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

Pediatric Considerations
Cervical cancer is very 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 2+ 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 (2).
  • 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 (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 35–55 years.

Incidence
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.

Prevalence
  • ∼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 18–22 years of age (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 and accounts 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. HPV6 and 11 (cause 90% of benign anogenital warts) can lead to low-grade squamous intraepithelial lesion (LSIL) and CIN 1.

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 for at least 5–7 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: 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, and 6 months, approved for use in females ages 9–26 years. Only the quadrivalent vaccine is approved for males (ages 9–26 years) for prevention of anogenital warts.
      • Cervarix (bivalent: HPV2): Reduces dysplasia due to HPV 16 and 18 infection and CIN. 3 doses at 0, 1, and 6 months, approved for use in females ages 10–25 years.
  • 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 and Older]” and separate algorithm [Ages 21–24])
      • <21 years: so not screen (5) (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 (5)[A]. Do not screen with HPV testing alone or combined with cytology (5).
      • 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 (5).
  • Special circumstances: Women after hysterectomy with removal of the cervix and with no history of CIN 2+: do not screen (6)[A].

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 (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 increases the sensitivity further.
  • HPV viral typing: High-risk HPV subtype testing is more sensitive but less specific for identifying women with prevalent CIN 3+.
  • Co-testing: HPV typing in combination with Pap smear for women ≥30
  • 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, CIN1
      • 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/Surgery

Algorithms differ for women age 21–24 years; see “ASCCP Guideline” (2) and algorithm “Pap, Normal and Abnormal in Nonpregnant Women Ages 21–24.” 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 (6)[B]
    • 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 +, proceed to colposcopy (2)[B]
      • if HPV negative, repeat co-testing 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 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 (2).
  • HSIL: 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+, 18+, and persistent HPV)
    • Follow-up without treatment: co-testing 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 21–24: Management is slightly different than above, see “ASCCP Guidelines” (2), or algorithm “Pap, Normal and Abnormal in Nonpregnant Women Ages 21–24.”

Test Interpretation
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 postcolposcopic diagnostics and therapeutics and are available online at http://www.asccp.org/Guidelines (2).

General Measures

Office evaluation and observation; promote smoking cessation; promote protected intercourse; promote 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 BID × 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 cream 3×/wk at bedtime up to 16 weeks

Surgery/Other Procedures

  • Persistent CIN 1, CIN 2, or 3: Ablative or excisional methods. If inadequate colposcopy for CIN 2 or 3 or recurrent CIN 2 or 3, 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 2 or 3, women may reenter routine screening only after negative co-testing at 12 and 24 months. Screening should be continued for 20 years (6)[B].

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 CIN2 and 32% of CIN3 lesions may regress. CIN3 has a 30% probability of becoming invasive cancer over a 30-year period, although only about 1% if treated
  • CIN3 becomes invasive (7). 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% (4).

Complications

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

Additional Reading

See Also

Cervical Malignancy; Condyloma Acuminata; Trichomoniasis; Vulvovaginitis, PrepubescentAlgorithm: Pap (Abnormal), >21 Years of Age; Pap (Abnormal), Pap, Use of HPV DNA Co-Testing in Women Over 30

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.
  • Know and adhere to recognized screening guidelines to avoid the harms of overscreening.

Authors


Fozia Akhtar 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. Massad S, Eienstein MH, Warner KH. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5):S1–S27. [PMID:23519301]
  3. American Cancer Society. Cancer facts and figures 2013. American Cancer Society Web site. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed May 21, 2013.
  4. American Cancer Society. Cancer facts and figures 2014. American Cancer Society Web site. http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed July 21, 2014.
  5. U.S. Preventive Services Task Force. Cervical cancer: screening U.S. Preventive Services Task Force Web site. http://www.uspreventiveservicestaskforce.org/uspstf11/cervcancer/cervcance.... Accessed July 23, 2014.
  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. [PMID:18407790]


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