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 histological 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
Cervical cancer screening with Pap smears has decreased cervical cancer incidence and mortality (1).

Pediatric Considerations
Women age <21 years should not be screened regardless of age of sexual initiation or other risk factors. Screenings of adolescents lead to unnecessary evaluation and overtreatment of preinvasive cervical lesions which are highly likely to spontaneously regress (1).

Geriatric Considerations
Women age >65 years (who have had adequate prior screening and are not high risk) with evidence of adequate negative prior screening and no history of CIN 2+ within the last 20 years should not be screened for cervical cancer (1).

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 (2).
  • Cervical biopsy should be avoided unless a malignancy is suspected. Endocervical sampling is contraindicated (2).

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.

Incidence
Low-grade squamous intraepithelial lesion ranges from 2–3% of all Pap smears. High-grade squamous intraepithelial lesion or invasive cancer is present on 1% of Pap smears. Other reactive, reparative, and ASC-US (atypical squamous cells of unknown significance) results are difficult to assess because of the lack of reporting mechanisms.

Prevalence
  • ~80% of sexually active women will have acquired a genital HPV infection by 50 years of age. Most HPV infections are transient and >50% of new infections are cleared by 6–18 months.
  • Overall, 26.8% of women are HPV positive. Point prevalence of HPV positivity is highest in those 18–22 year of age (as high as 70%), falling off rapidly as women enter their 30s.

Risk Factors

  • History of genital warts: Previous or current HPV infection
  • History of previous abnormal cervical Pap or anal Pap test results
  • Cigarette smoking
  • Early age at 1st coitus (<20 years), and multiple sexual partners
  • Some correlation to low socioeconomic level
  • Immunosuppression

General Prevention

  • Immunization: Immunization decreases high-risk HPV infections and cervical pathology for at least 5–7 years.
    • HPV immunization of girls, boys and women should be initiated prior to 1st 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 ages 9–26, immunization of males ages 9–26 approved for prevention of anogenital warts and recommended by Advisory Committee on Immunization Practices (ACIP).
      • 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 ages 10–25.
  • Screening:
    • In March 2012, USPSTF released the most current Cervical Cancer Screening Guidelines in conjunction with current American Cancer Society/American Society for Colposcopy and Cervical Pathology/American Society for Clinical Pathology (ACS/ASCCP/ASCP) guidelines (4). In the US, many populations may be overscreened (resulting in increased cost and cervical procedures, but not in benefit) because of failure to follow guidelines. The effectiveness of cervical cancer screening observed over several decades is attributed to the use of conventional cytology.
    • Pap smear is the main screening test for cervical cellular pathology. In many laboratories, automated cervical screening complements the Pap smear or supersedes it. Abnormal cervical smear results can range from benign cellular changes to suggestion of invasive cancer.
    • Screening recommendations by age and source:
      • <21 years: Do not screen. (USPSTF/ASCCP/ACS/ASCP/ACOG)
    • Frequency of screening recommendation: USPSTF/ASCCP/ACS/ASCP generally agree by age and screen:
      • 21–65 years: Screen with cytology (Pap smear) every 3 years. Do not screen with HPV testing (alone or with cytology).
      • 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.
  • Special circumstances: Women after hysterectomy with removal of the cervix and with no history of high-grade precancer or cervical cancer: Do not screen.

Pathophysiology

HPV DNA is found in virtually all cervical carcinomas and precursor lesions worldwide.

  • High-risk types: HPV viral types 16, 18, 45, 31, 33, 52, 58, and 35 are common high-risk or oncogenic virus types for cervical cancer. All cause high-grade squamous intraepithelial lesion (HSIL)/CIN 2/CIN 3. HPV 16 and 18 account for ~70% of cervical cancer.
  • 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 1.

Diagnosis

History

Usually asymptomatic. Occasionally, vaginal discharge related to sexually transmitted infection.

Physical Exam

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

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 ~70%; specificity of ~90%
Lab
  • 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: Of undetermined significance
        • AGCs: Favor neoplasia
      • AIS (endocervical adenocarcinoma in situ)
      • Adenocarcinoma
Diagnostic Procedures/Surgery
  • HPV viral typing: High-risk HPV sub-type testing is more sensitive, but less specific for identifying women with prevalent CIN 3+. No utility for low-risk viral type screening:
    • Several HPV tests are available for primary screening used as a co-test with a Pap in women age >30 years and for reflex testing after an ASC-US in women >21 years. All test for types 16 and 18, and an additional 10–12 high-risk types.
    • Co-testing: HPV typing in combination with Pap smear for women ≥30:
      • Low-risk women with negative cytology and who are negative for high-risk HPV may be followed every 5 years.
      • Women co-testing HPV positive, cytology negative should NOT be referred directly to colposcopy. According to ASCCP Guidelines:
        • Option 1: Repeat co-testing in 12 months or
        • Option 2: Immediate HPV genotype specific testing for HPV 16 or for HPV 16 and 18:
          • Positive: If probe (+) for 16 or 18, evidence suggests the risk of a high-grade lesion justifies colposcopy.
          • Negative: If HPV (−) for 16 and 18 with a negative Pap and a high-risk HPV screen positive, the risk of a high-grade lesion is ~15-fold less, and repeat Pap + HPV screen in 1 year is recommended. At 1 year, if either the Pap or the HPV test is not negative, then coloscopy.
  • Colposcopy, with or without biopsy, recommended for the following (per ASCCP management algorithms:online) (5,6):
    • ASC-US with HR HPV (+) (on reflex HPV Hybrid Capture 2 Test)
    • ASC-US present on 2 Pap smears 6 months apart if HPV testing not available
    • ASC-H
    • LSIL, HSIL (with endocervical assessment or immediate Loop Electrosurgical Excision Procedure [LEEP])
    • AGC (colposcopy with endometrial sampling: Initial work-up of women with AGC except atypical endometrial cells)
    • Any abnormal or suspicious lesion of the cervix or vagina that is visualized by the eye
  • LEEP: “See and treat” for HSIL.
  • Cone biopsy

Pathological Findings
Atypical squamous or columnar cells; coarse nuclear material; increased nuclear diameter; koilocytosis (HPV hallmark)

Differential Diagnosis

Acute or chronic cervicitis; cervical glandular neoplasia; invasive cervical malignancy; uterine malignancy (rare)

Treatment

ASCCP guidelines: Evidence-based management algorithms guide Pap smear and post colposcopic diagnostics and therapeutics and are available online (6).

Medication (Drugs)

  • Infective/Reactive Pap smear: Metronidazole 250 mg t.i.d. PO for 7 days
  • Condyloma acuminatum: May be treated with cryotherapy, or:Podophyllin topically q1–2wk or podofilox 0.5% applied b.i.d. x 3 days then off 4 days, repeated for1–4 weeks OR trichloroacetic acid, applied topically by a physician and covered for 5–6 days OR imiquimod cream 3x/wk at bedtime up to 16weeks

Additional Treatment

General Measures
Office evaluation and observation; promote smoking cessation; promote protected intercourse; promote immunization

Surgery/Other Procedures

LSILs and HSILs and carcinoma in situ can be treated with outpatient surgery: 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

  • LSIL/CIN1:
    • Observation with Pap smear repeated at 6 and 12 months OR high-risk HPV testing at 12 months, especially with confirmed CIN I, with repeat colposcopy for continued positive cytology or high-risk HPV
    • HPV-related CIN I typically resolves within 2–3 years.
    • LSIL persisting >2–3 years in a young woman is indication for colposcopy. It is likely that management guidelines will soon reflect less aggressive colposcopy and treatment recommendations for women up to age 25.
  • HSIL: After treatment (excision or ablation) for high-grade CIN women may re-enter routine screening only after negative cytology at 6, 12, and 24 months and should be continued for 20 years (7).

Diet

Promote increased intake of antioxidant-rich foods.

Patient Education

Promote HPV immunization. Promote smoking cessation. Promote protected intercourse. Promote regular Pap smears according to recognized new guidelines. Many women need to be educated that this is not usually yearly.

Prognosis

Generally excellent: <50% of persistent infective, reactive, reparative, or ASC-US Pap/cervical smears will have more advanced lesions. Only a small percentage of LSILs will progress to more advanced lesion (≥80% adolescent and young adult CIN I resolves in 2–3 years). Lesions discovered early are amenable to treatment with excellent results and few recurrences.

Complications

  • Minor abnormalities on Pap/cervical smears can mask more advanced lesions. HSIL does progress to invasive cancer. Best estimate of risk of CIN III progression to invasive cervical cancer is >50%.
  • Aggressive cervical surgery may be associated with cervical stenosis, cervical incompetence, and scarring affecting cervical dilatation in labor.

Additional Reading

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

  • N87.9 Dysplasia of cervix uteri, unspecified
  • N87.0 Mild cervical dysplasia
  • N87.1 Moderate cervical dysplasia
  • R87.619 Unsp abnormal cytolog findings in specmn from cervix uteri

SNOMED

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

Clinical Pearls

  • HPV is present in virtually all cervical cancers (99.7%), but most HPV infections are transient.
  • Vaccine is much less effective for prevention of cervical dysplasia if offered after women are infected with HPV, and no effect on regression of existing CIN has been seen thus far in trials. Vaccine should be offered prior to onset of any sexual activity (even nonintercourse activity) for maximum effectiveness.
  • Know and adhere to recognized screening guidelines to avoid the harms of over screening.

Authors


Rowena D. Pingul-Ravano, MD
Susanna R. Magee, MD, MPH

Bibliography

  1. Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force 2012. Accessed April 14, 2012 at http://www.ahrg.gov/clinic/3rduspstf/cervcan/cervcanrr.htm
  2. FleuryAC, Birsner ML, Fader AN. Management of the abnormal Papanicolaou smear and colposcopy in pregnancy: An evidenced-based review. Minerva Ginecol. 2012;64(2):137–148.  [PMID:22481624]
  3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. ;62(1):10–29. Epub 2012 Jan 4.
  4. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis. 2012;16(3):175–204.  [PMID:22418039]
  5. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 99: Management of abnormal cervical cytology and histology. Obstet Gynecol. 2008;112(6):1419–1444.  [PMID:19037054]
  6. Wright TC, Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197(4):346–355.  [PMID:17904957]
  7. Kocken M, Helmerhorst TJ, Berkhof J, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: A long-term multi-cohort study. Lancet Oncol. 2011;12(5):441–450.  [PMID:21530398]


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