Cervical cancer screening

Summary

Cervical cancer is the third most common cancer of the female genital tract in the US. Persistent infection with any high-risk HPV genotype is the most common cause of cervical cancer. HPV immunization, counseling on safe sex practices, and screening for cervical cancer are the most effective prevention measures. All asymptomatic individuals with a cervix between the ages of 21–65 years of age are at increased risk of cervical cancer and should be screened at regular intervals (the age to initiate screening is a point of debate; the American Cancer Society recommends initiating screening at 25 years of age). Screening modalities include primary HPV testing, cytology-alone screening, and HPV/Pap cotesting. Endocervical sampling and p16 immunohistochemistry may be considered in select situations. Management of abnormalities detected on screening has shifted away from a result-based approach to an individualized risk-based approach. There are some exceptions to the risk-based approach (e.g., abnormalities detected in individuals < 25 years of age, certain cytology results). Management options include expedited treatment (e.g., with conization, LEEP, laser cone biopsy), diagnostic excision (i.e., colposcopic biopsy), and surveillance. Individuals with high-grade precursor lesions remain at high risk of developing invasive cervical cancer even after treatment and should be followed up for recurrence for at least 25 years after management. Invasive cervical cancer is detailed in a separate article.

Pathology

Overview of terminology [1][2] A unified system of reporting histological and cytological samples of all squamous intraepithelial lesions (SIL) of the anogenital tract. Three-tiered terminology Cervical intraepithelial neoplasia; (CIN) is characterized by epithelial dysplasia that begins at the basal layer of the squamocolumnar junction and extends outward. Based on the degree of dysplasia, lesions are classified as CIN1 (mild), CIN2 (moderate), or CIN3 (severe). Current standard The current standard for reporting cervical histopathology and cytopathology to ensure optimal management is a combination of the two-tier and three-tier system (i.e., the two-tiered nomenclature with an additional qualifier using the intraepithelial neoplasia nomenclature). Cervical cytology findings [1] Grading of cytological abnormalities Bethesda system for reporting cervical cytology [1][3][4] Characteristic features Low-grade cervical cytology [5] Negative for intraepithelial lesion or malignancy (NILM) No malignant or premalignant changes Additional findings may be reported, e.g.: Atypical squamous cells of undetermined significance (ASC-US) Changes in squamous cells that do not qualify as squamous intraepithelial lesion (SIL) but are more significant than inflammatory or reactive changes. Cytological LSIL High-grade cervical cytology Cytological HSIL Atypical squamous cells likely to contain HSIL cells (ASC-H) Changes in squamous cells HSIL is not confirmed but cannot be excluded. Persistent ASC-H is considered a high-grade cytology result. [5] Atypical glandular cells (AGCs) Endometrial cells are typically a benign cytology finding but can suggest endometrial neoplasia in women ≥ 45 years of age. [3][5] Cervical histology findings [1][2] Koilocytes are epithelial cells with perinuclear halos that are pathognomonic of HPV infection and may be present from early HPV infection. [1][2]

Overview of screening recommendations

Cervical cancer screening should be performed in all individuals with a cervix (regardless of their HPV vaccination status or sexual history). This includes individuals who are pregnant, have same-sex partners, have a history of a supracervical hysterectomy, or are transgender. [6][7][8][9] Average-risk individuals [5][6][7][11] An overview of recommendations is described here. See “Cervical cancer screening for individuals at average risk” for details. Recommended screening period 21–65 years of age The American Cancer Society recommends initiating screening at 25 years of age. [6] Management of abnormalities detected on screening The “ASCCP Management Guidelines App & Web Application” can be used to estimate risk and determine the appropriate next steps; see “Tips & Links.” Women ≥ 25 years of age: Management is based on the individual's risk of having or developing CIN3+ (risk-based approach). Women < 25 years of age: A result-based approach is recommended. In women who undergo colposcopy and biopsy for abnormalities detected on screening, further management is determined by cervical histology results. HSIL (CIN3): Excisional treatment is recommended regardless of the patient's age. HSIL (CIN2) or LSIL (CIN1) Women < 25 years of age: surveillance Women ≥ 25 years of age: excisional treatment, diagnostic excision, or surveillance (depending on the test results) Long-term follow-up Following treatment of a high-grade cervical lesion, surveillance should be continued for at least 25 years. High-risk individuals [5][7][9] An overview of recommendations is described here. See “Cervical cancer screening for individuals at high risk” for details.

Screening modalities

hrHPV genotyping [5][6][12] Cervical cells are collected (similar to Pap smear collection) and screened for high-risk HPV genotypes via PCR-based assays. Samples may be collected by the patient themselves (self-sampling) or as an office procedure. Findings A cytological test in which a cell sample from the cervix is stained with Papanicolaou dye and examined for cellular abnormalities, including precancerous changes Proper sample collection is essential. Findings are described under “Cervical cytology findings.” Sample collection [6][9][13] Visualize the cervix (including the cervical transformation zone) using a sterile speculum. If needed, cleanse the cervix using a saline-soaked cotton swab. Insert the collection device in the external os. [14] Rotate the device to scrape the endocervix, ectocervix, and the transition zone. [13] Extended-tip spatula and endocervical brush Insert the extended tip of the spatula into the endocervix, and gently rotate it 360° around the external os a few times (in one direction). Next, insert the endocervical brush into the endocervical canal and slowly rotate it 180° in one direction. Endocervical broom Insert the central bristles into the endocervix; ensure that the shorter bristles are in contact with the ectocervix. Rotate the broom 5 times in the same direction. Prepare the sample for staining with Papanicolaou dye. [7] Conventional cytology: Smear and fixate the sample on a labeled glass slide. Liquid-based cytology (LBC): Rinse the sample in the preservative medium. Conventional cytology should be performed 10–20 days after the first day of menses, while liquid-based cytology can be performed at any time. [9] If using a spatula in conjunction with an endocervical brush, both samples can be placed on a single slide or within a single vial of the preservative medium. [13] HPV/Pap cotesting [5][6] Endocervical sampling [12][15] Indications [15] Tools and procedure [15][16] Endocervical curette: Circumferentially scrape the endocervical canal with the curette (using a rotational motion or an in-and-out motion); preferably under colposcopic guidance. Endocervical brush (cytobrush) : Swipe the endocervix approx. 12 times with the brush. [12] Endocervical sampling is contraindicated in pregnancy because of the increased risk of complications (e.g., cervical or membrane perforation, pregnancy loss). [5][15] Endocervical samples and cervical biopsies should be sent in separate, clearly marked containers for histopathological or cytological examination. [12][15] p16 immunohistochemistry (p16 IHC) [1][5] Indications [1] Histological diagnosis of CIN2 (on cervical cancer screening) To rule out benign differential diagnoses of precancerous lesions Findings: Strong, diffuse p16 staining indicates that the lesion is more likely high-grade (precancerous). The natural course of p16-positive CIN1 or p16-negative CIN3 is not currently known. Hence, p16 IHC is not routinely recommended for histologically unequivocal CIN1 or CIN3 as it does not change management. [1]

Screening individuals at average risk for cervical cancer

The following recommendations are applicable to asymptomatic immunocompetent individuals who do not have a high-risk condition for cervical cancer. Screening recommendations vary. The main differences are: Age to start screening Screening modality Age-appropriate cervical cancer screening for individuals at average risk USPSTF (2018) [5][7][8][12][17][18] ACS (2020) [6][17] Recommended screening period Screening modalities Discontinuation of screening [6][7][17][18] Discontinue screening of average-risk individuals with a cervix at age > 65 years if all the following criteria are fulfilled: Documented adequate screening with negative results over the last 10 years, defined as any of the following: [6] The most recent screening test should have been performed within the last 3–5 years. No history of CIN 2+ within the past 25 years Discontinue screening in individuals (of any age) with a limited life expectancy. [6] Screening is not routinely recommended for average-risk individuals < 21 years because HPV infections and cervical intraepithelial neoplasias in this age group are likely to resolve without intervention. [7][9] In the absence of any life-limiting conditions, individuals > 65 years without previously documented negative results should continue to be screened until criteria to discontinue are met. [6]

Initial management for abnormal results

Risk assessment [5][11][12][17][19] Recommendations for managing abnormal screening results have shifted away from test result-based algorithms and toward risk-based estimates. [5][11] Personalized risk-based management [5][11][19] Immediate risk of CIN3 ≥ 4% High risk of CIN3 Lower risk of CIN3 Immediate risk of CIN3 < 4% Shared decision-making is recommended when considering expedited treatment. Patients should be informed of the risks and benefits of expedited treatment and its potential adverse effects on future pregnancy (e.g., PROM after LEEP). [5][6][20] Exceptions to the risk-based approach [5] A result-based (rather than risk-based) approach to managing abnormalities detected on screening is indicated in the following select situations. An overview of the management of these situations is described below; refer to the “ASCCP Management Guidelines App & Web Application” in “Tips & Links” for further details. Women < 25 years of age [5] Management of cervical abnormalities detected on cytology-alone screening in this group of individuals includes: Expedited treatment is not recommended in women < 25 years of age with high-grade cervical cytology as most cervical abnormalities in this population undergo spontaneous regression. [5] Women ≥ 25 years of age with any of the following abnormalities detected on screening [5] Colposcopy and cervical biopsy (followed by management of abnormalities detected on cervical histology) are recommended for all of the following scenarios.

Subsequent management after colposcopy and biopsy

Some individuals need to undergo colposcopy and biopsy for further evaluation of abnormalities detected on cervical cancer screening. Subsequent management is determined by the patient's age, abnormalities detected on cervical histology, and the preceding cervical cytology results. General principles [5][11] Excisional treatment (e.g., LEEP, conization, laser cone biopsy) is preferred over ablation to manage histological HSIL. If surveillance is being considered: Consider p16 immunohistochemistry to: [1][5] Rule out a benign condition (e.g., benign epithelial change) Better identify high-grade CIN2 lesions An overview of the initial management of these situations is described below; refer to the “ASCCP Management Guidelines App & Web Application” in “Tips & Links” for further details, including surveillance intervals. HPV infections are highly prevalent in women < 25 years of age, therefore, HPV-based testing is not recommended for surveillance in this group of individuals. [5] If criteria for surveillance are not met, a diagnostic excisional procedure is recommended. [5] CIN3 is an immediate precursor to invasive cervical cancer and should be treated regardless of age, unless the patient is pregnant. [5] Hysterectomy is not recommended for the management of histological HSIL. [5] Women ≥ 25 years of age Consider excisional treatment for all nonpregnant patients. Surveillance may be considered if the patient's concerns about potential adverse effects on future pregnancies outweigh their concerns about cancer. Women < 25 years of age: Surveillance is recommended. Women ≥ 25 years of age: Excisional treatment is recommended for all nonpregnant patients. Women < 25 years of age: Surveillance is acceptable. Women ≥ 25 years of age: Consider surveillance, diagnostic excision, or treatment (excision or ablation) depending on the preceding cervical cytology results. Women < 25 years of age: Surveillance is recommended.