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 women 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.

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-positive cytology “contesting” 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.
  • 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. It is the second leading cause of cancer death in women aged 20 to 39 years (1). However, in the United States, due to improved screening practices, cervical cancer has dropped to 14th place in the list of most common cancers. 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 United States: In 2018, approximately 13,240 new cases of invasive cervical cancer will be diagnosed and 4,170 women will die from the disease (1).
  • 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 2015, there were an estimated 257,524 women living with cervical cancer in the United States.
  • 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 (2).

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
  • 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 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. Per the Advisory Committee on Immunization Practices (ACIP), offer HPV vaccine to adolescents 11 to 12 years of age.
    • Gardasil 9: approved in December 2014 for use in females and males ages 9 to 26 years and in 2018 for ages 27 to 45 years; reduces 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 vaccine begun before 15th birthday: 2 doses only 6 to 12 months apart
    • If vaccine begun on or after 15th birthday: 3 doses at 0, 2, and 6 months
    • Immunocompromising conditions: 3 doses needed
  • Safe sex practices: condom use
  • Screening
    • Pap smear has been the main screening test for cervical cellular pathology, with or without cotesting for HPV. A 2017 draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommends either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30 to 65 years of age. Clinicians will need to choose whether to adopt an HPV-only approach or a cotesting approach (3)[B].
    • 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 (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 (Pap smear) every 3 years (4)[A]. Do not screen with HPV testing alone or combined with cytology (4).
      • 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 (4).
  • Special circumstances: women 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+ should continue screening until 20 years following their diagnosis of CIN II+.
  • HIV-positive women: 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.
  • Sensitivity of conventional Pap smear ranges from 30% to 70% for lesser cervical abnormalities. For detection of CIN II or higher, sensitivity was higher (44–99%) and had narrower specificity (91–98%) (5). Pap smears done routinely at recommended intervals increase the sensitivity further.
  • The sensitivity and specificity of using HPV and Pap 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, but it is likely that testing for high-risk HPV without cytology will become the dominant strategy, particularly for poorly screened or unscreened populations (6)[A].
  • 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 (ASC) (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
      • AGCs (atypical glandular cells)
        • AGCs: not otherwise specified
        • AGCs: favor neoplasia
      • AIS (adenocarcinoma in situ)
      • Adenocarcinoma

Diagnostic Procedures/Other

Some algorithms differ for women age 21 to 24 years; see “ASCCP guidelines” (7) 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 positive, proceed to colposcopy; if negative, repeat cotesting at 1 year.
    • 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 (7)[B].
      • If HPV negative, repeat cotesting at 3 years (7)[B].
    • Option 2: Repeat cytology at 1 year (acceptable) (7).
      • 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 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 preferred, but it is acceptable to defer colposcopy to postpartum (7)
  • HSIL: loop electrosurgical excision procedure (LEEP) or colposcopy (7)[B]
  • AGCs: colposcopy with endocervical sampling and endometrial sampling (if 35 years or older or at risk for endometrial neoplasia) (7)[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 years: Management is slightly different than above; see “ASCCP guidelines” (7) or algorithm “Pap, Normal and Abnormal in Women Ages 21–24 Years.”
  • Age >30 years: 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)

Treatment

ASCCP guidelines: Evidence-based management algorithms guide Pap smear and postcolposcopic diagnostics and therapeutics are available online at http://www.asccp.org/asccp-guidelines (7).

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

  • 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 AIS, 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.”

Ongoing Care

Follow-up Recommendations

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.

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 (3).
  • 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% (3).

Complications

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

Additional Reading

  • American Society for Colposcopy and Cervical Pathology. Management guidelines. http://www.asccp.org/asccp-guidelines. Accessed January 5, 2018.
  • 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 overscreening.
    • Optimal screening strategy is in evolution. HPV primary with cytology-secondary strategies will likely supplant current guidelines in near future.

    Authors


    Tharani Ravi, MD
    Fozia Akhtar Ali, MD
    Jeremy Golding, MD, FAAFP

    Bibliography

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.  [PMID:22711081]
    2. Markowitz LE, Gee J, Chesson H, et al. Ten years of human papillomavirus vaccination in the United States. Acad Pediatr. 2018;18(Suppl 2):S3–S10.  [PMID:28055103]
    3. Ogilvie GS, van Niekerk D, Krajden M, et al. Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial. JAMA. 2018;320(1):43–52.  [PMID:17942872]
    4. Moyer VA; for U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156(12):880–891.  [PMID:23519301]
    5. Naucler P, Ryd W, Törnberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;357(16):1589–1597.  [PMID:18407790]
    6. Melnikow J, Henderson JT, Burda BU, et al. Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2018. Report No. 17-05231-EF-1.
    7. 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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