What are the grades of Human Papillomavirus (HPV) cervical pathology and how are they managed in a female patient with a history of HPV infection or abnormal Pap (Papanicolaou) test results?

Grades of HPV Cervical Pathology

HPV-related cervical pathology is classified into cytologic (Pap test) and histologic (biopsy) grades, with cytology ranging from ASC-US to HSIL and histology graded as CIN 1, CIN 2, or CIN 3, each requiring distinct management based on disease risk and patient age. 1

Cytologic Classification (Pap Test Results)

Cervical cytology abnormalities are reported using the Bethesda System and progress from lowest to highest cancer risk as follows: 1

Low-Risk Cytologic Abnormalities

• ASC-US (Atypical Squamous Cells of Undetermined Significance): The most common abnormality, occurring in approximately 4% of cytologic smears, with a 9.7% risk of CIN 2 or worse 1
• LSIL (Low-Grade Squamous Intraepithelial Lesion): Represents HPV infection with mild dysplasia, with 80-86% being high-risk HPV positive 2

High-Risk Cytologic Abnormalities

• ASC-H (Atypical Squamous Cells–Cannot Exclude HSIL): Carries up to 50% prevalence of CIN 2/3, requiring immediate colposcopy 1
• HSIL (High-Grade Squamous Intraepithelial Lesion): Carries approximately 85% predicted 5-year risk for CIN 2 or worse 1
• Invasive Carcinoma: The highest-grade cytologic finding 1

Glandular Cell Abnormalities

• AGC (Atypical Glandular Cells): May represent endocervical or endometrial pathology, requiring colposcopy with endocervical sampling regardless of HPV status 1, 3
• AIS (Adenocarcinoma In Situ): Requires immediate colposcopy with endocervical sampling 1

Histologic Classification (Biopsy Results)

Histologic grades represent the actual tissue diagnosis obtained through colposcopy-directed biopsy: 1

• CIN 1 (Cervical Intraepithelial Neoplasia Grade 1): Mild dysplasia with high spontaneous regression rates (>90% within 24 months), managed conservatively in most cases 2
• CIN 2 (Cervical Intraepithelial Neoplasia Grade 2): Moderate dysplasia, considered the treatment threshold in the United States, though approximately 40% regress over 6 months 1
• CIN 3 (Cervical Intraepithelial Neoplasia Grade 3): Severe dysplasia/carcinoma in situ, requiring treatment with excisional procedures 1, 4

Management Algorithm by Grade

ASC-US Management

Reflex HPV DNA testing is the preferred triage option for adult women with ASC-US. 1

• If HPV positive: Proceed to colposcopy 1
• If HPV negative: Repeat HPV testing or cotesting in 12 months 3
• Alternative acceptable options include immediate colposcopy or repeat cytology at 6 and 12 months 1

LSIL Management

Immediate colposcopy is recommended for all adult women with LSIL cytology, as HPV testing does not provide useful triage (80-86% are HR-HPV positive). 2, 4

• Post-colposcopy with CIN 1 or negative biopsy: Conservative follow-up with repeat cytology every 6-12 months or HPV testing at 12 months 2
• If CIN 1 persists for ≥2 years: Consider treatment with excision or ablation 2, 4

ASC-H and HSIL Management

Colposcopy is mandatory for ASC-H and HSIL regardless of HPV status due to high risk of underlying high-grade disease. 1, 4, 3

• Immediate excision ("see and treat") is acceptable for adult women with HSIL but unacceptable in adolescents 1
• For non-pregnant patients ≥25 years with HSIL cytology and positive HPV 16: Expedited treatment is an alternative to colposcopy 4

CIN 2/3 Management

Treatment is recommended for CIN 2 and CIN 3, with excisional procedures (LEEP, cold-knife conization) preferred over ablative methods. 1, 4

• CIN 2 in younger women: Observation may be considered given 40% regression rate 1, 4
• CIN 3: Treatment with excisional procedure is mandatory 4

Special Population Considerations

Adolescents (Age <21 years)

Conservative management is recommended for adolescents with any cytologic or histologic diagnosis except CIN 3 and adenocarcinoma in situ. 1

• No screening before age 21 regardless of sexual history 1
• For LSIL: Repeat cytology at 12 months rather than immediate colposcopy due to high spontaneous regression rates 2
• Immediate treatment is unacceptable for adolescents with HSIL 1

Pregnant Women

Colposcopy is preferred for pregnant women with LSIL and HSIL, but evaluation of LSIL may be deferred until ≥6 weeks postpartum. 1

• Colposcopic biopsy of lesions suspicious for cancer or CIN 2/3 is preferred, but endocervical curettage is unacceptable 1
• Treatment during pregnancy is unacceptable unless invasive carcinoma is identified 1

Women ≥30 Years

Cotesting (cytology plus HPV testing) every 5 years is preferred for women aged 30-65 years. 1

• A single negative HPV test carries negligible risk for CIN 3 1
• Screening may cease at age 65 with adequate prior screening and normal results 1

Immunocompromised/HIV-Positive Women

More aggressive surveillance is required, with cervical cytology screening twice within the first year after HIV diagnosis and annual screening thereafter. 2, 4

• HIV-infected women have 10-11 times higher rates of abnormal cervical cytology even without HPV 3

Critical Pitfalls to Avoid

• Never use HPV testing alone to triage LSIL: 80-86% are HPV positive, making it non-discriminatory 2
• Never delay colposcopy for high-grade abnormalities (HSIL, ASC-H) based on negative HPV results: These require colposcopy regardless of HPV status 3
• Never treat CIN 1 immediately: Over 90% regress spontaneously within 24 months 2
• Never perform endocervical curettage in pregnant women: Colposcopic biopsy only when necessary 1
• Never screen women <21 years: Cytologic abnormalities are common but clinically important lesions are rare 1