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Abnormal Pap and Cervical Dysplasia
Fozia Akhtar Ali, MD
Tharani Vadivelu Prasad, MD
image BASICS
  • 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
Cervical cancer is rare before age 21 years. Screening women younger than age 21 years (regardless of sexual 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 (1)[A].
Geriatric Considerations
  • Women age >65 years who have 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 results or two consecutive, 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 20 years after spontaneous regression or appropriate management of a high-grade precancerous lesion, even if this extends screening past the age 65 years.
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 (2).
  • Unless cancer is identified or suspected, treatment of cervical intraepithelial neoplasia is contraindicated during pregnancy.
  • Cervical cancer is the 3rd most common cancer among women worldwide and ranks 14th for cancer deaths in women (3).
  • Predominant age: can occur at any age, but incidence of CIN III peaks between ages 25 and 29; invasive disease peaks 15 years later. Cervical cancer most commonly occurs in women aged 35 to 55 years.
The American Cancer Society estimates that, in 2014, 12,360 women will be diagnosed with invasive cervical cancer and 4,020 women will die from cervical cancer (4). Large declines in incidence rates over the past decades have begun to taper off. From 2006 to 2010, cervical cancer incidence rates have been stable in women younger than 50 years and decreasing by 3.1% per year in women 50 years and older.
  • ˜80% of sexually active women will have acquired a genital HPV infection by 50 years of age.
  • Overall, 26.8% of women are HPV positive. Point prevalence of HPV positivity is highest in those 18 to 22 years of age (as high as 70%), falling off rapidly as women enter their 30s.
HPV DNA is found in virtually all cervical carcinomas and precursor lesions worldwide.
  • High-risk HPV types: 16, 18, 31, 33, 35, 45, 52, and 58 are common oncogenic virus types for cervical cancer.
  • HPV 16 is the most carcinogenic HPV genotype and accounts for 55-60% of all cervical cancers.
  • HPV 18 is the next most carcinogenic HPV genotype. HPV 18 causes a greater proportion of glandular cancers, adenocarcinoma, and adenosquamous carcinoma than squamous cell carcinoma.
  • 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.
  • 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.
  • 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
  • Early age at first coitus (<20 years) and multiple sexual partners
  • Some correlation with low socioeconomic status, high parity, oral contraceptive use, and poor nutrition
  • Immunization: Immunization decreases high-risk HPV infections and cervical pathology for at least 5 to 7 years but has not yet been shown to decrease cervical cancer.
    • Ideally, HPV immunization of girls, boys, and women should be initiated prior to first intercourse.
      • Gardasil (quadrivalent: HPV 4):
        • Reduces dysplasia due to HPV types 16 and 18 (70% of cervical cancer) and types 6 and 11 (anogenital warts)
        • Three doses at 0, 2, and 6 months, approved for use in females ages 9 to 26 years. Only the quadrivalent vaccine is approved for males (ages 9 to 26 years) for prevention of anogenital warts.
      • Cervarix (bivalent: HPV 2): reduces dysplasia due to HPV 16 and 18 infection and CIN. Three doses at 0, 1, and 6 months, approved for use in females ages 10 to 25 years.
  • Gardasil 9: approved in December 2014 for use in females ages 9 to 26 and males ages 9 to 15; adds protection against five additional HPV types which cause approximately 25% of CIN II+ lesions
  • Safe sex practices: condom use
  • Screening
    • Pap smear is the main screening test for cervical cellular pathology.
    • Screening recommendations by age and source (see algorithm “Pap, Normal and Abnormal in Nonpregnant Women Ages 25 Years and Older” and separate algorithm “Pap, Normal and Abnormal in Women Ages 21-24 Years”)
      • <21 years: Do not screen (5) (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 (Pap smear) every 3 years (5)[A]. Do not screen with HPV testing alone or combined with cytology (5).
      • 30 to 65 years: Screen with cytology every 3 years (acceptable) or cotesting (cytology/HPV testing) every 5 years (preferred).
      • >65 years (who have had adequate prior screening and are not high risk): Do not screen (5).
  • Special circumstances: women after hysterectomy with removal of the cervix and with no history of CIN II+: Do not screen (6)[A].
Pelvic exam occasionally reveals external HPV lesions. Examine for exophytic or ulcerative cervical lesions, with or without bleeding.
Acute or chronic cervicitis; cervical glandular hyperplasia; cervical polyp; cervical fibroid; HPV infection; invasive cervical malignancy; uterine malignancy
  • Current evidence indicates no clinically important differences between conventional cytology and liquid-based cytology in detecting cervical cancer precursors (6)[A]. Conventional Pap smear involves a cervical sample plated on a microscope slide with fixative. Thin prep is a liquid-based collection and thin-layer preparation.
  • Sensitivity of a single Pap smear for HSIL ˜60-70%; specificity of ˜90%. Pap smears done routinely at recommended intervals increase the sensitivity further.
  • HPV viral typing: High-risk HPV subtype testing is more sensitive but less specific for identifying women with prevalent CIN III+.
  • 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)
  • P.5

  • Bethesda system (cytologic grading) epithelial cell abnormalities
    • Squamous cell
      • Atypical squamous cell (ASC) (of undetermined significance [ASC-US], cannot exclude high-grade squamous intraepithelial lesion [ASC-H])
      • HPV, mild dysplasia, CIN I
      • Moderate/severe dysplasia CIS, CIN II, and CIN III
    • Glandular cell
      • AGCs (atypical glandular cells)
        • AGCs: not otherwise specified
        • AGCs: favor neoplasia
      • AIS (adenocarcinoma in situ)
      • Adenocarcinoma
Diagnostic Procedures/Other
Algorithms differ for women age 21 to 24 years; see “ASCCP guidelines” (2) and algorithm “Pap, Normal and Abnormal in Women Ages 21-24 Years.” Below recommendations for ages as noted.
  • HPV positive, cytology negative (30 years of age and older)
    • Option 1: HPV DNA typing: if HPV 16 or 18+, proceed to colposcopy; if negative, repeat cotesting at 1 year (6)[B].
    • Option 2: Repeat cotesting at 1 year: if ASC or HPV positive, proceed to colposcopy; if negative, repeat cotesting at 3 years.
  • ASC-US: (>24 years of age)
    • Option 1: HPV testing (preferred)
      • If HPV positive, proceed to colposcopy (2)[B].
      • If HPV negative, repeat cotesting at 3 years (2)[B].
    • Option 2: Repeat cytology at 1 year (acceptable) (2)
      • If repeat cytology ASC or greater, proceed to colposcopy.
      • If repeat cytology is negative, proceed to routine screening in 3 years.
  • ASC-H: Colposcopy is required.
  • LSIL: (>24 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.
    • LSIL with no HPV test or positive HPV test: Proceed to colposcopy.
    • LSIL in pregnancy: Colposcopy is preferred, but it is acceptable to defer colposcopy to postpartum (2).
  • HSIL: loop electrosurgical excision procedure (LEEP) or colposcopy (2)[B]
  • Atypical glandular cells: colposcopy with endocervical sampling and endometrial sampling (if 35 years or older or at risk for endometrial neoplasia) (2)[A]
  • Atypical endometrial cells: endometrial and endocervical sampling
    • If negative, perform colposcopy.
  • Women with no lesion on colposcopy or CIN I (preceded by “lesser abnormalities” such as ASC-US, LSIL, HPV 16+, HPV 18+, and persistent HPV)
    • Follow-up without treatment: cotesting at 12 months
    • If both HPV and cytology are negative, age-appropriate retesting 3 years later
    • If either positive, proceed to colposcopy. If persistent CIN I for at least 2 years, proceed to treatment with ablative or excisional methods.
  • Ages 21 to 24: Management is slightly different than above; see “ASCCP guidelines” (2) or algorithm “Pap, Normal and Abnormal in Women Ages 21-24 Years.”
  • Age >30: If cytology is negative but HPV is positive, repeat cotesting at 1 year is acceptable.
Test Interpretation
Atypical squamous or columnar cells, coarse nuclear material, increased nuclear diameter, koilocytosis (HPV hallmark)
ASCCP guidelines: Evidence-based management algorithms guide Pap smear and postcolposcopic diagnostics and therapeutics and are available online at http://www.asccp.org/Guidelines (2).
Office evaluation and observation; promote smoking cessation; promote protected intercourse; promote immunization.
  • Infective/reactive Pap smear: Treat trichomoniasis, symptomatic candida, or shift in flora suggestive of bacterial vaginosis found on Pap smear results.
  • Condyloma acuminatum: may be treated with cryotherapy or podophyllin topically q1-2wks or podofilox 0.5% applied BID × 3 days then off 4 days, repeated for 1 to 4 weeks, OR trichloroacetic acid applied topically by a physician and covered for 5 to 6 days, OR imiquimod cream 3 times per week at bedtime, up to 16 weeks
  • Persistent CIN I, II, or III: ablative or excisional methods. If inadequate colposcopy for CIN II or III or recurrent CIN II or III, diagnostic excisional procedure is done. For adenocarcinoma in situ, hysterectomy is preferred.
  • Cryotherapy, laser ablation, LEEP/large loop excision of transition zone, or cold-knife conization are all effective but require different training and with different side effects for patient. If cervical malignancy, see “Cervical Malignancy.”
After treatment (excision or ablation) of CIN II or III, women may reenter routine screening only after negative cotesting between 12 and 24 months. Screening should be continued for 20 years (6)[B].
Promote increased intake of antioxidant-rich foods.
HPV vaccination, smoking cessation, protected intercourse, regular screening with Pap smear per guidelines
  • 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 (7). Lesions discovered early are amenable to treatment with excellent results and few recurrences.
  • One- and five-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% (4).
1. Yang KY. Abnormal pap smear and cervical cancer in pregnancy. Clin Obstet Gynecol. 2012;55(3):838-848.
2. Massad S, 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.
3. American Cancer Society. Cancer facts & figures 2013. American Cancer Society Web site. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed July 7, 2015.
4. American Cancer Society. Cancer facts & figures 2014. American Cancer Society Web site. http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed July 7, 2015.
5. U.S. Preventive Services Task Force. Cervical cancer: screening. U.S. Preventive Services Task Force Web site. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cervical-cancer-screening. Accessed July 7, 2015.
6. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 131: screening for cervical cancer. Washington, DC: American College of Obstetricians and Gynecologists; 2012.
7. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9(5):425-434.
Additional Reading
American Society for Colposcopy and Cervical Pathology. Management guidelines. http://www.asccp.org/Guidelines-2/Management-Guidelines-2
See Also
  • Cervical Malignancy; Condylomata Acuminata; Trichomoniasis; Vulvovaginitis, Prepubescent
  • Algorithm: Pap, Normal and Abnormal in Nonpregnant Women Ages 25 Years and Older; Pap, Normal and Abnormal in Women Ages 21-24 Years
  • R87.619 Unspecified abnormal cytological findings in specimens from cervix uteri
  • N87.9 Dysplasia of cervix uteri, unspecified
  • N87.1 Moderate cervical dysplasia
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.
  • Know and adhere to recognized screening guidelines to avoid the harms of overscreening.