Abnormal Pap and Cervical Dysplasia

Basics

Description

  • Cervical dysplasia: premalignant cervical disease that is also called cervical intraepithelial neoplasia (CIN); precancerous epithelial changes in the transformation zone of the uterine cervix almost always associated with human papillomavirus (HPV) infections
  • CIN encompasses a range of histologic diagnoses.
    • CIN I: mild dysplasia; low-grade lesion; cellular changes are limited to the lower 1/3 of the squamous epithelium.
    • CIN II: moderate dysplasia; high-grade lesion; cellular changes are limited to the lower 2/3 of the squamous epithelium.
    • CIN III or carcinoma in situ: severe dysplasia; high-grade lesion; cellular changes involve the full thickness of the squamous epithelium.
  • System(s) affected: reproductive

Pediatric Considerations
Only 0.1% of cervical cancers occur before age 20 years. Screening any individual with a cervix age <21 years (regardless of sexual debut and history) does not reduce cervical cancer incidence and mortality compared with beginning screening at age 21 years. Screenings of adolescents lead to unnecessary evaluation and overtreatment of cervical lesions, which are highly likely to spontaneously regress.

Geriatric Considerations

  • Any individual with a cervix age >65 years who has had adequate prior screening and no history of CIN II+ in the last 20 years should not be screened for cervical cancer. Adequate prior screening is defined as three consecutive, negative cytology only results or two consecutive, negative HPV testing alone or negative cytology “cotesting” with negative HPV results within 10 years before cessation of screening (with the most recent test within the last 5 years).
  • Routine screening should continue for at least 25 years at 3-year intervals with HPV testing or cotesting after spontaneous regression or appropriate management of a high-grade precancerous lesion, even if this extends screening past the age 65 years (1)[C].

Pregnancy Considerations

  • Squamous intraepithelial lesions can progress during pregnancy but often regress postpartum.
  • Colposcopy only to exclude the presence of invasive cancer in high-risk women.
  • Endocervical curettage is contraindicated during pregnancy.
  • Unless cancer is identified or suspected, treatment of CIN is contraindicated during pregnancy.

Epidemiology

Cervical cancer is the fourth most common type of cancer in women worldwide. In the United States, due to improved screening practices, cervical cancer has dropped to 18th place in causes of cancer death in 2019 (2). Incidence of CIN III peaks between ages 25 and 29 years; invasive disease peaks 15 years later. Cervical cancer most commonly occurs in women aged 35 to 44 years. >15% of cervical cancer cases occur in women >65 years of age (occurs in those who did not get regular screening).

Incidence
  • In 2020, it was projected that there would be 13, 800 new cases of cervical cancer diagnosed, and 4, 290 women will die from the disease (2).
  • The incidence of cervical cancer in the United States has decreased by >50% in the past 40 years because of widespread cervical cancer screening tests.
Prevalence
  • In 2017, there were an estimated 291,704 women living with cervical cancer in the United States (2).
  • In 2013 to 2014, the estimated prevalence of CIN II among 21- to 24-year-olds was 732/100,000 screened women in the United States.
  • Multiple studies in populations around the world have found that prevalence of high-grade dysplasia has fallen significantly in HPV-immunized populations (3).

Etiology and Pathophysiology

HPV DNA is found in virtually all cervical carcinomas and precursor lesions worldwide. HPV is so common that most sexually active men and women will get at least one type of HPV at some point in their lives.

  • High-risk HPV types: 16, 18, 31, 33, 35, 45, 52, and 58 are common oncogenic virus types for cervical cancer.
  • HPV 16 and 18 are associated with ~70% of all cervical cancers.
  • Most HPV infections are transient, becoming undetectable within 1 to 2 years. Persistent infections are what place women at significant risk for developing precancerous lesions. Compared to younger women, women age >30 years are less likely to clear a new HPV infection.
  • Low-risk types: HPV viral types 6, 11, 42, 43, and 44 are considered common low-risk types and may cause genital warts. HPV 6 and 11 (cause 90% of benign anogenital warts) can lead to low-grade squamous intraepithelial lesion (LSIL) and CIN I.

Risk Factors

  • Previous or current HPV infection
  • HIV infection and other immunosuppressive conditions
  • In utero exposure to diethylstilbestrol
  • Previous treatment of a high-grade precancerous lesion or cervical cancer
  • Cigarette smoking
  • Multiple sexual partners
  • Some correlation with low socioeconomic status, high parity, oral contraceptive use, and poor nutrition

General Prevention

  • Immunization: Immunization decreases high-risk HPV infections and CIN 2 and CIN 3 cervical pathology for at least 5 to 7 years but has not yet been shown to decrease cervical cancer. It is likely that prevention of invasive cancer will be demonstrated within a few years.
    • Ideally, HPV immunization of girls, boys, and any individual with a cervix should be initiated prior to first intercourse. Per the Advisory Committee on Immunization Practices (ACIP), offer HPV vaccine to adolescents 11 to 12 years of age and can start vaccination as early as 9 years old.
    • Gardasil 9: The U.S. FDA approved in October 2018 for use in females and males ages 9 to 26 years and via shared clinical decision for ages 27 to 45 years; 88% effective preventing dysplasia due to HPV types 16 and 18 (75% of cervical cancer), types 6 and 11 (anogenital warts), and protection against five additional HPV types which cause approximately 25% of CIN II+ lesions.
    • Vaccine schedule: If the first vaccine began before the 15th birthday only second dose required to complete series only 6 to 12 months later
    • If vaccine began on or after the 15th birthday: 3 doses at 0, 2, and 6 months
    • Immunocompromising conditions: 3 doses needed
  • Safe sex practices: condom use
  • Advise smoking cessation
  • Screening
    • Pap smear has been the main screening test for cervical cellular pathology, with or without cotesting for HPV. A 2018 draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommends either cytology-only testing at 3-year intervals or primary HPV testing versus cotesting at 5-year intervals for women 30 to 65 years of age. Clinicians will choose to adopt the most feasible screening and testing approach depending on assay availability.
    • Screening recommendations by age and source (see algorithm “Pap, Normal and Abnormal in Nonpregnant Individuals Ages 25 Years and Older” and separate algorithm “Pap, Normal and Abnormal in Individuals Ages 21–24 Years”)
      • <21 years: Do not screen (4)[A] (USPSTF/ASCCP/ACS/ASCP/ACOG).
    • Frequency of screening recommendation: USPSTF/ASCCP/ACS/ASCP generally agree by age and screen.
      • 21 to 29 years: Screen with cytology every 3 years. For patients 25 years and older, screen every 5 years with primary HPV testing using an assay method explicitly approved for primary HPV (only) testing (preferred) or every 3 years with cytology (acceptable) (1).
      • 30 to 65 years: Screen with either primary HPV testing using an assay specifically approved for this or cotesting (cytology/HPV testing) every 5 years (1)[C]. Cytology every 3 years if cotesting or HPV-only testing not available is also acceptable (1),(4).
      • >65 years (who have had adequate prior screening and are not high risk): Do not screen (4)[A].
  • Special circumstances: patients after hysterectomy with removal of the cervix and with no history of CIN II+: Do not screen (4)[A]. Women with history of CIN II+ or status treatment should continue screening until at least 25 years following their diagnosis of CIN II+ (1)[C].
  • HIV-positive patients: Screen every 3 years in those who have had three consecutive normal annual Pap tests and every 3 years cotesting in women ages 30 years and older.

Diagnosis

History

Usually asymptomatic until there is invasive disease. Patients may present with vaginal discharge, abnormal vaginal bleeding, postcoital bleeding, pelvic pain, cervical mass, or bladder obstruction.

Physical Exam

Pelvic exam occasionally reveals external HPV lesions. Examine for exophytic or ulcerative cervical lesions, with or without bleeding.

Differential Diagnosis

Acute or chronic cervicitis; cervical glandular hyperplasia; cervical polyp; cervical fibroid; HPV infection; invasive cervical malignancy; uterine malignancy

Diagnostic Tests & Interpretation

  • Current evidence indicates no clinically important differences between conventional cytology and liquid-based cytology in detecting cervical cancer precursors. Conventional Pap smear involves a cervical sample plated on a microscope slide with fixative. ThinPrep is a liquid-based collection and thin-layer preparation.
  • To ensure an adequate sample of both the ecto- and endocervix, use a cytobrush and an extended tip spatula.
  • The sensitivity and specificity of using HPV and cytology testing together (cotesting) for dysplasia is near 100% and 92.5%, respectively. Cotesting leads to earlier diagnosis of CIN III+ and cancer than does cytology alone. Testing for high-risk HPV using an assay specifically approved for primary screening without cytology is preferred for individuals with a cervix age 25 years or older, particularly for poorly screened or unscreened populations. Per updated 2019 ASCCP guidelines, cytology screening alone is also acceptable when HPV or cotesting is not feasible.
  • Cytology report component: specimen type (conventional Pap smear or liquid based), adequacy (presence of endocervical cells), and categorization (negative for intraepithelial lesion or malignancy or epithelial cell abnormality; i.e., squamous/glandular)
  • Bethesda 2014 system (cytologic grading) epithelial cell abnormalities
    • Squamous cell
      • Atypical squamous cells (ASCs) (of undetermined significance [ASC-US], cannot exclude high-grade squamous intraepithelial lesion or HSIL [ASC-H])
      • HPV, mild dysplasia, CIN I
      • Moderate/severe dysplasia CIS, CIN II, and CIN III
    • Glandular cell
      • AIS (adenocarcinoma in situ)
      • AGCs (atypical glandular cells)
        • AGCs: not otherwise specified
        • AGCs: favor neoplasia
      • Adenocarcinoma

Diagnostic Procedures/Other

Clinical action depend on immediate risk of CIN 3+ for cases age 25 years or older (1)[C]. Algorithms from 2012 ASCCP guidelines differ for women age 21 to 24 years, provided below (5)[C].

  • ASC-US: (<25 years of age)
    • Option 1: HPV testing (preferred)
      • If HPV positive, proceed to clinical action depending on immediate CIN 3+ risk (1),(5)[C].
      • If HPV negative, repeat cotesting at 3 years (5)[C].
    • Option 2: Repeat cytology at 1 year (acceptable) (5)[C].
      • If repeat cytology ASC or greater, proceed to colposcopy or other clinical action if immediate CIN 3+ risk is known (2).
      • If repeat cytology is negative, proceed to routine screening.
  • ASC-H (<25 years of age): colposcopy required
  • LSIL: (<25 years of age)
    • LSIL with negative HPV test: Repeat cotesting at 1 year (preferred).
      • If repeat cotesting is negative, repeat cotesting in 3 years.
      • If cotesting is positive, proceed to colposcopy or repeat cotesting in 1 year.
    • LSIL with no HPV test or positive HPV test: Proceed to colposcopy.
    • LSIL in pregnancy: colposcopy preferred, but it is acceptable to defer colposcopy to postpartum (5)[B].
  • HSIL/CIN 2 or 3+/AGCs/atypical endometrial cells (21 years or older): likely colposcopy but clinical action ultimately depends on immediate CIN 3+ risk (1)[C]
  • Age 25 years or older/special populations/rarely screened/status posttreatment/history of CIN 2, CIN 3, AIS or invasive cancer: clinical action only when immediate CIN 3+ risk is 4% or greater with stress on shared decision-making; can proceed to treatment if immediate CIN 3+ risk is > 60% and bypass colposcopy biopsy (1)

Test Interpretation
Atypical squamous or columnar cells, coarse nuclear material, increased nuclear diameter, koilocytosis (HPV hallmark)

Treatment

ASCCP smartphone application includes 2012 guidelines: Evidence-based management phone application includes algorithms to guide Pap smear and post-colposcopic diagnostics and therapeutics are available online at https://www.asccp.org/mobile-app with 2012 guidelines available online at https:www.asscp.org/Guidelines (1),(5).

General Measures

Office evaluation and observation; promote smoking cessation; promote protected intercourse; promote immunization.

Medication

  • Infective/reactive Pap smear: Treat trichomoniasis, symptomatic Candida, or shift in flora suggestive of bacterial vaginosis found on Pap smear results.
  • Condyloma acuminatum treatment options: See chapter “Condylomata Acuminata.”

Surgery/Other Procedures

  • Expedited treatment that bypasses colposcopy biopsy is recommended for nonpregnant patients 25 years or older with immediate CIN 3+ risk of >60% and is acceptable for immediate CIN 3+ risk between 25% and 60%, while stressing the importance of shared decision-making (1).
  • Observation is preferred to treatment for CIN I (1). Colposcopy can be deferred for certain patients, and repeat HPV testing or cotesting in 1 year is recommended if immediate CIN 3+ risk is low risk (<4%).
  • Excisional treatment is preferred to ablative treatment for histologic HSIL (CIN 2 or 3). For AIS, excision is recommended (1).
  • If cervical malignancy, see “Cervical Malignancy.”

Ongoing Care

Follow-up Recommendations

After treatment (excision or ablation) of HSIL, CIN II or III or AIS and initial posttreatment management, women may reenter screening with HPV testing or cotesting at 3-year intervals for at least 25 years (1).

Diet

Promote increased intake of antioxidant-rich foods.

Patient Education

HPV vaccination, smoking cessation, protected intercourse, regular screening with Pap smear per guidelines

Prognosis

  • Progression of CIN to invasive cervical cancer is slow, and the likelihood of regression is high: Up to 43% of CIN II and 32% of CIN III lesions may regress. CIN III has a 30% probability of becoming invasive cancer over a 30-year period, although only about 1% if treated.
  • CIN III becomes invasive: Lesions discovered early are amenable to treatment with excellent results and few recurrences.
  • 1- and 5-year relative survival rates for cervical cancer patients are 87% and 68%, respectively. The 5-year survival rate for patients diagnosed with localized disease is 91%.

Complications

Aggressive cervical surgery may be associated with cervical stenosis, cervical incompetence (leading to preterm labor), and scarring affecting cervical dilatation in labor.

Additional Reading

  • American Society for Colposcopy and Cervical Pathology. Updated risk-based management guidelines. https://www.asccp.org/Guidelines. Accessed August 11, 2020.
  • See Also

    Codes

    ICD-10

    • D06.9 Carcinoma in situ of cervix, unspecified
    • N87.0 Mild cervical dysplasia
    • N87.1 Moderate cervical dysplasia
    • N87.9 Dysplasia of cervix uteri, unspecified
    • R87.619 Unspecified abnormal cytological findings in specimens from cervix uteri

    ICD-9

    • 233.1 Carcinoma in situ of cervix uteri
    • 622.10 Dysplasia of cervix, unspecified
    • 622.11 Mild dysplasia of cervix
    • 622.12 Moderate dysplasia of cervix
    • 795.00 Abnormal glandular Papanicolaou smear of cervix

    SNOMED

    • 285836003 Cervical intraepithelial neoplasia grade 1 (disorder)
    • 285838002 Cervical intraepithelial neoplasia grade 2 (disorder)
    • 439888000 abnormal cervical Papanicolaou smear (finding)
    • 73391008 dysplasia of cervix (disorder)
    • 92564006 Carcinoma in situ of uterine cervix (disorder)

    Clinical Pearls

    • HPV is present in virtually all cervical cancers (99.7%), but most HPV infections are transient.
    • Vaccine should be offered prior to onset of any sexual activity for maximum effectiveness but may be offered up to age 45 years (88% protective in women age 27 to 45 years against warts, squamous intraepithelial lesion, and cancer).
    • Know and adhere to recognized screening guidelines to avoid the harms of over screening.
    • Optimal screening strategy is in evolution. HPV only screening is now preferred due to test being more sensitive than cytology alone (1), but the approved assay is not yet widely available in late 2020.

    Authors


    Anna K. Zheng, MD

    Bibliography

    1. 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.  [PMID:32243307]
    2. National Cancer Institute. Cancer stat facts: cervical cancer. https://seer.cancer.gov/statfacts/html/cervix.html. Accessed August 19, 2020.
    3. Drolet M, Bénard É, Pérez N, et al. Population-level impact and herd effects following the introduction of human papilloma-virus vaccination programmes: updated systematic review and meta-analysis. Lancet. 2019;394(10197):497–509.  [PMID:31255301]
    4. Curry SJ, Krist AH, Owens DK, et al; for U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. JAMA. 2018;320(7):674–686.  [PMID:30140884]
    5. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.  [PMID:23519301]


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