What is the recommended follow-up for a patient with an Atypical Squamous Cells of Undetermined Significance (ASC-US) Pap test result and a negative Human Papillomavirus (HPV) test result?

Management of ASC-US with Negative HPV Testing

For a patient with ASC-US Pap test and negative HPV result, repeat HPV testing (with or without concurrent Pap) in 3 years is recommended. 1, 2

Risk Stratification

• Women with HPV-negative ASC-US have a 5-year CIN3+ risk of 0.48%, which is higher than after a completely negative cotest (0.11%) but closer to the risk after a negative Pap test alone (0.31%). 3
• The cancer risk at 5 years is 0.043%, which is not sufficiently low to allow routine 5-year intervals or to permit cessation of screening at age 65. 4, 3
• This intermediate risk profile justifies a shortened surveillance interval compared to negative cotesting but does not warrant immediate colposcopy. 1, 2

Follow-Up Algorithm

Primary recommendation:

• Return for repeat testing in 3 years (not 5 years as previously recommended in 2012). 4, 1, 2
• The 2019 ASCCP guidelines updated this interval from 5 years to 3 years based on expanded Kaiser Permanente Northern California cohort data showing higher-than-expected risk. 4, 1

At the 3-year follow-up visit:

• Perform HPV testing with or without concurrent Pap testing. 4, 1
• If both tests are negative, return to routine age-based screening intervals. 1, 2
• If either test is abnormal (abnormal cytology or positive HPV), refer for colposcopy. 4, 1

Alternative acceptable approach (when HPV testing unavailable):

• Repeat Pap testing alone in 12 months is acceptable if HPV testing is not available. 4, 1, 2
• Continue repeat testing at 6- and 12-month intervals until two consecutive negative results are obtained. 1, 2

Critical Management Points

Do NOT perform immediate colposcopy:

• The current CIN3+ risk after HPV-negative ASC-US is below the threshold for colposcopy referral. 4, 1, 2
• High-grade histological changes are detected in less than 12% of ASC-US cases overall, and the risk is even lower with negative HPV. 1, 2

Do NOT use HPV 16/18 genotyping:

• Genotyping should not be performed for ASC-US results because it does not alter management—all HPV-positive ASC-US cases warrant colposcopy regardless of genotype. 4

Do NOT return to 5-year intervals:

• The 2012 recommendation of 5-year follow-up has been superseded by the current 3-year recommendation based on updated risk data. 4, 1

Age-Specific Considerations

For women aged 30-65 years:

• Cotesting (HPV plus cytology) is the preferred screening approach with 5-year intervals when both are negative. 1
• When ASC-US occurs with negative HPV, the interval shortens to 3 years. 1, 2

For women approaching age 65:

• HPV-negative ASC-US results are NOT sufficiently reassuring to allow cessation of screening at age 65. 4, 1
• Women reaching age 65 with HPV-negative ASC-US should be retested in 3 years and continue surveillance until achieving 2 consecutive negative cotests or 3 consecutive negative Pap tests. 4

Common Pitfalls to Avoid

• Avoid returning too soon (before 3 years): This leads to unnecessary testing and potential overtreatment. 1, 2
• Avoid waiting 5 years: The risk is demonstrably higher than after negative cotesting, making 5-year intervals unsafe. 4, 1, 3
• Avoid immediate colposcopy for all ASC-US regardless of HPV status: This results in unnecessary invasive procedures for low-risk patients. 1, 2
• Avoid assuming HPV-negative ASC-US carries the same ultralow risk as a negative cotest: The risk profile is distinctly different and requires modified management. 1, 2, 3