Cervical Cancer Screening

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.

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

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