Cervical Cancer Screening

Cervical cancer is the 3rd most common gynecologic cancer. More than 90% of cervical cancer cases are associated with high-risk human papillomavirus (hrHPV), which is transmitted by sexual contact. Cervical cancer can be prevented by early detection and treatment of precancerous lesions caused by hrHPV. The methods of detection are cervical cytology and HPV testing. Screening is recommended by the age of 21 and is generally repeated every 3 years up to the age of 29 in an average-risk individual. By age 30, HPV testing with cytology is obtained. Since the screening program was initiated, there has been a 75% decline in the incidence of and mortality from cervical cancer.

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Overview

Cervical cancer

  • 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

Epidemiology

  • 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

Risk factors

  • HPV-related:
    • 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
    • Immunosuppression
    • 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 Rationale

  • 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.
ThinPrep Pap smear HPV

Slide image from a Pap smear for cervical cancer screening: Normal squamous cells are on the left; HPV-infected cells with mild dysplasia are on the right.

Image: “ThinPrep Pap smear HPV” by Ed Uthman. License: Public Domain

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

High-risk individuals

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

Prior hysterectomy

  • 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
  • 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. 

Pap Test

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)
      • Adenocarcinoma
  • Organism:
    • 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
    • Atrophy
    • Inflammation
Pap smear showing bacterial vaginosis with many clue cells HIV

Pap smear showing bacterial vaginosis with many clue cells
Clue cells are vaginal epithelial cells studded with adherent coccobacilli that are best appreciated at the edge of the cells. The bacteria are stained blue-purple by the Pap stain (arrows).

Image: “Cervical cytological changes in HIV-infected patients” by Mwakigonja AR, Torres LM, Mwakyoma HA, Kaaya EE. License: CC BY 2.0, edited by Lecturio

Interpretation of results

  • Negative for intraepithelial lesion or malignancy: no cellular evidence of neoplasia
  • ASC: 
    • 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
    • Categories:
      • 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
    • LSIL: 
      • 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
    • HSIL: 
      • 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.
  • ASC-US:
    • 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
  • LSIL:
    • 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

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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.
  6. Karjane, N., & Ivey, S. (2018). Pap smear. Medscape. https://emedicine.medscape.com/article/1947979-overview#a9
  7. Papadakis M.A., McPhee S.J., & Bernstein J. (Eds.). (2020). Cervical cancer. Quick Medical Diagnosis & Treatment 2020. McGraw-Hill.
  8. U.S. Preventive Service Task Force (2018). Cervical cancer: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/cervical-cancer-screening#fullrecommendationstart
  9. 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

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