5-Minute Clinical Consult

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 papilloma virus (HPV) infections.
  • Cervical intraepithelial neoplasia (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

ALERT
Incidence of cervical cancer has decreased by >50% in the last 30 years due to cervical cytology screening.

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 regress spontaneously (1).

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 3 consecutive negative cytology results or 2 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 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.
  • Unless cancer is identified or suspected, treatment of cervical intraepithelial neoplasia is contraindicated during pregnancy

Epidemiology

  • Cervical cancer is the 3rd most common cancer among women worldwide, and ranks 14th for cancer deaths in women (2).
  • 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 age 35–55 years.

Incidence
The American Cancer Society estimates that 12,340 women will be diagnosed with invasive cervical cancer in 2013 (2). Since 2004, cervical cancer incidence rates have decreased by 2.1% per year in women younger than 50 years, and by 3.1% per year in women age 50 years and older.

Prevalence
  • ∼80% of sexually active women will have acquired a genital HPV infection by age 50 years.
  • Overall, 26.8% of women are HPV positive. Point prevalence of HPV positivity is highest in those age 18–22 years (as high as 70%), falling off rapidly as women enter their 30s.

Pathophysiology

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.
  • HPV16 is the most carcinogenic HPV genotype, accounting for 55–60% of all cervical cancers
  • HPV18 is the next most carcinogenic HPV genotype. HPV18 causes a greater proportion of glandular cancers, adenocarcinoma and adenosquamous carcinoma, than squamous cell carcinoma.
  • Most HPV infections are transient, becoming undetectable within 1–2 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.

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
  • 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

General Prevention

  • Immunization: Immunization decreases high-risk HPV infections and cervical pathology.
    • Ideally, HPV immunization of girls, boys, and women should be initiated prior to first intercourse:
      • Gardasil (quadrivalent: HPV4):
        • Reduces dysplasia due to HPV types 16 and 18 (70% of cervical cancer) and types 6 and 11 (anogenital warts).
        • 3 doses at 0, 2, 6 months, approved for use in women age 9–26. Only the quadrivalent vaccine is approved for males (ages 9–26) for prevention of anogenital warts.
      • Cervarix (bivalent: HPV2): Reduces dysplasia due to HPV 16 and 18 infection and CIN. 3 doses at 0, 1, 6 months, approved for use in females age 10–25.
  • Safe sex practices: Condom use
  • Screening:
    • Pap smear is the main screening test for cervical cellular pathology.
    • Screening recommendations by age and source:
      • <21 years: Do not screen. (Grade D) (USPSTF/ASCCP/ACS/ASCP/ACOG)
    • Frequency of screening recommendation: USPSTF/ASCCP/ACS/ASCP generally agree by age and screen:
      • 21–29 years: Screen with cytology (Pap smear) every 3 years (Grade A). Do not screen with HPV testing alone or combined with cytology (Grade D).
      • 30–65 years: Screen with cytology every 3 years (acceptable) or co-testing (cytology/HPV testing) every 5 years (preferred).
      • >65 years (who have had adequate prior screening and are not high risk): Do not screen (Grade D).
  • Special circumstances: Women after hysterectomy with removal of the cervix and with no history of CIN II+: Do not screen.

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 and 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.
  • Sensitivity of a single Pap smear for HSIL ∼60–70%; specificity of ∼90%. Pap smears done routinely at recommended intervals further increases the sensitivity.
  • HPV viral typing: High-risk HPV subtype testing is more sensitive, but less specific for identifying women with prevalent CIN III+.
  • Co-testing: HPV typing in combination with Pap smear for women age ≥30 years
  • 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 system (cytologic grading) epithelial cell abnormalities:
    • Squamous cell:
      • ASC (atypical squamous cells) [ASC-US (of undetermined significance), ASC-H (cannot exclude high-grade squamous intraepithelial lesion)]
      • HPV, mild dysplasia, CIN I
      • Moderate/severe dysplasia CIS, CIN II, and CIN III
    • Glandular cell:
      • AGC (atypical glandular cells):
        • AGCs: Not otherwise specified
        • AGCs: Favor neoplasia
      • AIS (adenocarcinoma in situ)
      • Adenocarcinoma

Diagnostic Procedures/Other

Algorithms differ for women age 21–24 years; see ASCCP Guideline (3). 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 co-testing at 1 year
  • Option 2: Repeat co-testing at 1 year: If ≥ASC or HPV positive, proceed to colposcopy; if negative, repeat co-testing at 3 years

ASC-US: (>24 years of age)

  • Option 1: HPV testing (preferred)
    • If HPV positive, proceed to colposcopy
    • If HPV negative, repeat co-testing at 3 years
  • Option 2: Repeat cytology at 1 year (acceptable)
    • If repeat cytology ASC or greater, proceed to colposcopy
    • If repeat cytology is negative, proceed to routine screening in 3 years

ASC-H: Colposcopy required

LSIL: (>24 years of age)

  • LSIL with negative HPV test: Repeat co-testing at 1 year (preferred)
    • If repeat co-testing is negative, repeat co-testing in 3 years
    • If co-testing is positive, proceed to colposcopy
  • LSIL with no HPV test or positive HPV test: Proceed to colposcopy

HSIL: LEEP or colposcopy

Atypical glandular cells: Colposcopy with endocervical sampling and endometrial sampling (if age 35 years or older or at risk for endometrial neoplasia)

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+, 18+, and persistent HPV):

  • Follow-up without treatment: Co-testing at 12 months
  • If both HPV and cytology 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

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

Treatment

ASCCP guidelines: Evidence-based management algorithms guide Pap smear and post colposcopic diagnostics and therapeutics and are available online (3).

General Measures

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

Medication (Drugs)

  • 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 q1–2wk or podofilox 0.5% applied b.i.d. ×3 days then off 4 days, repeated for 1–4 weeks OR trichloroacetic acid, applied topically by a physician and covered for 5–6 days OR imiquimod cream3×/wk at bedtime up to 16 weeks

Surgery/Other Procedures

  • Persistent CIN I, CIN 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 all effective, but require different training and with different side effects for patient. If cervical malignancy, see “Cervical Malignancy.”

Ongoing Care

Follow-Up Recommendations

After treatment (excision or ablation) of CIN II or III, women may re-enter routine screening only after negative co-testing at 12 and 24 months. Screening should be continued for 20 years (4).

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% of treated
  • CIN III will become invasive (4). Lesions discovered early are amenable to treatment with excellent results and few recurrences.
  • One- 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% (2).

Complications

Aggressive cervical surgery may be associated with cervical stenosis, cervical incompetence, and scarring affecting cervical dilatation in labor.

Additional Reading

  • Screening for Cervical Cancer: U.S. Preventive Services Task Force Recommendation Statement. Accessed May 16, 2013 at http://www.uspreventiveservicestaskforce.org/uspstf11/cervcancer/cervcance....
  • See Also

    Codes

    ICD-9

    • 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

    ICD-10

    • 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

    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)

    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 over screening.

    Authors


    Fozia Ali, MD
    Tharani Vadivelu Prasad, MD

    Bibliography

    1. Yang KY. Abnormal pap smear and cervical cancer in pregnancy. Clin Obstet Gynecol. 2012;55(3):838–848.  [PMID:22828115]
    2. Cancer Facts and Figures 2013: American Cancer Society 2013. Accessed May 16, 2013 at http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf.
    3. Massad S, Eienstein MH, Warner KH. 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Lower Genital Tract Dis. 2013;17(5):S1–S27.
    4. 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.  [PMID:18407790]


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