Abnormal Pap and Cervical Dysplasia

Abnormal Pap and Cervical Dysplasia

Basics

Description

Cervical dysplasia: Precancerous epithelial changes in the transformation zone of the uterine cervix almost always associated with human papillomavirus (HPV) infections:

• Mild dysplasia (cervical intraepithelial neoplasia [CIN] I): Cellular changes are limited to the lower 1/3 of the squamous epithelium.
• Moderate dysplasia (CIN II): Cellular changes are limited to the lower 2/3 of the squamous epithelium.
• Severe dysplasia (CIN III or carcinoma in situ): Cellular changes involve the full thickness of the squamous epithelium.
• Pap smear:
  • 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.
• System(s) affected: Reproductive

Alert

Cervical cancer arises from HPV, which is a sexually acquired disease. Good evidence that screening for cervical cancer with Pap smears reduces incidence of and mortality from cervical cancer (1)[A].

Geriatric Considerations

Natural progression of cervical dysplasia involves acquisition of HPV at or after first coitus with a small percentage of lesions progressing. See guidelines below.

Pregnancy Considerations

• Squamous intraepithelial lesions can progress during pregnancy, but often regress postpartum.
• Colposcopy only to rule out invasive cancer in high-risk women (2)

Epidemiology

• Predominant age: Can occur at any age
• 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 and invasive cancer present on 1% of Pap smears.
• Other reactive, reparative, and ASC-US (atypical squamous cells of undetermined significance) results are difficult to assess because of the lack of reporting mechanisms.

Prevalence

26.8% of women are HPV-positive.

Risk Factors

• Cigarette smoking
• Possible deficiency of antioxidants
• Early age at first coitus
• Multiple sexual partners
• Some correlation to low socioeconomic level
• Intercourse with a high-risk male partner
• HPV infection
• Immunosuppression

General Prevention

• HPV immunization of girls and women prior to first intercourse (e.g., Gardasil) 3 doses (0, 2, 6 months) (3)[C] reduces dysplasia due to covered and related HPV strains; long-term effect on cancer as yet uncertain. Role of immunization of boys and men not yet established.
• Delay first intercourse beyond early adolescence
• Monogamous relationship for both partners
• Smoking cessation
• Adequate antioxidant-rich food intake has been associated with decreased risk
• Obtain routine Pap smears (see guidelines below)
• Use barrier methods of birth control if in nonmonogamous relationship (likely decreases but does not eliminate HPV transmission)
• Screening guidelines:
  • Screening indicated for woman beginning at age 21
  • Frequency of screening recommendations vary:
    • United States Preventive Services Task Force: Every 3 years
    • American Cancer Society/American Congress of Obstetricians and Gynecologists: Every 2 years until age 30 then every 3 years if normal
    • May be beneficial to do combined cellular screening (Pap) and high-risk HPV test in women >age 30. If normal cytology and high-risk HPV negative, screening should be repeated in no less than 3 years. If cytology is normal but HPV is positive, repeat BOTH cytology and HPV in 1 year, and if HPV remains positive (or if abnormal cytology), proceed to colposcopy (2,4).
• Screen until age 65–70. May discontinue if 3 or more consecutive, satisfactory normal or negative smears, no abnormal smears in past 10 years, or until total hysterectomy for benign conditions (1,5)

Pathophysiology

• HPV DNA is found in virtually all cervical carcinomas and precursor lesions worldwide.
• HPV viral types 16, 18, 31, 35, 45, 51, 52, 56, and 58 are common high-risk or oncogenic virus types for cervical cancer.
• HPV viral types 6, 11, 42, 43, and 44 are considered common low-risk types, and may cause genital warts.

Diagnosis

Frequently no symptoms

History

• Occasionally vaginal discharge related to sexually transmitted disease
• Rarely vaginal bleeding

Physical Exam

Pelvic exam occasionally reveals external HPV lesions.

Diagnostic Tests & Interpretation

• ThinPrep is a fluid-based collection and thin-layer preparation for cervical cancer screening.
• Sensitivity of a single Pap smear for HSIL ∼70%; specificity of ∼90%

Lab

• Bethesda system for reporting Pap/cervical smear results (cytologic grading) (6)
• Specimen adequacy
• Presence of endocervical cells:
  • Negative for intraepithelial lesion or malignancy
  • Epithelial cell abnormalities:
    • ASC: Atypical squamous cells
    • ASC-US: ASC of undetermined significance
    • ASC-H: Atypical cells cannot exclude high-grade squamous intraepithelial lesion (SIL)
    • LSIL: Low-grade SIL (combines mild dysplasia (CIN I) with HPV)
    • HSIL: High-grade SIL (combines CIN II and III)
    • Squamous cell carcinoma
    • Glandular cells
    • AGC: Atypical glandular cells
    • AGCs of undetermined significance
    • Atypical glandular cells, favor neoplasia
    • Endocervical adenocarcinoma in situ
    • Adenocarcinoma

Diagnostic Procedures/Surgery

• Colposcopy with or without biopsy recommended for the following (2) (and see algorithms):
  • Initial Pap smear with LSIL (exception for adolescent, although screening of adolescents no longer recommended), HSIL; ASCUS that is + for high-risk HPV types on (reflex) HPV hybrid capture 2 test.
  • ASC-US present on 2 Pap smears 6 months apart if HPV testing not available
  • ASC-H needs colposcopic evaluation.
  • Any abnormal or suspicious lesion of the cervix or vagina that is visualized by the eye
  • Atypical glandular cells (mandate colposcopy and uterine sampling)
• HPV viral typing:
  • Hybrid capture 2 test has 2 viral type probes: a low-risk probe and a high-risk probe.
  • High-risk (HR) probe can be used to identify patients with ASC-US who need colposcopy follow-up.
    P.3
    
    
  • HPV typing may be used 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 3 years.
    • Women with negative cytology but positive (HR) probe may be approached with 1 of 2 strategies (optimal strategy uncertain): Repeat Pap and HPV in 1 year. If either Pap abnormal or HPV HR positive, then colposcopy. Order an HPV 16/18-specific probe on cytology fluid. If either probe for 16 or 18 is positive, evidence suggests the risk of a high-grade lesion is still similar to the risk for ASCUS/HPV+, and colposcopy is recommended. If HPV 16 and 18 are negative with a negative Pap and a high-risk HPV screen positive, the risk of a high-grade lesion is about 15-fold less, and repeat Pap plus HPV screen in 1 year is recommended. At 1 year, if either the Pap or the HPV test is NOT negative, then colposcopy is recommended.
  • Little utility for low-risk viral type screening
• Loop electrosurgical excision procedure (LEEP):
  • “See and treat” for HSIL in nonadolescent age groups acceptable, but not for adolescents (as they should no longer be screened).
• Cone biopsy
• Cervicography: Photographic evaluation of cervix

Pathological Findings

• Atypical squamous or columnar cells
• Coarse nuclear material
• Increased nuclear diameter
• Koilocytosis (HPV hallmark)

Differential Diagnosis

• Acute or chronic cervicitis
• Cervical squamous intraepithelial neoplasia
• Cervical glandular neoplasia
• Invasive cervical malignancy
• Uterine malignancy (rare)

Treatment

Evidence-based management algorithms guide Pap smear and post-colposcopic diagnostics and therapeutics (2,4).

Medication

• Infective/reactive Pap smear:
  • Metronidazole 250 mg t.i.d. p.o. for 7 days
• Condyloma acuminatum:
  • Cryotherapy
  • Podophyllin topically q1–2wk
  • Trichloroacetic acid, applied topically by a physician and covered for 5–6 days

Additional Treatment

General Measures

• Office evaluation and observation
• Promote smoking cessation.
• Promote protected intercourse.

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 requiring 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 every 6 months or high-risk HPV testing every year is appropriate for young women with LSIL, especially with confirmed CIN I.
• HPV-related CIN I typically resolves within 2–3 years.
• LSIL persisting beyond 2–3 years in a young woman is indication for colposcopy

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 guidelines.
• Reschedule follow-up consultation for any abnormality.

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% or more of 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% (7).
• Aggressive cervical surgery may be associated with cervical stenosis, cervical incompetence, and scarring affecting cervical dilatation in labor.