, or deferred until 6 weeks postpartum)
- HSIL: colposcopy
- AGC and AIS: colposcopy
- Feldman, S., Goodman, A. (2020). Screening for cervical cancer in resource-rich settings. UpToDate. Retrieved December 14, 2020, from https://www.uptodate.com/contents/screening-for-cervical-cancer-in-resource-rich-settings
- Frumovitz, M. (2020). Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis. UpToDate. Retrieved December 17, 2020, from https://www.uptodate.com/contents/invasive-cervical-cancer-epidemiology-risk-factors-clinical-manifestations-and-diagnosis
- Feldman, S., & Crum, C.P. (2020). Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing. UpToDate. Retrieved December 17, 2020, from https://www.uptodate.com/contents/cervical-cancer-screening-tests-techniques-for-cervical-cytology-and-human-papillomavirus-testing
- Crum, C.P, and Huh, W.K. (2020). Cervical and vaginal cytology: Interpretation or results (Pap test report). UpToDate. Retrieved December 20, 2020, from https://www.uptodate.com/contents/cervical-and-vaginal-cytology-interpretation-of-results-pap-test-report
- Iniesta M.D., Schmeler K.M., & Ramirez P.T. (2016). Tumors of the uterine cervix. In Kantarjian H.M., & Wolff R.A. (Eds.), The MD Anderson Manual of Medical Oncology, 3rd ed. McGraw-Hill.
- Karjane, N., & Ivey, S. (2018). Pap smear. Medscape. https://emedicine.medscape.com/article/1947979-overview#a9
- Papadakis M.A., McPhee S.J., & Bernstein J. (Eds.). (2020). Cervical cancer. Quick Medical Diagnosis & Treatment 2020. McGraw-Hill.
- U.S. Preventive Service Task Force (2018). Cervical cancer: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/cervical-cancer-screening#fullrecommendationstart
- The American Cancer Society (2020). Guidelines for the prevention and early detection of cervical cancer. https://www.cancer.org/cancer/cervical-cancer/detection-diagnosis-staging/cervical-cancer-screening-guidelines.html