When to repeat Pap smear for a patient with a first-time Atypical Squamous Cells of Undetermined Significance (ASC-US) result and a negative Human Papillomavirus (HPV) test?

Management of First-Time ASC-US with Negative HPV Test

Patients with a first-time Atypical Squamous Cells of Undetermined Significance (ASC-US) Pap result and a negative HPV test should have repeat screening in 3 years. 1, 2

Rationale for 3-Year Follow-up Interval

The American Cancer Society (ACS) and other major guidelines recommend a 3-year follow-up interval based on the following evidence:

• The risk profile of HPV-negative ASC-US is more similar to a negative Pap test alone than to a negative cotest (HPV-negative/Pap-negative) 1, 3
• Data from Kaiser Permanente Northern California involving over 1.1 million women showed that:
  • 5-year risk of CIN3+ after HPV-negative ASC-US was 0.48% vs 0.31% for negative Pap alone (p=0.0019) 3
  • 5-year cancer risk was 0.043% vs 0.031% for negative Pap alone (p=0.4) 3
  • These risks were significantly higher than for negative cotest results (CIN3+ risk: 0.11%, p<0.0001; cancer risk: 0.014%, p=0.016) 3

Management Algorithm

1. Initial ASC-US result with HPV testing:

   • If HPV-negative: Repeat screening in 3 years 1, 2
   • If HPV-positive: Proceed to colposcopy 2

2. Special considerations:

   • For patients ≥25 years with HPV 16/18 positive results: Immediate colposcopy regardless of cytology 2
   • For patients with previous negative screening within 5 years: Consider HPV testing with or without Pap test in 1 year 2

Important Clinical Caveats

• The 3-year interval recommendation represents a change from earlier guidelines that had suggested a 5-year interval 1
• This recommendation applies the principle of "equal management of equal risks" - managing HPV-negative ASC-US similarly to a negative Pap test alone 1
• Over 500,000 women are diagnosed with HPV-negative ASC-US each year, making this recommendation clinically significant 1
• For women approaching age 65, an HPV-negative ASC-US result is insufficient for exiting screening, as there may be a higher risk of invasive cancer in women ages 60-65 with this result compared to women with a negative cotest 1

Evidence Quality and Consensus

The ACS recommendation for a 3-year interval is graded as "weak" using the GRADE framework, acknowledging some uncertainty in the data 1. However, this recommendation aligns with:

• The American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines 1, 2
• Evidence from the ASCUS-LSIL Triage Study (ALTS) supporting HPV testing as the most efficient approach to ASC-US management 2
• Multiple studies showing that HPV-negative ASC-US carries a risk profile closer to negative Pap alone than to negative cotest 1, 3

This 3-year interval balances the need for appropriate surveillance with avoiding unnecessary testing, while maintaining consistency with the anticipated move toward primary HPV testing with a 3-year screening interval 1.